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How non-coding RNAs shape nuclear structure to regulate gene expression
No full textThe nucleus is a highly organized arrangement of RNA, DNA, and protein molecules that are compartmentalized within three-dimensional (3D) structures involved in shared functional and regulatory processes. Although RNA has long been proposed to play a global role in organizing nuclear structure, exploring this role has remained a challenge because no existing methods can simultaneously measure RNA and DNA contacts within 3D structures. To address this, we developed RNA & DNA SPRITE (RD-SPRITE) to comprehensively map the spatial organization of all RNAs relative to DNA. Using this approach, we identify hundreds of ncRNAs that form high-concentration territories in spatial proximity to their transcriptional loci and show that dozens of ncRNAs guide diffusible regulatory proteins into these 3D structures. We show that many of these ncRNA-mediated compartments act to regulate RNA processing, heterochromatin assembly, and gene expression. Our results demonstrate a unique mechanism by which ncRNAs act to shape nuclear structure by forming high concentration territories immediately upon transcription, binding to diffusible regulators, and guiding them into spatial compartments to regulate a wide range of essential nuclear functions. Moreover, we discuss how ncRNAs can drive amplification of regulatory proteins in 3D space to enable robust control of gene expression
Using angle-dependent velocity to detect fast states in rotary motors
No full textA data-driven modeling method of the molecular machine F1-ATPase is presented. On the one hand, our theory is built to treat a variety of different type of single-molecule and ensemble experiments used to probe the F1-ATPase. On the other hand, the model is applied to different F-ATPase species, like the Thermophilic Bacillus and Paracoccus Denitrificans, since their α₃β₃ ring structure is highly conserved and hence the mechano-chemistry is presumably similar, even though their stepping kinetics vary. An elastic molecular transfer theory provides a framework for a multi-state model which includes the probe used in single-molecule imaging and magnetic manipulation. When applied to unconstrained rotation of single F1-ATPase, the model is able to enhance the resolution of the single-molecule imaging. In the rotation of the F1-ATPase, the use of the angle-dependent velocity provides a tool for the detection of fast states of microsecond life time which are hidden by the fluctuations of the imaging probe. Ultimately, the motivation is to gain biological/physiological insight: our model-based method was used to predict the life time of the intermediate during the correlated behaviour in F-ATPase. The release of nucleotides would be a bottleneck process, but the binding of another nucleotide to another site acts to accelerate the release by 5-6 orders of magnitude. The correlated behavior is captured in our model via the angle-dependent rate constants of the individual substeps. We propose that the allosteric mechanism is universally found in all F-ATPase species and may be present in other members of the AAA+ ring proteins
Model Reduction of Linear Dynamical Systems via Balancing for Bayesian Inference
No full textWe consider the Bayesian approach to the linear Gaussian inference problem of inferring the initial condition of a linear dynamical system from noisy output measurements taken after the initial time. In practical applications, the large dimension of the dynamical system state poses a computational obstacle to computing the exact posterior distribution. Model reduction offers a variety of computational tools that seek to reduce this computational burden. In particular, balanced truncation is a system-theoretic approach to model reduction which obtains an efficient reduced-dimension dynamical system by projecting the system operators onto state directions which trade off the reachability and observability of state directions as expressed through the associated Gramians. We introduce Gramian definitions relevant to the inference setting and propose a balanced truncation approach based on these inference Gramians that yield a reduced dynamical system that can be used to cheaply approximate the posterior mean and covariance. Our definitions exploit natural connections between (i) the reachability Gramian and the prior covariance and (ii) the observability Gramian and the Fisher information. The resulting reduced model then inherits stability properties and error bounds from system theoretic considerations, and in some settings yields an optimal posterior covariance approximation. Numerical demonstrations on two benchmark problems in model reduction show that our method can yield near-optimal posterior covariance approximations with order-of-magnitude state dimension reduction
QUBIC III: Laboratory characterization
No full textWe report on an extensive test campaign of a prototype version of the QUBIC (Q & U Bolometric Interferometer for Cosmology) instrument, carried out at Astroparticle Physics and Cosmology (APC) in Paris. Exploiting the novel concept called bolometric interferometry, QUBIC is designed to measure the CMB polarization at 150 and 220 GHz from a high altitude site at Alto Chorillo, Argentina. The prototype model called QUBIC Technological Demonstrator (QUBIC-TD) operates in a single frequency band (150 GHz) and with a reduced number of baselines, but it contains all the elements of the QUBIC instrument in its final configuration. The test campaign included measurements of the synthesized beam and of the polarization performance, as well as a verification of the interference fringe pattern. A modulated, frequency-tunable millimetre-wave source was placed in the telescope far-field and was used to simulate a point source. The QUBIC-TD field of view was scanned across the source to produce beam maps. Our measurements confirm the frequency-dependent behaviour of the beam profile, which gives QUBIC the possibility to do spectral imaging. The measured polarization performance indicates a cross-polarization leakage less than 0.6%. We also successfully tested the polarization modulation system, which is provided by a rotating half wave plate. We demonstrate the full mapmaking pipeline using data from this measurement campaign, effectively giving an end-to-end checkout of the entire QUBIC system, including all hardware subsystems, their interfaces, and the software to operate the whole system and run the analysis. Our results confirm the viability of bolometric interferometry for measurements of the CMB polarization
The Current Status and Future Prospects of KAGRA, the Large-Scale Cryogenic Gravitational Wave Telescope Built in the Kamioka Underground
No full textKAGRA is a gravitational-wave (GW) detector constructed in Japan with two unique key features: It was constructed underground, and the test-mass mirrors are cooled to cryogenic temperatures. These features are not included in other kilometer-scale detectors but will be adopted in future detectors such as the Einstein Telescope. KAGRA performed its first joint observation run with GEO600 in 2020. In this observation, the sensitivity of KAGRA to GWs was inferior to that of other kilometer-scale detectors such as LIGO and Virgo. However, further upgrades to the detector are ongoing to reach the sensitivity for detecting GWs in the next observation run, which is scheduled for 2022. In this article, the current situation, sensitivity, and future perspectives are reviewed
To drum or not to drum: Selectivity in tree buttress drumming by chimpanzees (Pan troglodytes verus) in the Nimba Mountains, Guinea
No full textChimpanzees live in fission-fusion social organizations, which means that party size, composition, and spatial distribution are constantly in flux. Moreover, chimpanzees use a remarkably extensive repertoire of vocal and nonvocal forms of communication, thought to help convey information in such a socially and spatially dynamic setting. One proposed form of nonvocal communication in chimpanzees is buttress drumming, in which an individual hits a tree buttress with its hands and/or feet, thereby producing a low-frequency acoustic signal. It is often presumed that this behavior functions to communicate over long distances and is, therefore, goal-oriented. If so, we would expect chimpanzees to exhibit selectivity in the choice of trees and buttresses used in buttress drumming. Selectivity is a key attribute of many other goal-directed chimpanzee behaviors, such as nut-cracking and ant dipping. Here, we investigate whether chimpanzees at the Seringbara study site in the Nimba Mountains, Guinea, West Africa, show selectivity in their buttress drumming behavior. Our results indicate that Seringbara chimpanzees are more likely to use larger trees and select buttresses that are thinner and have a greater surface area. These findings imply that tree buttress drumming is not a random act, but rather goal-oriented and requires knowledge of suitable trees and buttresses. Our results also point to long-distance communication as a probable function of buttress drumming based on selectivity for buttress characteristics likely to impact sound propagation. This study provides a foundation for further assessing the cognitive underpinnings and functions of buttress drumming in wild chimpanzees
Model and Predictive Uncertainty: A Foundation for Smooth Ambiguity Preferences
No full textSmooth ambiguity preferences (Klibanoff, Marinacci, and Mukerji (2005)) describe a decision maker who evaluates each act f according to the twofold expectation,
V(f) = ∫_p Φ(∫_Ω u(f)dp)dµ(p), defined by a utility function u, an ambiguity index ϕ, and a belief μ over a set of probabilities. We provide an axiomatic foundation for the representation, taking as a primitive a preference over Anscombe–Aumann acts. We study a special case where P is a subjective statistical model that is point identified, that is, the decision maker believes that the true law p ϵ P can be recovered empirically. Our main axiom is a joint weakening of Savage's sure-thing principle and Anscombe–Aumann's mixture independence. In addition, we show that the parameters of the representation can be uniquely recovered from preferences, thereby making operational the separation between ambiguity attitude and perception, a hallmark feature of the smooth ambiguity representation
Fixation Can Change the Appearance of Phase Separation in Living Cells
No full textFixing cells with paraformaldehyde (PFA) is an essential step in numerous biological techniques as it is thought to preserve a snapshot of biomolecular transactions in living cells. Fixed cell imaging techniques such as immunofluorescence have been widely used to detect liquid-liquid phase separation (LLPS) in vivo. Here, we compared images, before and after fixation, of cells expressing intrinsically disordered proteins that are able to undergo LLPS. Surprisingly, we found that PFA fixation can both enhance and diminish putative LLPS behaviors. For specific proteins, fixation can even cause their droplet-like puncta to artificially appear in cells that do not have any detectable puncta in the live condition. Fixing cells in the presence of glycine, a molecule that modulates fixation rates, can reverse the fixation effect from enhancing to diminishing LLPS appearance. We further established a kinetic model of fixation in the context of dynamic protein-protein interactions. Simulations based on the model suggest that protein localization in fixed cells depends on an intricate balance of protein-protein interaction dynamics, the overall rate of fixation, and notably, the difference between fixation rates of different proteins. Our work reveals that PFA fixation changes the appearance of LLPS from living cells, presents a caveat in studying LLPS using fixation-based methods, and suggests a mechanism underlying the fixation artifact
Projects at Palomar: New and Traditional Roles for the Caltech Library
No full textIn the last year, two projects illustrate opportunities for our Library to work in new ways to document and preserve the research of Palomar and Caltech. Observing log books from Palomar telescopes are being digitized and presented online. These logs go back to the 1930s and are a unique window into early observing activities at Palomar. Eventually, both observer and plate logs will be available. We envision astronomers, amateur astronomers and those interested in the history of science being interested in this work. Current Palomar research has different needs. Our institutional repository (IR), CaltechAUTHORS is used to track and expose research associated with the Zwicky Transient Factory. This National Science Foundation (NSF) funded instrument is mounted on the 48-inch telescope at Palomar. CaltechAUTHORS is continuously updated with new papers and when NSF reports are due they are added to research.gov to support the award. In both of these projects new collaborations needed to be forged in order to accomplish the work. Internally, the log book project relied on interlibrary loan staff, our archivist and our digital technologies librarian. On the Palomar side we leaned on retired and current staff from the optical observatories. Our work supporting research grants has evolved as we’ve established relationships with PIs, grants managers and the Office of Sponsored Research at Caltech. These are just two projects but both represent work that is evolving as the library and its services adjust to meet the changing research and preservation needs of the Institute
Widely-tunable optical parametric oscillator in lithium niobate nanophotonics
No full textWidely-tunable coherent sources in nanophotonics are desirable for a multitude of applications ranging from communications to sensing. The mid-infrared spectral region (wavelengths beyond 2 μm) is particularly important for applications relying on molecular spectroscopy. Among tunable sources, optical parametric oscillators typically offer some of the broadest tuning ranges; however, their implementations in nanophotonics have been limited to modest tuning ranges and only at visible and near-infrared wavelengths. Here, we surpass these limits by demonstrating octave-spanning tunable optical parametric oscillators in dispersion-engineered periodically-poled lithium niobate nanophotonics. With a pump wavelength near 1 μm, we generate output wavelengths tunable from 1.53 μm to 3.25 μm, including common telecommunication bands and into the mid-infrared. Our results enable opportunities for numerous integrated photonic applications requiring compact tunable sources