The spread of modern humans across the globe has led to genetic adaptations to diverse local environments. Recent developments in genomic technologies, statistical analyses, and expanded sampled ...populations have led to improved identification and fine-mapping of genetic variants associated with adaptations to regional living conditions and dietary practices. Ongoing efforts in sequencing genomes of indigenous populations, accompanied by the growing availability of "-omics" and ancient DNA data, promises a new era in our understanding of recent human evolution and the origins of variable traits and disease risks.
Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the ...genomes of 92 individuals from 44 indigenous African populations.
Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120-100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54-16 kya. Eastern and western CRHG lineages diverged by ~ 50-31 kya, and the western CRHG lineages diverged by ~ 18-12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations.
We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans.
Hybrid nanowires combining semiconductor and superconductor materials appear well suited for the creation, detection, and control of Majorana bound states (MBSs). We demonstrate the emergence of MBSs ...from coalescing Andreev bound states (ABSs) in a hybrid InAs nanowire with epitaxial Al, using a quantum dot at the end of the nanowire as a spectrometer. Electrostatic gating tuned the nanowire density to a regime of one or a few ABSs. In an applied axial magnetic field, a topological phase emerges in which ABSs move to zero energy and remain there, forming MBSs. We observed hybridization of the MBS with the end-dot bound state, which is in agreement with a numerical model. The ABS/MBS spectra provide parameters that are useful for understanding topological superconductivity in this system.
We investigate effects of quasiparticle poisoning in a Majorana island with strong tunnel coupling to normal-metal leads. In addition to the main Coulomb blockade diamonds, "shadow" diamonds appear, ...shifted by 1e in gate voltage, consistent with transport through an excited (poisoned) state of the island. Comparison to a simple model yields an estimate of parity lifetime for the strongly coupled island (∼1 μs) and sets a bound for a weakly coupled island (>10 μs). Fluctuations in the gate-voltage spacing of Coulomb peaks at high field, reflecting Majorana hybridization, are enhanced by the reduced lever arm at strong coupling. When converted from gate voltage to energy units, fluctuations are consistent with previous measurements.
Threshold regression methods are developed for non-dynamic panels with individual-specific fixed effects. Least squares estimation of the threshold and regression slopes is proposed using ...fixed-effects transformations. A non-standard asymptotic theory of inference is developed which allows construction of confidence intervals and testing of hypotheses. The methods are applied to a 15-year sample of 565 US firms to test whether financial constraints affect investment decisions.
Gut microbiota from individuals in rural, non-industrialized societies differ from those in individuals from industrialized societies. Here, we use 16S rRNA sequencing to survey the gut bacteria of ...seven non-industrialized populations from Tanzania and Botswana. These include populations practicing traditional hunter-gatherer, pastoralist, and agropastoralist subsistence lifestyles and a comparative urban cohort from the greater Philadelphia region.
We find that bacterial diversity per individual and within-population phylogenetic dissimilarity differs between Botswanan and Tanzanian populations, with Tanzania generally having higher diversity per individual and lower dissimilarity between individuals. Among subsistence groups, the gut bacteria of hunter-gatherers are phylogenetically distinct from both agropastoralists and pastoralists, but that of agropastoralists and pastoralists were not significantly different from each other. Nearly half of the Bantu-speaking agropastoralists from Botswana have gut bacteria that are very similar to the Philadelphian cohort. Based on imputed metagenomic content, US samples have a relative enrichment of genes found in pathways for degradation of several common industrial pollutants. Within two African populations, we find evidence that bacterial composition correlates with the genetic relatedness between individuals.
Across the cohort, similarity in bacterial presence/absence compositions between people increases with both geographic proximity and genetic relatedness, while abundance weighted bacterial composition varies more significantly with geographic proximity than with genetic relatedness.
Metastatic castration resistant prostate cancer (mCRPC) is still the lethal stage for the whole spectrum of prostate cancer disease. Even though different treatment options have been introduced in ...the last decade with a significant survival improvement for this population, a lack of more reliable prognostic and predictive markers is still one of the main clinical challenges in management of mCRPC. The aim of this study was to investigate the correlation between Natural Killer cell activity (NKA) and both treatment effect and outcomes in patients with mCRPC treated with enzalutamide. A total of 87 patients with mCRPC treated with enzalutamide as the first line treatment were enrolled. NKA was estimated at baseline and prior to each treatment cycle. Endpoints included both treatment effect with biochemical response (BR), biochemical progression (BP) and radiological progression (RP), as well as outcome data with overall survival (OS), radiologic progression free survival (rPFS), and time to next treatment (TTT). At the time of BR, interferon-gamma (IFNγ) decreased significantly compared to levels detected at baseline (z-score = 2.33, p = 0.019). Regarding outcome data, the whole cohort was divided into four groups according to the change of IFNγ level during the first 3 cycles of enzalutamide treatment. In group 1 (n = 42) the IFNγ level remained within a normal range (≥ 250 pg/mL),while in group 2 (n = 7) it increased from an abnormal (< 250 pg/mL) to a normal level. In group 3 (n = 13) it dropped to an abnormal level, and it remained at an abnormal level during treatment in group 4 (n = 17). Patients in group 2 showed the worst prognosis with shorter both rPFS and TTT (HR 4.30, p = 0.037; and HR 6.82, p = 0.011, respectively). In this study inverse correlations between NKA and both treatment response and outcomes was observed in mCRPC patients receiving enzalutamide, suggesting an unfavourable role of NK cells in the late stage of PCa.
Nitrate contamination of subsurface aquifers is an ongoing environmental challenge due to nitrogen (N) leaching from intensive N
fertilization and management on agricultural fields. The distribution ...and fate
of nitrate in aquifers are primarily governed by geological, hydrological and
geochemical conditions of the subsurface. Therefore, we propose a novel
approach to modeling both geology and redox architectures simultaneously in high-resolution 3D (25m×25m×2m) using multiple-point geostatistical (MPS) simulation. Data consist of (1) mainly
resistivities of the subsurface mapped with towed transient electromagnetic
measurements (tTEM), (2) lithologies from borehole observations, (3) redox conditions from colors reported in borehole observations, and (4) chemistry analyses from water samples. Based on the collected data and supplementary
surface geology maps and digital elevation models, the simulation domain was
subdivided into geological elements with similar geological traits and
depositional histories. The conceptual understandings of the geological and redox architectures of the study system were introduced to the simulation as
training images for each geological element. On the basis of these training
images and conditioning data, independent realizations were jointly simulated
of geology and redox inside each geological element and stitched together into
a larger model. The joint simulation of geological and redox architectures,
which is one of the strengths of MPS compared to other geostatistical methods, ensures that the two architectures in general show coherent patterns. Despite the inherent subjectivity of interpretations of the
training images and geological element boundaries, they enable an easy and
intuitive incorporation of qualitative knowledge of geology and geochemistry
in quantitative simulations of the subsurface architectures. Altogether, we
conclude that our approach effectively simulates the consistent geological and
redox architectures of the subsurface that can be used for hydrological
modeling with nitrogen (N) transport, which may lead to a better understanding of N fate in the subsurface and to future more targeted
regulation of agriculture.
The bacterial domain produces numerous types of sphingolipids with various physiological functions. In the human microbiome, commensal and pathogenic bacteria use these lipids to modulate the host ...inflammatory system. Despite their growing importance, their biosynthetic pathway remains undefined since several key eukaryotic ceramide synthesis enzymes have no bacterial homolog. Here we used genomic and biochemical approaches to identify six proteins comprising the complete pathway for bacterial ceramide synthesis. Bioinformatic analyses revealed the widespread potential for bacterial ceramide synthesis leading to our discovery of a Gram-positive species that produces ceramides. Biochemical evidence demonstrated that the bacterial pathway operates in a different order from that in eukaryotes. Furthermore, phylogenetic analyses support the hypothesis that the bacterial and eukaryotic ceramide pathways evolved independently.
Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near
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that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at
was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in South Asian and Australo-Melanesian populations. Functional analyses indicate that
encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near
correlate with expression of ultraviolet response genes under selection in Eurasians.
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