Williamsonmonahan1666

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10-18), and increased osteoporosis (P-value = 4.2 × 10-5) and fracture risk (P-value = 1.6 × 10-5). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10-16, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.At the intersection of quantum theory and relativity lies the possibility of a clock experiencing a superposition of proper times. We consider quantum clocks constructed from the internal degrees of relativistic particles that move through curved spacetime. The probability that one clock reads a given proper time conditioned on another clock reading a different proper time is derived. From this conditional probability distribution, it is shown that when the center-of-mass of these clocks move in localized momentum wave packets they observe classical time dilation. We then illustrate a quantum correction to the time dilation observed by a clock moving in a superposition of localized momentum wave packets that has the potential to be observed in experiment. The Helstrom-Holevo lower bound is used to derive a proper time-energy/mass uncertainty relation.Overflow water from the Nordic Seas comprises the deepest limb of the Atlantic Meridional Overturning Circulation, yet questions remain as to where it is ventilated and how it reaches the Greenland-Scotland Ridge. Here we use historical hydrographic data from 2005-2015, together with satellite altimeter data, to elucidate the source regions of the Denmark Strait and Faroe Bank Channel overflows and the pathways feeding these respective sills. A recently-developed metric is used to calculate how similar two water parcels are, based on potential density and potential spicity. This reveals that the interior of the Greenland Sea gyre is the primary wintertime source of the densest portion of both overflows. After subducting, the water progresses southward along several ridge systems towards the Greenland-Scotland Ridge. Kinematic evidence supports the inferred pathways. Extending the calculation back to the 1980s reveals that the ventilation occurred previously along the periphery of the Greenland Sea gyre.Numerous examples of biosynthetic gene clusters (BGCs), including for compounds of agricultural and medicinal importance, have now been discovered in plant genomes. However, little is known about how these complex traits are assembled and diversified. Here, we examine a large number of variants within and between species for a paradigm BGC (the thalianol cluster), which has evolved recently in a common ancestor of the Arabidopsis genus. check details Comparisons at the species level reveal differences in BGC organization and involvement of auxiliary genes, resulting in production of species-specific triterpenes. Within species, the thalianol cluster is primarily fixed, showing a low frequency of deleterious haplotypes. We further identify chromosomal inversion as a molecular mechanism that may shuffle more distant genes into the cluster, so enabling cluster compaction. Antagonistic natural selection pressures are likely involved in shaping the occurrence and maintenance of this BGC. Our work sheds light on the birth, life and death of complex genetic and metabolic traits in plants.Time-lapse microscopy imaging provides direct access to the dynamics of soft and living systems. At mesoscopic scales, such microscopy experiments reveal intrinsic thermal and non-equilibrium fluctuations. These fluctuations, together with measurement noise, pose a challenge for the dynamical analysis of these Brownian movies. Traditionally, methods to analyze such experimental data rely on tracking embedded or endogenous probes. However, it is in general unclear, especially in complex many-body systems, which degrees of freedom are the most informative about their non-equilibrium nature. Here, we introduce an alternative, tracking-free approach that overcomes these difficulties via an unsupervised analysis of the Brownian movie. We develop a dimensional reduction scheme selecting a basis of modes based on dissipation. Subsequently, we learn the non-equilibrium dynamics, thereby estimating the entropy production rate and time-resolved force maps. After benchmarking our method against a minimal model, we illustrate its broader applicability with an example inspired by active biopolymer gels.The eukaryotic cell cycle involves a highly orchestrated series of events in which the cellular genome is replicated during a synthesis (S) phase and each of the two resulting copies are segregated properly during mitosis (M). Host cell factor-1 (HCF-1) is a transcriptional co-regulator that is essential for and has been implicated in basic cellular processes, such as transcriptional regulation and cell cycle progression. Although a series of HCF-1 transcriptional targets have been identified, few functional clues have been provided, especially for chromosome segregation. Our results showed that HCF-1 activated CDC42 expression by binding to the -881 to -575 region upstream of the CDC42 transcription start site, and the regulation of CDC42 expression by HCF-1 was correlated with cell cycle progression. The overexpression of a spontaneously cycling and constitutively active CDC42 mutant (CDC42F28L) rescued G1 phase delay and multinucleate defects in mitosis upon the loss of HCF-1. Therefore, these results establish that HCF-1 ensures proper cell cycle progression by regulating the expression of CDC42, which indicates a possible mechanism of cell cycle coordination and the regulation mode of typical Rho GTPases.