Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with ...particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis.
Action to reduce anthropogenic impact on the environment and species within it will be most effective when targeted towards activities that have the greatest impact on biodiversity. To do this ...effectively we need to better understand the relative importance of different activities and how they drive changes in species' populations. Here, we present a novel, flexible framework that reviews evidence for the relative importance of these drivers of change and uses it to explain recent alterations in species' populations. We review drivers of change across four hundred species sampled from a broad range of taxonomic groups in the UK. We found that species' population change (~1970-2012) has been most strongly impacted by intensive management of agricultural land and by climatic change. The impact of the former was primarily deleterious, whereas the impact of climatic change to date has been more mixed. Findings were similar across the three major taxonomic groups assessed (insects, vascular plants and vertebrates). In general, the way a habitat was managed had a greater impact than changes in its extent, which accords with the relatively small changes in the areas occupied by different habitats during our study period, compared to substantial changes in habitat management. Of the drivers classified as conservation measures, low-intensity management of agricultural land and habitat creation had the greatest impact. Our framework could be used to assess the relative importance of drivers at a range of scales to better inform our policy and management decisions. Furthermore, by scoring the quality of evidence, this framework helps us identify research gaps and needs.
The unique neuroanatomical underpinnings of internalizing symptoms and impulsivity during childhood are not well understood. In this study, we examined associations of brain structure with anxiety, ...depression, and impulsivity in children and adolescents. Participants were 7- to 21-year-olds (N = 328) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study who completed high-resolution, 3-Tesla, T1-weighted MRI and self-report measures of anxiety, depression, and/or impulsivity. Cortical thickness and surface area were examined across cortical regions-of-interest (ROIs), and exploratory whole-brain analyses were also conducted. Gray matter volume (GMV) was examined in subcortical ROIs. When considered separately, higher depressive symptoms and impulsivity were each significantly associated with reduced cortical thickness in ventromedial PFC/medial OFC, but when considered simultaneously, only depressive symptoms remained significant. Higher impulsivity, but not depressive symptoms, was associated with reduced cortical thickness in the frontal pole, rostral middle frontal gyrus, and pars orbitalis. No differences were found for regional surface area. Higher depressive symptoms, but not impulsivity, were significantly associated with smaller hippocampal GMV and larger pallidal GMV. There were no significant associations between anxiety symptoms and brain structure. Depressive symptoms and impulsivity may be linked with cortical thinning in overlapping and distinct regions during childhood and adolescence.
•Internalizing problems and impulsivity may have shared and distinct neuroanatomical substrates in childhood.•Higher depressive symptoms were uniquely associated with reduced cortical thickness in vmPFC/medial OFC.•Higher impulsivity was uniquely associated with reduced cortical thickness in lateral PFC regions.•Higher depressive symptoms were associated with smaller hippocampal volume and larger pallidal volume.•These shared and distinct neuroanatomical correlates may inform the design of prevention and intervention strategies.
Abstract
We report the serendipitous discovery of an overdensity of CO emitters in an X-ray-identified cluster (Log
10
M
halo
/
M
⊙
∼ 13.6 at
z
= 1.3188) using ALMA. We present spectroscopic ...confirmation of six new cluster members exhibiting CO(2–1) emission, adding to two existing optical/IR spectroscopic members undetected in CO. This is the lowest-mass cluster to date at
z
> 1 with molecular gas measurements, bridging the observational gap between galaxies in the more extreme, well-studied clusters (Log
10
M
halo
/
M
⊙
≳ 14) and those in group or field environments at cosmic noon. The CO sources are concentrated on the sky (within ∼1 arcmin diameter) and phase space analysis indicates the gas resides in galaxies already within the cluster environment. We find that CO sources sit in similar phase space as CO-rich galaxies in more massive clusters at similar redshifts (have similar accretion histories) while maintaining field-like molecular gas reservoirs, compared to scaling relations. This work presents the deepest CO survey to date in a galaxy cluster at
z
> 1, uncovering gas reservoirs down to
M
H
2
>
1.6
×
10
10
M
⊙
(5
σ
at 50% primary beam). Our deep limits rule out the presence of gas content in excess of the field scaling relations; however, combined with literature CO detections, cluster gas fractions in general appear systematically high, on the upper envelope or above the field. This study is the first demonstration that low-mass clusters at
z
∼ 1–2 can host overdensities of CO emitters with surviving gas reservoirs, in line with the prediction that quenching is delayed after first infall while galaxies consume the gas bound to the disk.
Developing indicators for European birds Gregory, Richard D; van Strien, Arco; Vorisek, Petr ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
02/2005, Letnik:
360, Številka:
1454
Journal Article
Recenzirano
Odprti dostop
The global pledge to deliver 'a significant reduction in the current rate of biodiversity loss by 2010' is echoed in a number of regional and national level targets. There is broad consensus, ...however, that in the absence of conservation action, biodiversity will continue to be lost at a rate unprecedented in the recent era. Remarkably, we lack a basic system to measure progress towards these targets and, in particular, we lack standard measures of biodiversity and procedures to construct and assess summary statistics. Here, we develop a simple classification of biodiversity indicators to assist their development and clarify purpose. We use European birds, as example taxa, to show how robust indicators can be constructed and how they can be interpreted. We have developed statistical methods to calculate supranational, multi-species indices using population data from national annual breeding bird surveys in Europe. Skilled volunteers using standardized field methods undertake data collection where methods and survey designs differ slightly across countries. Survey plots tend to be widely distributed at a national level, covering many bird species and habitats with reasonable representation. National species' indices are calculated using log-linear regression, which allows for plot turnover. Supranational species' indices are constructed by combining the national species' indices weighted by national population sizes of each species. Supranational, multi-species indicators are calculated by averaging the resulting indices. We show that common farmland birds in Europe have declined steeply over the last two decades, whereas woodland birds have not. Evidence elsewhere shows that the main driver of farmland bird declines is increased agricultural intensification. We argue that the farmland bird indicator is a useful surrogate for trends in other elements of biodiversity in this habitat.
Metabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer's ...disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human β-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI.
TG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry.
Rats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure.
These results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.
The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis’ fragment collection resulted in ...the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.
Constancy permits the evolution of types and characteristics to be identified, even in widely spread locations. It helps trace the origins of structures, despite later modifications. And change ...allows one to trace the effects of difference in environment, fashion, cultural ideas and economic influences. Change and constancy operate together, although one may or other may dominate at a particular time and place. In Vernacular Buildings Allen Noble extends the global survey contained in his earlier highly successful Traditional Buildings, to cover vernacular buildings and dwellings around the world. In a truly comprehensive account, he ranges from the fazenda of the pioneer Brazilian settlers, the Masai dwellings of Tanzania and the gothic houses of Shanghai, to Virginia Hall and Parlor houses, the thatched dwellings of the Eifel region of Germany and the three -decker houses of New York. Acknowledging the value of archival research the author is also firmly convinced of the importance of field observation and the book is extensively illustrated with photographs from his own personal collection. With a comprehensive bibliography, and incorporating new material from cultural geographers, historians, folklorists and anthropologists, Vernacular Buildings is a unique survey that will be welcomed by specialists and enthusiasts alike.
Abstract
We investigate the resolved kinematics of the molecular gas, as traced by the Atacama Large Millimeter/submillimeter Array in CO (2−1), of 25 cluster member galaxies across three different ...clusters at a redshift of
z
∼ 1.6. This is the first large-scale analysis of the molecular gas kinematics of cluster galaxies at this redshift. By separately estimating the rotation curve of the approaching and receding sides of each galaxy via kinematic modeling, we quantify the difference in total circular velocity to characterize the overall kinematic asymmetry of each galaxy. 3/14 of the galaxies in our sample that we are able to model have similar degrees of asymmetry as that observed in galaxies in the field at similar redshift based on observations of mainly ionized gas. However, this leaves 11/14 galaxies in our sample with significantly higher asymmetry, and some of these galaxies have degrees of asymmetry of up to ∼50 times higher than field galaxies observed at similar redshift. Some of these extreme cases also have one-sided tail-like morphology seen in the molecular gas, supporting a scenario of tidal and/or ram pressure interaction. Such stark differences in the kinematic asymmetry in clusters versus the field suggest the evolutionary influence of dense environments, established as being a major driver of galaxy evolution at low redshift, is also active in the high-redshift universe.
Abstract Childhood socioeconomic disadvantage is associated with disparities in development and health, possibly through adaptations in children’s brain function. However, it is not clear how early ...in development such neural adaptations might emerge. This study examined whether prenatal family socioeconomic status, operationalized as family income and average years of parental education, prospectively predicts individual differences in infant resting electroencephalography (EEG; theta, alpha, beta, and gamma power) at approximately 1 month of age (N = 160). Infants of mothers reporting lower family income showed more lower-frequency (theta) and less higher-frequency (beta and gamma) power. These associations held when adjusting for other prenatal and postnatal experiences, as well as infant demographic and health-related factors. In contrast, parental education was not significantly associated with infant EEG power in any frequency band. These data suggest that lower prenatal family income is associated with developmental differences in brain function that are detectable within the first month of life.
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