Alzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, ...with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74 046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry.
Three new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94 437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388 324 and 534 403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research.
The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.
The East Mediterranean Levant is a focal point for debate about evolutionary continuity among Late Pleistocene hominin populations. Changes in the Levantine Middle and Upper Palaeolithic ...archaeological records are almost invariably described in terms of adaptive shifts and behavioural transitions, rather than as changes in hominin populations. This paper examines evidence for hominin evolutionary continuity in the Levant between 130 and 25
ka. Two inflection points, one within the Middle Palaeolithic ca 75
ka and the other between the Middle and Upper Palaeolithic ca 45
ka, are examined in light of recently-discovered evidence for rapid climate change and environmental deterioration. It is proposed that both periods mark regional extinctions and turnovers of hominin populations. The first of these occurred among early
Homo sapiens, the second among Neanderthals. Each event was followed by dispersal of hominin populations into the Levant from adjacent regions. Differences in Middle vs. Upper Palaeolithic
Homo sapiens’ long-term success in the Levant may reflect recently-evolved strategies for coping with rapid climate change and with colder arid habitats.
Mountain ranges in Asia are important water suppliers, especially if downstream climates are arid, water demands are high and glaciers are abundant. In such basins, the hydrological cycle depends ...heavily on high-altitude precipitation. Yet direct observations of high-altitude precipitation are lacking and satellite derived products are of insufficient resolution and quality to capture spatial variation and magnitude of mountain precipitation. Here we use glacier mass balances to inversely infer the high-altitude precipitation in the upper Indus basin and show that the amount of precipitation required to sustain the observed mass balances of large glacier systems is far beyond what is observed at valley stations or estimated by gridded precipitation products. An independent validation with observed river flow confirms that the water balance can indeed only be closed when the high-altitude precipitation on average is more than twice as high and in extreme cases up to a factor of 10 higher than previously thought. We conclude that these findings alter the present understanding of high-altitude hydrology and will have an important bearing on climate change impact studies, planning and design of hydropower plants and irrigation reservoirs as well as the regional geopolitical situation in general.
GWAS summary statistics are fundamental for a variety of research applications yet no common storage format has been widely adopted. Existing tabular formats ambiguously or incompletely store ...information about genetic variants and associations, lack essential metadata and are typically not indexed yielding poor query performance and increasing the possibility of errors in data interpretation and post-GWAS analyses. To address these issues, we adapted the variant call format to store GWAS summary statistics (GWAS-VCF) and developed open-source tools to use this format in downstream analyses. We provide open access to over 10,000 complete GWAS summary datasets converted to this format ( https://gwas.mrcieu.ac.uk ).
Nanomaterials, when introduced into a complex, protein-rich environment, rapidly acquire a protein corona. The type and amount of proteins that constitute the corona depend significantly on the ...synthetic identity of the nanomaterial. For example, hydrogel nanoparticles (NPs) such as poly(N-isopropylacrylamide) (NIPAm) have little affinity for plasma proteins; in contrast, carboxylated poly(styrene) NPs acquire a dense protein corona. This range of protein adsorption suggests that the protein corona might be “tuned” by controlling the chemical composition of the NP. In this Account, we demonstrate that small libraries of synthetic polymer NPs incorporating a diverse pool of functional monomers can be screened for candidates with high affinity and selectivity to targeted biomacromolecules. Through directed synthetic evolution of NP compositions, one can tailor the protein corona to create synthetic organic hydrogel polymer NPs with high affinity and specificity to peptide toxins, enzymes, and other functional proteins, as well as to specific domains of large proteins. In addition, many NIPAm NPs undergo a change in morphology as a function of temperature. This transformation often correlates with a significant change in NP–biomacromolecule affinity, resulting in a temperature-dependent protein corona. This temperature dependence has been used to develop NP hydrogels with autonomous affinity switching for the protection of proteins from thermal stress and as a method of biomacromolecule purification through a selective thermally induced catch and release. In addition to temperature, changes in pH or buffer can also alter a NP protein corona composition, a property that has been exploited for protein purification. Finally, synthetic polymer nanoparticles with low nanomolar affinity for a peptide toxin were shown to capture and neutralize the toxin in the bloodstream of living mice. While the development of synthetic polymer alternatives to protein affinity reagents is in its early stages, these recent successes using only small libraries of functional monomers are most encouraging. It is likely that by expanding the chemical diversity of functional hydrogels and other polymers, a much broader range of NP–biomacromolecule affinity pairs will result. Since these robust, nontoxic polymers are readily synthesized in the chemistry laboratory, we believe the results presented in this Account offer a promising future for the development of low cost alternatives to more traditional protein affinity reagents such as antibodies.
Himalayan glacier tongues are commonly debris covered and they are an important source of melt water. However, they remain relatively unstudied because of the inaccessibility of the terrain and the ...difficulties in field work caused by the thick debris mantles. Observations of debris-covered glaciers are therefore scarce and airborne remote sensing may bridge the gap between scarce field observations and coarse resolution space-borne remote sensing. In this study we deploy an Unmanned Aerial Vehicle (UAV) before and after the melt and monsoon season (May and October 2013) over the debris-covered tongue of the Lirung Glacier in Nepal. Based on stereo-imaging and the structure for motion algorithm we derive highly detailed ortho-mosaics and digital elevation models (DEMs), which we geometrically correct using differential GPS observations collected in the field. Based on DEM differencing and manual feature tracking we derive the mass loss and the surface velocity of the glacier at a high spatial accuracy. On average, mass loss is limited and the surface velocity is very small. However, the spatial variability of melt rates is very high, and ice cliffs and supra-glacial ponds show mass losses that can be an order of magnitude higher than the average. We suggest that future research should focus on the interaction between supra-glacial ponds, ice cliffs and englacial hydrology to further understand the dynamics of debris-covered glaciers. Finally, we conclude that UAV deployment has large potential in glaciology and it may revolutionize methods currently applied in studying glacier surface features.
•An UAV is applied over a high-altitude, debris-covered glacier in the Himalayas.•Glacier elevation and surface changes are derived at very high resolution.•Overall melt rates are low, but very heterogeneous with high melt near ice cliffs.•Surface velocity is low except near the ice cliffs and supra-glacial ponds.•UAVs may revolutionize current glacier monitoring methods.
Projectile weaponry is a human cultural universal, but its origins and antiquity remain poorly understood. Stone- and bone-tipped projectile weapons have long been treated as emergent features of the ..."Upper Paleolithic" behavioral revolution. Recently it has been proposed that projectile technology was in widespread use among
Homo sapiens populations in Africa during Middle Stone Age (MSA) times. One obstacle to researching the origins of projectile point technology is that the criteria archaeologists employ for recognizing plausible and implausible stone projectile points are largely subjective (overall tool shape, microwear traces). Tip cross-sectional area (TCSA) is a ballistically significant dimension that works well at discriminating North American stone projectile points (spearthrower dart tips and arrowheads) from spear points. This paper compares the TCSA values of ethnographic North American stone projectile points to hypothetical Middle and Upper Paleolithic stone projectile points from Africa, the Levant, and Europe. The results of this comparison do not support the hypothesis of widespread use of stone-tipped projectiles in Africa, the Levant, or Europe prior to 40
Ka. In the New World and in Australia, where we have the richest ethnographic record of stone projectile point use, these implements are largely employed in big-game hunting and in warfare. One or both of these factors may have played a role in the widespread adoption of stone projectile point technology after 40
Ka.
Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer’s disease (AD) risk. In particular, AD risk alleles primarily affect ...the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.
Romero-Molina, Garretti, and colleagues illustrate their hypothesis that genetic variants associated with AD modulate disease susceptibility by affecting genes and pathways that play critical roles in efferocytosis, the phagocytic clearance of cholesterol-rich cellular debris by macrophages like microglia.
Background
Mitochondria regulate energy and metabolic homeostasis, with increasing evidence implicating mitochondrial dysfunction in Alzheimer’s disease (AD) pathogenesis. Each mitochondrion contains ...multiple copies of the mitochondrial genome (mtDNA), with mtDNA copy number (mtDNAcn) been used as a surrogate measure of mitochondrial function. Here we evaluate the association of mtDNAcn with neuropathological diagnosis of AD and evaluate shared genetic etiology between AD and mtDNAcn.
Methods
We evaluated the association of mtDNAcn with a neuropathological diagnosis of AD in 1194 non‐Hispanic white subjects (cases = 706, controls = 468) from three cohorts (ROSMAP, MSBB, Mayo) from the Accelerating Medicines Partnership Alzheimer’s disease (AMP‐AD). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA using whole genome sequencing data from DNA isolated from brain tissue. Neuropathological AD was determined based on neuropathological burden of amyloid plaques and tangles. Logistic regression adjusting for mitochondrial haplogroup, age of death, sex, APOE, post‐mortem interval and source tissue was used to evaluate the association of mtDNAcn with AD in each cohort separately and jointly in an inverse weighted fixed‐effects meta‐analysis (IVW FE). Additionally, we estimated the genetic correlation between mtDNAcn and AD, evaluated the association of a mtDNAcn polygenic risk score (PRS) with clinical AD (cases = 13312, controls = 13119), and conducted bidirectional two‐sample Mendelian randomization to estimate the causal relationship between mtDNAcn and AD.
Results
Higher mtDNAcn was associated with a reduced risk of neuropathological AD (IVW FE: OR95%CI = 0.70 0.58, 0.84. mtDNAcn was not genetically correlated with AD (rg = 0.13 (0.16), p = 0.4) and a mtDNAcn PRS was not associated with clinical AD (OR95%CI = 1 0.97, 1.03, p = 0.884). Mendelian randomization did not support a causal relationship between mtDNAcn and AD (OR95%CI = 0.93 0.74, 1.14, p = 0.46).
Conclusion
Elevated mtDNAcn estimated from brain tissue was associated with a reduced risk of neuropathological AD, suggesting that mitochondrial dysfunction is associated with AD pathogenesis. However, genetically predicted mtDNAcn estimated from peripheral blood was not associated with AD using genetically informed approaches. As such, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by‐product of AD pathogenesis.
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