cssi/SciSciGPT-SciSciNet huggingface dataset:
Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes.
fMRI reveals language-specific predictive coding during naturalistic sentence comprehension

Much research in cognitive neuroscience supports prediction as a canonical computation of cognition across domains. Is such predictive coding implemented by feedback from higher-order domain-general circuits, or is it locally implemented in domain-specific circuits? What information sources are used to generate these predictions? This study addresses these two questions in the context of language processing. We present fMRI evidence from a naturalistic comprehension paradigm (1) that predictive coding in the brain's response to language is domain-specific, and (2) that these predictions are sensitive both to local word co-occurrence patterns and to hierarchical structure. Using a recently developed continuous-time deconvolutional regression technique that supports data-driven hemodynamic response function discovery from continuous BOLD signal fluctuations in response to naturalistic stimuli, we found effects of prediction measures in the language network but not in the domain-general multiple-demand network, which supports executive control processes and has been previously implicated in language comprehension. Moreover, within the language network, surface-level and structural prediction effects were separable. The predictability effects in the language network were substantial, with the model capturing over 37% of explainable variance on held-out data. These findings indicate that human sentence processing mechanisms generate predictions about upcoming words using cognitive processes that are sensitive to hierarchical structure and specialized for language processing, rather than via feedback from high-level executive control mechanisms.
Towards Highly Efficient State Estimation With Nonlinear Measurements in Distribution Systems

This letter proposes a novel and highly efficient distribution system state estimation (DSSE) method with nonlinear measurements from supervisory control and data acquisition (SCADA) systems. Conventional DSSE based on the weighted least square (WLS) criterion requires multiple Monte Carlo simulations for overall accuracy evaluation and high calculation cost due to a nonlinear iterative process. The proposed method uses the Taylor series of voltages for constructing a linear DSSE model in the interval form and then solves this model by interval arithmetic. This method obtains accurate and robust estimates via a single random sampling of measurements and is computationally efficient. The comparative analysis in the IEEE 34-bus distribution system points to improved estimation results relative to the nonlinear WLS-based method.
Unhappiness and Age

I examine the relationship between unhappiness and age using data from eight well-being data files on nearly 14 million respondents across forty European countries and the United States and 168 countries from the Gallup World Poll. I use twenty different individual characterizations of unhappiness including many not good mental health days; anxiety; worry; loneliness; sadness; stress; pain; strain, depression and bad nerves; phobias and panic; being downhearted; having restless sleep; losing confidence in oneself; not being able to overcome difficulties; being under strain; being unhappy; feeling a failure; feeling left out; feeling tense; and thinking of yourself as a worthless person. I also analyze responses to a further general attitudinal measure regarding whether the situation in the respondent's country is getting worse. Responses to all these unhappiness questions show a, ceteris paribus, hill shape in age, with controls and many also do so with limited controls for time and country. Unhappiness is hill-shaped in age and the average age where the maximum occurs is 49 with or without controls. There is an unhappiness curve.
Diagonally Dominant Principal Component Analysis

We consider the problem of decomposing a large covariance matrix into the sum of a low-rank matrix and a diagonally dominant matrix, and we call this problem the “diagonally dominant principal comp...
Optimal Document Exchange and New Codes for Insertions and Deletions

We give the first communication-optimal document exchange protocol. For any n and k < n our randomized scheme takes any n-bit file F and computes a Θ(k log n/k) -bit summary from which one can reconstruct F, with high probability, given a related file F' with edit distance ED(F,F') ≤ k. The size of our summary is information-theoretically order optimal for all values of k, giving a randomized solution to a longstanding open question of [Orlitsky; FOCS'91]. It also is the first non-trivial solution for the interesting setting where a small constant fraction of symbols have been edited, producing an optimal summary of size O(H(δ)n) for k=δ n. This concludes a long series of better-and-better protocols which produce larger summaries for sub-linear values of k and sub-polynomial failure probabilities. In particular, the recent break-through of [Belazzougui, Zhang; FOCS'16] assumes that k < n^e, produces a summary of size O(klog^2 k + k log n), and succeeds with probability 1-(k log n)^ -O(1). We also give an efficient derandomized document exchange protocol with summary size O(k log^2 n/k). This improves, for any k, over a deterministic document exchange protocol by Belazzougui with summary size O(k^2 + k log^2 n). Our deterministic document exchange directly provides new efficient systematic error correcting codes for insertions and deletions. These (binary) codes correct any δ fraction of adversarial insertions/deletions while having a rate of 1 - O(δ log^2 1/δ) and improve over the codes of Guruswami and Li and Haeupler, Shahrasbi and Vitercik which have rate 1 - Θ (√δ log^O(1) 1/e).
A tight analysis of greedy yields subexponential time approximation for uniform decision tree

Decision Tree is a classic formulation of active learning: given n hypotheses with nonnegative weights summing to 1 and a set of tests that each partition the hypotheses, output a decision tree using the provided tests that uniquely identifies each hypothesis and has minimum (weighted) average depth. Previous works showed that the greedy algorithm achieves a O(log n) approximation ratio for this problem and it is NP-hard beat a O(log n) approximation, settling the complexity of the problem. However, for Uniform Decision Tree, i.e. Decision Tree with uniform weights, the story is more subtle. The greedy algorithm's O(log n) approximation ratio was the best known, but the largest approximation ratio known to be NP-hard is 4 − e. We prove that the greedy algorithm gives a [MATH HERE] approximation for Uniform Decision Tree, where Copt is the cost of the optimal tree and show this is best possible for the greedy algorithm. As a corollary, we resolve a conjecture of Kosaraju, Przytycka, and Borgstrom [20]. Our results also hold for instances of Decision Tree whose weights are not too far from uniform. Leveraging this result, for all α ∈ (0, 1), we exhibit a [MATH HERE] approximation algorithm to Uniform Decision Tree running in subexponential time 2O(nα). As a corollary, achieving any super-constant approximation ratio on Uniform Decision Tree is not NP-hard, assuming the Exponential Time Hypothesis. This work therefore adds approximating Uniform Decision Tree to a small list of natural problems that have subexponential time algorithms but no known polynomial time algorithms. Like the analysis of the greedy algorithm, our analysis of the subexponential time algorithm gives similar approximation guarantees even for slightly nonuniform weights. A key technical contribution of our work is showing a connection between greedy algorithms for Uniform Decision Tree and for Min Sum Set Cover.
XPRESSyourself: Enhancing, standardizing, and automating ribosome profiling computational analyses yields improved insight into data.

Ribosome profiling, an application of nucleic acid sequencing for monitoring ribosome activity, has revolutionized our understanding of protein translation dynamics. This technique has been available for a decade, yet the current state and standardization of publicly available computational tools for these data is bleak. We introduce XPRESSyourself, an analytical toolkit that eliminates barriers and bottlenecks associated with this specialized data type by filling gaps in the computational toolset for both experts and non-experts of ribosome profiling. XPRESSyourself automates and standardizes analysis procedures, decreasing time-to-discovery and increasing reproducibility. This toolkit acts as a reference implementation of current best practices in ribosome profiling analysis. We demonstrate this toolkit’s performance on publicly available ribosome profiling data by rapidly identifying hypothetical mechanisms related to neurodegenerative phenotypes and neuroprotective mechanisms of the small-molecule ISRIB during acute cellular stress. XPRESSyourself brings robust, rapid analysis of ribosome-profiling data to a broad and ever-expanding audience and will lead to more reproducible and accessible measurements of translation regulation. XPRESSyourself software is perpetually open-source under the GPL-3.0 license and is hosted at https://github.com/XPRESSyourself, where users can access additional documentation and report software issues.
Robustness of the Closest Unstable Equilibrium Point Along a P-V Curve

In this paper, we study numerically the behavior of the closest unstable equilibrium point (UEP) on the stability boundary of a stable equilibrium point (SEP) of a post-switching power system along a P-V curve. Using the structure-preserving model of the WSCC 9-bus 3-machine system, we show that along the load curve, the closest UEP can switch to a new UEP. We also show that the stability region of the post-switching SEP can expand and contract as the load moves towards the nose point of the P-V curve. Our numerical results also show the impact of the direction of movement of the closest UEP on the size and shape of the stability region of a SEP.
Electrophilic Cleavage of Cyclopropanes. Acetolysis of Alkylcyclopropanes

Der durch das Losungsmittel verursachte kinetische Isotopieeffekt der Titelreaktion weist die prim. Protonierung als teilweise geschwindigkeitsbestimmenden Schritt aus.
The local structures of human mobility in Chicago

A large literature establishes the role of mobility in the maintenance of neighborhood social structures. Jane Jacobs famously argued that social capital is maintained through “cross-use of space,”...
Early Causes of Financial Disquiet and the Gender Gap in Financial Literacy: Evidence from College Students in the Southeastern United States

Financial literacy, a cornerstone of family economic well-being, is surprisingly low in the United States. The literature has established that financial literacy is lower among women than among men. As sound financial decision-making among both male and female household heads is of paramount importance to well-being, we look to identify the underlying causes that may initiate and perpetuate this differential. We found that a gender-based gap in understanding develops by early college age, before individuals have had the opportunity to develop financial skills through experience or specialization in household roles. The literature indicates that women tend to underestimate their abilities relative to men, particularly in areas of math and financial decision-making. Math ability, financial confidence, and financial and math education have been found to enhance financial literacy, and so we focus on math self-efficacy as an early indicator of financial assurance and literacy. Using an ordered probit model and data from a sample of 529 college students across three institutions in the southeastern United States, we extend the current literature to find that for men, objective math ability drives financial literacy. For women, on the other hand, self-efficacy—and not objective ability—is predictive of financial literacy. Understanding the underlying causes of the gender-based financial literacy gap can inform the creation of better education, family, and cultural intervention methods by which to close this gap in financial literacy, decisions, and outcomes.
Prognostic factors of long-term survival to guide selection of asymptomatic patients for carotid endarterectomy.

Introduction According to the current guidelines, prophylactic carotid endarterectomy (CEA) should be considered for patients with asymptomatic carotid stenosis (ACS) who are at high-risk of becoming symptomatic, provided they have a 3- to 5-year life-expectancy and perioperative stroke/death rates are ≤3%. We reviewed the literature to identify negative prognostic factors for long-term survival in ACS patients to avoid offering CEA to those not likely to benefit from the procedure. Evidence acquisition PubMed/MedLine was searched until April 1, 2019, for risk prediction models to find ACS patients with poor long-term survival. Evidence synthesis Fourteen studies were identified. Cardiac disease/congestive heart failure, advanced age, chronic obstructive pulmonary disease, diabetes mellitus, dialysis/renal insufficiency, lack of statin use and active/previous smoking were negative predictors of long-term survival following CEA. The concomitant presence of >1 prognostic factor had a cumulative effect on long-term mortality rates. High-volume, experienced surgeons and type of hospital (academic rather than urban) were positive predictors and affected early and long-term survival rates. Conclusions The presence of one or more prognostic factors as well as the various risk prediction models can guide selection of ACS patient subgroups for which a prophylactic CEA should or should not be offered. Decisions to offer prophylactic CEA should weigh in factors like surgeon's experience and hospital expertise/volume. Asymptomatic patients not expected to live long enough to benefit from the procedure should not be considered for CEA, but should be offered best medical treatment.
An adversarial approach for the robust classification of pneumonia from chest radiographs

While deep learning has shown promise in the domain of disease classification from medical images, models based on state-of-the-art convolutional neural network architectures often exhibit performance loss due to dataset shift. Models trained using data from one hospital system achieve high predictive performance when tested on data from the same hospital, but perform significantly worse when they are tested in different hospital systems. Furthermore, even within a given hospital system, deep learning models have been shown to depend on hospital- and patient-level confounders rather than meaningful pathology to make classifications. In order for these models to be safely deployed, we would like to ensure that they do not use confounding variables to make their classification, and that they will work well even when tested on images from hospitals that were not included in the training data. We attempt to address this problem in the context of pneumonia classification from chest radiographs. We propose an approach based on adversarial optimization, which allows us to learn more robust models that do not depend on confounders. Specifically, we demonstrate improved out-of-hospital generalization performance of a pneumonia classifier by training a model that is invariant to the view position of chest radiographs (anterior-posterior vs. posterior-anterior). Our approach leads to better predictive performance on external hospital data than both a standard baseline and previously proposed methods to handle confounding, and also suggests a method for identifying models that may rely on confounders.
Methods for comparing uncertainty quantifications for material property predictions

Data science and informatics tools have been proliferating recently within the computational materials science and catalysis fields. This proliferation has spurned the creation of various frameworks for automated materials screening, discovery, and design. Underpinning these frameworks are surrogate models with uncertainty estimates on their predictions. These uncertainty estimates are instrumental for determining which materials to screen next, but the computational catalysis field does not yet have a standard procedure for judging the quality of such uncertainty estimates. Here we present a suite of figures and performance metrics derived from the machine learning community that can be used to judge the quality of such uncertainty estimates. This suite probes the accuracy, calibration, and sharpness of a model quantitatively. We then show a case study where we judge various methods for predicting density-functional-theory-calculated adsorption energies. Of the methods studied here, we find that the best performer is a model where a convolutional neural network is used to supply features to a Gaussian process regressor, which then makes predictions of adsorption energies along with corresponding uncertainty estimates.
Observation of Ion Electrosorption in Metal–Organic Framework Micropores with In Operando Small-Angle Neutron Scattering

A molecular-level understanding of transport and adsorption mechanisms of electrolyte ions in nanoporous electrodes under applied potentials is essential to control the performance of double-layer capacitors. Here, in operando small-angle neutron scattering (SANS) is used to directly detect ion movements into the nanopores of a conductive metal-organic framework (MOF) electrode under operating conditions. Neutron-scattering data reveals that most of the void space within the MOF is accessible to the solvent. Upon the addition of the electrolyte sodium triflate (NaOTf), the ions are adsorbed on the outer surface of the protrusions to form a 30 A layer instead of entering the ionophobic pores in the absence of an applied charging potential. The changes in scattering intensity when potentials are applied suggests the ion rearrangement in the micropores following different mechanisms depending on the electrode polarization. These observations shed insights on ion electrosorption in electrode materials.
Pseudoholomorphic quilts with figure eight singularity

We show that the novel figure eight singularity in a pseudoholomorphic quilt can be continuously removed when composition of Lagrangian correspondences is cleanly immersed. The proof of this result requires a collection of width-independent elliptic estimates that allow for non-standard complex structures on the domain.
Comparative Penning-Trap Tests of Lorentz and CPT Symmetry

The theoretical and experimental prospects for Lorentz- and CPT-violating quantum electrodynamics in Penning traps are reviewed in this work. With the recent reported results for the measurements of magnetic moments for both protons and antiprotons, improvements with factors of up to 3000 for the constraints of various coefficients for Lorentz and CPT violation are obtained.
Euler characteristics of Brill-Noether varieties

We prove an enumerative formula for the algebraic Euler characteristic of Brill-Noether varieties, parametrizing degree d and rank r linear series on a general genus g curve, with ramification profiles specified at up to two general points. Up to sign, this Euler characteristic is the number of standard set-valued tableaux of a certain skew shape with g labels. We use a flat degeneration via the Eisenbud-Harris theory of limit linear series, relying on moduli-theoretic advances of Osserman and Murray-Osserman; the count of set-valued tableaux is an explicit enumeration of strata of this degeneration.
An implementation of steepest-descent augmentation for linear programs

Abstract Generalizing the simplex method, circuit augmentation schemes for linear programs follow circuit directions through the interior of the underlying polyhedron. Steepest-descent augmentation is especially promising, but an implementation of the iterative scheme is a significant challenge. We work towards a viable implementation through a model in which a single linear program is updated dynamically to remain in memory throughout. Computational experiments exhibit dramatic improvements over a naive approach and reveal insight into the next steps required for large-scale computations.
The Nixon shock after forty years: the import surcharge revisited

On 15 August 1971, President Richard Nixon closed the gold window and imposed a 10% surcharge on all dutiable imports in an effort to force other countries to revalue their currencies against the dollar. The import surcharge was lifted four months later after the Smithsonian agreement led to new exchange rate parities. This paper examines the political, economic, and legal issues surrounding this use of trade sanctions to achieve exchange rate adjustments.
Quadratic Simulations of Merlin–Arthur Games

The known proofs of MA ⊆ PP incur a quadratic overhead in the running time. We prove that this quadratic overhead is necessary for black-box simulations; in particular, we obtain an oracle relative to which MA-TIME (t) ⊈ P-TIME (o(t2)). We also show that 2-sided-error Merlin–Arthur games can be simulated by 1-sided-error Arthur–Merlin games with quadratic overhead. We also present a simple, query complexity based proof (provided by Mika Goos) that there is an oracle relative to which MA ⊈ NPBPP (which was previously known to hold by a proof using generics).
Vv-Orionis - a Well-Behaved Early-Type Eclipsing Binary System

VV Orionis is a detached eclipsing binary system consisting of stars of spectral types B1 V and B4 V with a period of 1.d4854. There is also a third component whose orbital period about the eclipsing pair is about 120 days. In recent years there have been several new photoelectric and spectroscopic investigations of this system, and the results of these are compared. Both the geometric and photometric orbital elements appear to be well determined. VV Ori A appears to be of normal size and mass for its spectral class, but VV Ori B seems to be somewhat smaller than would be expected for a normal B4 V star. Linear limb-darkening coefficients are derived for VV Ori A, and these are in good agreement with theory. This system is of particular importance, because it is only one of very few earlytype systems for which reliable limb-darkening coefficients can be expected to be obtained. The contribution of the light of the third component to the system has also been determined, and it appears most likely that VV Ori C is a star of spectral type A3 V.
Optimal Taxation and Human Capital Policies over the Life Cycle

This paper derives optimal income tax and human capital policies in a life cycle model with risky human capital. The government faces asymmetric information regarding agents’ ability, its evolution, and labor supply. When the wage elasticity with respect to ability is increasing in human capital, the optimal subsidy involves less than full deductibility of human capital expenses on the tax base and falls with age. Income-contingent loans or a deferred deductibility scheme can implement the optimum. Numerical results suggest that full deductibility of expenses is close to optimal and that simple linear age-dependent policies perform very well.
Correlation between density of tunneling states and fragility of glasses

We present the evidence of a correlation between the density of tunneling states, derived from low temperature specific heats, and the fragility of glasses.
Resonant-cavity enhanced thermal emission

In this paper we present a vertical-cavity enhanced resonant thermal emitter---a highly directional, narrow-band, tunable, partially coherent thermal source. This device enhances thermal emittance of a metallic or any other highly reflective structure to unity near a cavity resonant frequency. The structure consists of a planar metallic surface (e.g., silver, tungsten), a dielectric layer on top of the metal that forms a vertical cavity, followed by a multilayer dielectric stack acting as a partially transparent cavity mirror. The resonant frequency can easily be tuned by changing the cavity thickness (thus shifting resonant emission peak), while the angle at which the maximum emittance appears can be tuned as well by changing the number of dielectric stack layers. The thermal emission exhibits an extremely narrow angular emission lobe, suggesting increased spatial coherence. Furthermore, we show that we can enhance the thermal emission of an arbitrarily low-emittance material, choosing a properly designed thermal cavity, to near unity.
Property Rights and Financial Development: The Legacy of Japanese Colonial Institutions

Several studies link development to institutions transplanted by European colonizers and here we extend this line of research to Asia. Japan imposed its system of well-defined property rights on some of its Asian colonies. In 1939, Japan began to register private land in its island colonies, an effort that was completed in Palau but interrupted elsewhere by World War II. Within Micronesia, robust economic development followed only in Palau where individual property rights were well defined. We show that well-defined property rights in Korea and Taiwan secured land taxation and enabled farmers to obtain bank loans for irrigation systems. Considering Japanese colonies, we use the presence or absence of a land survey as an instrument to identify the causal impact of new institutions. Our estimates show that property-defining institutions were important for economic development, results that are confirmed when using a similar approach with British Colonies in Asia.
26 – Nuclear explosions

Publisher Summary This chapter describes nuclear explosions, nuclear weapons proliferation and safeguards, disarmament, and the options for disposal of weapons material. The chapter reviews some important facts and ideas about nuclear explosions and their uses. In this context, the chapter distinguishes between nuclear power and nuclear weapons. It then identifies the technical aspects and strategic issues involved in the military use of nuclear processes. to the chapter then indicates the continued need for control of nuclear materials. Although spent fuel from power reactors contains plutonium, it is not the same as a nuclear weapon. The original atom bombs used U-235 and Pu, but the powerful modern weapons are based on the fusion of hydrogen isotopes. Intercontinental ballistic missiles from land and missiles from submarines make up the bulk of the arsenals of the U.S. and the former U.S.S.R. Continual efforts are made to prevent further proliferation of nuclear weapons.
A cohomology for foliated manifolds

for a e T(v A V ) , X1? . . . , Xk + 1 e T(T). Since the curvature tensor of V restricted to T is identically zero we have that d o d = 0. Denote the homology of this complex by F*(T; V). This is the cohomology of the Lie algebra of vector fields tangent to the foliation with coefficients in sections of the normal bundle, the representation being given by the connection [GF]. In general the groups F\x ; v) are not finitely generated (the complex is not elliptic) but they satisfy the following. (i) F* is a functor from the category of foliated manifolds and transverse maps to the category of abelian groups and homomorphisms. (ii) If ƒ : N -» M is an embedded transverse submanifold, we can define relative cohomology groups F*(T; v, ƒ) and obtain the usual long exact sequence. (iii) F* is an invariant of the diffeomorphism type of the foliation. However, F* is not an invariant of the integrable homotopy type of the foliation when M is an open manifold.
A Public Health Framework for COVID-19 Business Liability

Businesses that reopen amid the COVID-19 pandemic face potential legal liability to customers and workers who contract the coronavirus through those enterprises’ operations Federal and state lawmakers are actively considering proposals to narrow or expand such liability These proposals have important economic and public-health implications This article presents an analytical framework for evaluating liability regimes in the context of a communicable disease The framework highlights the contrasting public-health consequences of liability before and after a customer or worker is exposed to the virus Ex ante (before exposure), potential liability generates incentives for businesses to take precautions that reduce the risk of virus transmission Ex post (after exposure), liability fears may deter businesses from proactively informing customers and workers that they have been exposed to the virus through the business’s operations To minimize the potentially perverse ex-post consequences of liability without sacrificing significant ex-ante benefits, we propose a limited safe harbor from liability for businesses that promptly contact customers and workers after learning about a possible exposure The article also suggests changes to workers’ compensation rules that seek a balance between ex-ante benefits and ex-post costs
Plug-and-play, mix-and-match: a capital systems theory of digital technology platforms

Digital technology platforms have transformed the modern economy, disrupting existing industries and creating new ones. In this paper I synthesize Austrian capital theory with general systems theory to analyze why these digital platforms have had such a large and relatively rapid impact. In large part this impact arises from certain architectural features of digital technologies and networks, particularly modularity, which enables digital platforms to change their scale of operations and be adaptable to unknown and changing conditions. Modularity reduces the costs of combining and reconfiguring combinations of individual elements in networks. Austrian capital theory’s focus on the combination of specific capital elements in production thus provides a valuable lens through which to analyze digital technology platforms and the economic reasons for their large and rapid development.
Thermodynamic Integration in 3n Dimensions Without Biases or Alchemy for Protein Interactions

Thermodynamic integration (TI), a powerful formalism for computing the Gibbs free energy, has been implemented for many biophysical processes with alchemical schemes that require delicate human efforts to choose/design biasing potentials for sampling the desired biophysical events and to remove their artifactitious consequences afterwards. Theoretically, an alchemical scheme is exact but practically, an unsophisticated implementation of this exact formula can cause error amplifications. Small relative errors in the input parameters can be amplified many times in their propagation into the computed free energy [due to subtraction of similar numbers such as (105±5)‒(100±5)=5±7]. In this paper, we present an unsophisticated implementation of TI in 3n dimensions (3nD) (n=1,2,3...) for the potential of mean force along a 3nD path connecting one state in the bound state ensemble to one state in the unbound state ensemble. Fluctuations in these 3nD are integrated in the bound and unbound state ensembles but not along the 3nD path. Using TI3nD, we computed the standard binding free energies of three protein complexes: trometamol in Salmonella effector SpvD (n=1), biotin-avidin (n=2), and Colicin E9 endonuclease with cognate immunity protein Im9 (n=3). We employed three different protocols in three independent computations of E9-Im9 to show TI3nD’s robustness. We also computed the hydration energies of ten biologically relevant compounds (n=1 for water, acetamide, urea, glycerol, trometamol, ammonium and n=2 for erythritol, 1,3-propanediol, xylitol, biotin). Each of the 15 computations is accomplishable within one (for hydration) to ten (for E9-Im9) days on an inexpensive GPU workstation. The computed results all agree with the available experimental data.
The Insulin Receptor Adaptor IRS2 is an APC/C Substrate That Promotes Cell Cycle Protein Expression and a Robust Spindle Assembly Checkpoint.

Insulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1. Consistent with the APC/C's role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.
Human iPSC-Derived Cardiomyocytes , are Susceptible to SARS-CoV-2 Infection

Summary Coronavirus disease 2019 (COVID-19) is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is defined by respiratory symptoms, but cardiac complications including viral myocarditis are also prevalent. Although ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well understood. Here, we utilize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and RNA sequencing demonstrate that SARS-CoV-2 can enter hiPSC-CMs via ACE2. Viral replication and cytopathic effect induce hiPSC-CM apoptosis and cessation of beating after 72 h of infection. SARS-CoV-2 infection activates innate immune response and antiviral clearance gene pathways, while inhibiting metabolic pathways and suppressing ACE2 expression. These studies show that SARS-CoV-2 can infect hiPSC-CMs in vitro, establishing a model for elucidating infection mechanisms and potentially a cardiac-specific antiviral drug screening platform.
Talk to Papers: Bringing Neural Question Answering to Academic Search

We introduce Talk to Papers, which exploits the recent open-domain question answering (QA) techniques to improve the current experience of academic search. It’s designed to enable researchers to use natural language queries to find precise answers and extract insights from a massive amount of academic papers. We present a large improvement over classic search engine baseline on several standard QA datasets and provide the community a collaborative data collection tool to curate the first natural language processing research QA dataset via a community effort.
Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity

Abstract Background Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. Genetic information can improve drug discovery rates by facilitating the identification of novel biological targets and potential drugs for repurposing. Methods The present study utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify additional risk genes for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280). iRIGS incorporates several genomic features and closeness of these genes in network space to compute a posterior probability for protein coding genes near each SNP. We subsequently used the Target Central Resource Database to search for drug-protein interactions for these newly identified genes and previously identified risk genes for alcohol consumption. Results We identified several genes that are novel contributions to the previously published alcohol consumption GWAS. Namely, ACVR2A, which is critical for liver function and linked to anxiety and cocaine self-administration, and PRKCE, which has been linked to alcohol self-administration. Notably, only a minority of the SNPs (18.4 %) were linked to genes with confidence ( > 0 .75), underscoring the need to apply multiple methods to assign function to loci. Finally, some previously identified risk genes for alcohol consumption code for proteins that are implicated in liver function and are targeted by drugs, some of which are candidates for managing hepatotoxicity. Conclusions This study demonstrates the value of incorporating regulatory information and drug-protein interaction data to highlight additional molecular targets and drug repurposing candidates for treating AUD and ALD.
Coupled Time‐lapse Full Waveform Inversion for Subsurface Flow Problems using Intrusive Automatic Differentiation

We describe a novel framework for estimating subsurface properties, such as rock permeability and porosity, from time-lapse observed seismic data by coupling full-waveform inversion, subsurface flow processes, and rock physics models. For the inverse modeling, we handle the back-propagation of gradients by an intrusive automatic differentiation strategy that offers three levels of user control: (1) at the wave physics level, we adopted the discrete adjoint method in order to use our existing high-performance FWI code; (2) at the rock physics level, we used built-in operators from the $\texttt{TensorFlow}$ backend; (3) at the flow physics level, we implemented customized PDE operators for the potential and nonlinear saturation equations. These three levels of gradient computation strike a good balance between computational efficiency and programming efficiency, and when chained together, constitute a coupled inverse system. We use numerical experiments to demonstrate that (1) the three-level coupled inverse problem is superior in terms of accuracy to a traditional decoupled inversion strategy; (2) it is able to simultaneously invert for parameters in empirical relationships such as the rock physics models; and (3) the inverted model can be used for reservoir performance prediction and reservoir management/optimization purposes.
Functional limitation in later-life: the impact of sips, socialization, and sadness

Objectives: Findings on the health impact of moderate alcohol use in later-life have been discrepant. Unaddressed mechanisms of action and validity concerns may contribute to contrasting results. S...
Morphological Awareness Skills of Second- and Third-Grade Students With and Without Speech Sound Disorders

Purpose Morphological awareness is the ability to consciously manipulate the smallest units of meaning in language. Morphological awareness contributes to success with literacy skills for children with typical language and those with language impairment. However, little research has focused on the morphological awareness skills of children with speech sound disorders (SSD), who may be at risk for literacy impairments. No researcher has examined the morphological awareness skills of children with SSD and compared their skills to children with typical speech using tasks representing a comprehensive definition of morphological awareness, which was the main purpose of this study. Method Thirty second- and third-grade students with SSD and 30 with typical speech skills, matched on age and receptive vocabulary, completed four morphological awareness tasks and measures of receptive vocabulary, real-word reading, pseudoword reading, and word-level spelling. Results Results indicated there was no difference between the morphological awareness skills of students with and without SSD. Although morphological awareness was moderately to strongly related to the students' literacy skills, performance on the morphological awareness tasks contributed little to no additional variance to the children's real-word reading and spelling skills beyond what was accounted for by pseudoword reading. Conclusions Findings suggest that early elementary-age students with SSD may not present with concomitant morphological awareness difficulties and that the morphological awareness skills of these students may not play a unique role in their word-level literacy skills. Limitations and suggestions for future research on the morphological awareness skills of children with SSD are discussed.
Genetic architecture of complex traits and disease risk predictors

Genomic prediction of complex human traits (e.g., height, cognitive ability, bone density) and disease risks (e.g., breast cancer, diabetes, heart disease, atrial fibrillation) has advanced considerably in recent years. Using data from the UK Biobank, predictors have been constructed using penalized algorithms that favor sparsity: i.e., which use as few genetic variants as possible. We analyze the specific genetic variants (SNPs) utilized in these predictors, which can vary from dozens to as many as thirty thousand. We find that the fraction of SNPs in or near genic regions varies widely by phenotype. For the majority of disease conditions studied, a large amount of the variance is accounted for by SNPs outside of coding regions. The state of these SNPs cannot be determined from exome-sequencing data. This suggests that exome data alone will miss much of the heritability for these traits-i.e., existing PRS cannot be computed from exome data alone. We also study the fraction of SNPs and of variance that is in common between pairs of predictors. The DNA regions used in disease risk predictors so far constructed seem to be largely disjoint (with a few interesting exceptions), suggesting that individual genetic disease risks are largely uncorrelated. It seems possible in theory for an individual to be a low-risk outlier in all conditions simultaneously.
Calcium and osteoporosis

It seems we are about back to square one and the question that still needs an answer is whether diet, or calcium intake, plays a really significant role in the etiology of osteoporosis, especially hip fractures. Logic may tell us that calcium intake ought to be important but the evidence is weak.
Internal Geometry Effects on Inherent Damping Performance of Additively Manufactured Components

A recently developed vibration suppressing design approach that leverages the laser powder bed fusion (LPBF) additive manufacturing process is under investigation for damping performance improvemen...
ct-fuzz: Fuzzing for Timing Leaks

Testing-based methodologies like fuzzing are able to analyze complex software which is not amenable to traditional formal approaches like verification, model checking, and abstract interpretation. Despite enormous success a texposing countless security vulnerabilities in many popular software projects, applications of testing-based approaches mainly targeted checking traditional safety properties like memory safety. While unquestionably important, this class of properties does not precisely characterize other important security aspects such as information leakage, e.g., through side channels.In this work we extend testing-based software analysis methodologies to two-safety properties, which enables the precise discovery of information leaks in complex software. In particular, we present the ct-fuzz tool, which lends coverage-guided grey box fuzzers the ability to detect two safety property violations. Our approach is capable of exposing violations to any two-safety property expressed a sequality between two program traces. Empirically, we demonstrate that ct-fuzz swiftly reveals timing leaks in popular cryptographic implementations.
On the Feasibility of Exploiting Traffic Collision Avoidance System Vulnerabilities

Traffic Collision Avoidance Systems (TCAS) are safety-critical systems required on most commercial aircrafts in service today. However, TCAS was not designed to account for malicious actors. While in the past it may have been infeasible for an attacker to craft radio signals to mimic TCAS signals, attackers today have access to open-source digital signal processing software, like GNU Radio, and inexpensive software defined radios (SDR) that enable the transmission of spurious TCAS messages. In this paper, methods, both qualitative and quantitative, for analyzing TCAS from an adversarial perspective are presented. To demonstrate the feasibility of inducing near mid-air collisions between current day TCAS-equipped aircraft, an experimental Phantom Aircraft generator is developed using GNU Radio and an SDR against a realistic threat model.
Every planar set has a conformally removable subset with the same Hausdorff dimension

In this paper we show that given any compact set $E \subset \hat{\mathbb{C}}$, we can always find a conformally removable subset with the same Hausdorff dimension as $E$.