Showing papers by "University of Pennsylvania published in 2022"

An on-chip photonic deep neural network for image classification

Abstract: Deep neural networks with applications from computer vision to medical diagnosis1-5 are commonly implemented using clock-based processors6-14, in which computation speed is mainly limited by the clock frequency and the memory access time. In the optical domain, despite advances in photonic computation15-17, the lack of scalable on-chip optical non-linearity and the loss of photonic devices limit the scalability of optical deep networks. Here we report an integrated end-to-end photonic deep neural network (PDNN) that performs sub-nanosecond image classification through direct processing of the optical waves impinging on the on-chip pixel array as they propagate through layers of neurons. In each neuron, linear computation is performed optically and the non-linear activation function is realized opto-electronically, allowing a classification time of under 570 ps, which is comparable with a single clock cycle of state-of-the-art digital platforms. A uniformly distributed supply light provides the same per-neuron optical output range, allowing scalability to large-scale PDNNs. Two-class and four-class classification of handwritten letters with accuracies higher than 93.8% and 89.8%, respectively, is demonstrated. Direct, clock-less processing of optical data eliminates analogue-to-digital conversion and the requirement for a large memory module, allowing faster and more energy efficient neural networks for the next generations of deep learning systems.

Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity

Abstract: Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J m−2) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with ‘Janus’ surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications. A hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a tendon-adhesive surface on the other side boosts tissue healing in rat models of tendon rupture.

The Pantheon+ Analysis: The Full Data Set and Light-curve Release

Abstract: Abstract Here we present 1701 light curves of 1550 unique, spectroscopically confirmed Type Ia supernovae (SNe Ia) that will be used to infer cosmological parameters as part of the Pantheon+ SN analysis and the Supernovae and H 0 for the Equation of State of dark energy distance-ladder analysis. This effort is one part of a series of works that perform an extensive review of redshifts, peculiar velocities, photometric calibration, and intrinsic-scatter models of SNe Ia. The total number of light curves, which are compiled across 18 different surveys, is a significant increase from the first Pantheon analysis (1048 SNe), particularly at low redshift ( z ). Furthermore, unlike in the Pantheon analysis, we include light curves for SNe with z < 0.01 such that SN systematic covariance can be included in a joint measurement of the Hubble constant ( H 0 ) and the dark energy equation-of-state parameter ( w ). We use the large sample to compare properties of 151 SNe Ia observed by multiple surveys and 12 pairs/triplets of “SN siblings”—SNe found in the same host galaxy. Distance measurements, application of bias corrections, and inference of cosmological parameters are discussed in the companion paper by Brout et al., and the determination of H 0 is discussed by Riess et al. These analyses will measure w with ∼3% precision and H 0 with ∼1 km s −1 Mpc −1 precision.

Age-specific rate of severe and critical SARS-CoV-2 infections estimated with multi-country seroprevalence studies

Abstract: Knowing the age-specific rates at which individuals infected with SARS-CoV-2 develop severe and critical disease is essential for designing public policy, for infectious disease modeling, and for individual risk evaluation.In this study, we present the first estimates of these rates using multi-country serology studies, and public data on hospital admissions and mortality from early to mid-2020. We combine these under a Bayesian framework that accounts for the high heterogeneity between data sources and their respective uncertainties. We also validate our results using an indirect method based on infection fatality rates and hospital mortality data.Our results show that the risk of severe and critical disease increases exponentially with age, but much less steeply than the risk of fatal illness. We also show that our results are consistent across several robustness checks.A complete evaluation of the risks of SARS-CoV-2 for health must take non-fatal disease outcomes into account, particularly in young populations where they can be 2 orders of magnitude more frequent than deaths.

Prosocial behavior and reputation: When does doing good lead to looking good?

Abstract: One reason people engage in prosocial behavior is to reap the reputational benefits associated with being seen as generous. Yet, there isn't a direct connection between doing good deeds and being seen as a good person. Prosocial actors are often met with suspicion and sometimes castigated as disingenuous braggarts, empty virtue-signalers, or holier-than-thou hypocrites. In this article, we review recent research on how people evaluate those who engage in prosocial behavior and identify key factors that influence whether observers will praise or denigrate a prosocial actor for doing a good deed.

Fabrication of MSC-laden composites of hyaluronic acid hydrogels reinforced with MEW scaffolds for cartilage repair

Abstract: Hydrogels are of interest in cartilage tissue engineering due to their ability to support the encapsulation and chondrogenesis of mesenchymal stromal cells (MSCs). However, features such as hydrogel crosslink density, which can influence nutrient transport, nascent matrix distribution, and the stability of constructs during and after implantation must be considered in hydrogel design. Here, we first demonstrate that more loosely crosslinked (i.e., softer, ~2 kPa) norbornene-modified hyaluronic acid (NorHA) hydrogels support enhanced cartilage formation and maturation when compared to more densely crosslinked (i.e., stiffer, ~6-60 kPa) hydrogels, with a >100-fold increase in compressive modulus after 56 days of culture. While soft NorHA hydrogels mature into neocartilage suitable for the repair of articular cartilage, their initial moduli are too low for handling and they do not exhibit the requisite stability needed to withstand the loading environments of articulating joints. To address this, we reinforced NorHA hydrogels with polycaprolactone (PCL) microfibers produced via melt-electrowriting (MEW). Importantly, composites fabricated with MEW meshes of 400 m spacing increased the moduli of soft NorHA hydrogels by ~50-fold while preserving the chondrogenic potential of the hydrogels. There were minimal differences in chondrogenic gene expression and biochemical content (e.g., DNA, GAG, collagen) between hydrogels alone and composites, whereas the composites increased in compressive modulus to ~350 kPa after 56 days of culture. Lastly, integration of composites with native tissue was assessed ex vivo; MSC-laden composites implanted after 28 days of pre-culture exhibited increased integration strengths and contact areas compared to acellular composites. This approach has great potential towards the design of cell-laden implants that possess both initial mechanical integrity and the ability to support neocartilage formation and integration for cartilage repair.

The central dogma and cosmological horizons

Abstract: The central dogma of black hole physics -- which says that from the outside a black hole can be described in terms of a quantum system with exp$(\text{Area}/4G_N)$ states evolving unitarily -- has recently been supported by computations indicating that the interior of the black hole is encoded in the Hawking radiation of the exterior. In this paper, we probe whether such a dogma for cosmological horizons has any support from similar computations. The fact that the de Sitter bifurcation surface is a minimax surface (instead of a maximin surface) causes problems with this interpretation when trying to import calculations analogous to the AdS case. This suggests anchoring extremal surfaces to the horizon itself, where we formulate a two-sided extremization prescription and find answers consistent with general expectations for a quantum theory of de Sitter space: vanishing total entropy, an entropy of $A/4G_N$ when restricting to a single static patch, an entropy of a subregion of the horizon which grows as the region size grows until an island-like transition at half the horizon size when the entanglement wedge becomes the entire static patch interior, and a de Sitter version of the Hartman-Maldacena transition.

Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer

Abstract: Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies.Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.

Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications

Abstract: Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a pivotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. These pose major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.

The unequal burden of the Covid-19 pandemic: Capturing racial/ethnic disparities in US cause-specific mortality

Abstract: Despite a growing body of literature focused on racial/ethnic disparities in Covid-19 mortality, few previous studies have examined the pandemic's impact on 2020 cause-specific mortality by race and ethnicity. This paper documents changes in mortality by underlying cause of death and race/ethnicity between 2019 and 2020. Using age-standardized death rates, we attribute changes for Black, Hispanic, and White populations to various underlying causes of death and show how these racial and ethnic patterns vary by age and sex. We find that although Covid-19 death rates in 2020 were highest in the Hispanic community, Black individuals faced the largest increase in all-cause mortality between 2019 and 2020. Exceptionally large increases in mortality from heart disease, diabetes, and external causes of death accounted for the adverse trend in all-cause mortality within the Black population. Within Black and White populations, percentage increases in all-cause mortality were similar for men and women, as well as for ages 25-64 and 65+. Among the Hispanic population, however, percentage increases in mortality were greatest for working-aged men. These findings reveal that the overall impact of the pandemic on racial/ethnic disparities in mortality was much larger than that captured by official Covid-19 death counts alone.

The Impact of Incarceration on Recidivism

Abstract: The US prison population stands at 1.43 million persons, with an additional 740,000 persons in local jails. Nearly all will eventually return to society. This review examines the available evidence...

Electronic, elastic, and thermal properties, fracture toughness, and damage tolerance of TM5Si3B (TM = V and Nb) MAB phases

Abstract: The first-principles calculations are employed herein to predict the electronic, elastic, and thermal properties, fracture toughness, and damage tolerance of TM5Si3B (TM = V and Nb) MAB phases. According to formation enthalpy, phonon dispersion and single-crystal elastic constants, V5Si3B and Nb5Si3B are thermodynamically, dynamically, and mechanically stable. Pugh's ratio, Cauchy pressure, hardness, fracture toughness, and elastic anisotropic indexes are calculated, and V5Si3B and Nb5Si3B are brittle, tolerant to damage, and elastic anisotropic. The possible cleavage plane and slip systems are the (0001) plane and < 11¯00 > |{112¯0} and < 112¯0 > |{0001}, respectively, which is determined by the strong TMII-Si, TM-B, and TMI-Si bonds parallel to the (0001) plane. Finally, lattice thermal conductivity, minimum lattice thermal conductivity, and dependence of heat capacity on temperature are predicted.

The Pantheon+ Analysis: SuperCal-fragilistic Cross Calibration, Retrained SALT2 Light-curve Model, and Calibration Systematic Uncertainty

Abstract: Abstract We present a recalibration of the photometric systems in the Pantheon+ sample of Type Ia supernovae (SNe Ia) including those in the SH0ES distance-ladder measurement of H 0 . We utilize the large and uniform sky coverage of the public Pan-STARRS stellar photometry catalog to cross calibrate against tertiary standards released by individual SN Ia surveys. The most significant updates over the “SuperCal” cross calibration used for the previous Pantheon and SH0ES analyses are: (1) expansion of the number of photometric systems (now 25) and filters (now 105), (2) solving for all filter offsets in all systems simultaneously to produce a calibration uncertainty covariance matrix for cosmological-model constraints, and (3) accounting for the change in the fundamental flux calibration of the Hubble Space Telescope CALSPEC standards from previous versions on the order of 1.5% over a Δ λ of 4000 Å. We retrain the SALT2 model and find that our new model coupled with the new calibration of the light curves themselves causes a net distance modulus change ( d μ / dz ) of 0.04 mag over the redshift range 0 < z < 1. We introduce a new formalism to determine the systematic impact on cosmological inference by propagating the covariance in the fitted calibration offsets through retraining simultaneously with light-curve fitting and find a total calibration uncertainty impact of σ w = 0.013; roughly half the size of the sample statistical uncertainty. Similarly, we find the systematic SN calibration contribution to the SH0ES H 0 uncertainty is less than 0.2 km s −1 Mpc −1 , suggesting that SN Ia calibration cannot resolve the current level of the “Hubble Tension.”

Myosin modulators: emerging approaches for the treatment of cardiomyopathies and heart failure

Abstract: Myosin modulators are a novel class of pharmaceutical agents that are being developed to treat patients with a range of cardiomyopathies. The therapeutic goal of these drugs is to target cardiac myosins directly to modulate contractility and cardiac power output to alleviate symptoms that lead to heart failure and arrhythmias, without altering calcium signaling. In this Review, we discuss two classes of drugs that have been developed to either activate (omecamtiv mecarbil) or inhibit (mavacamten) cardiac contractility by binding to β-cardiac myosin (MYH7). We discuss progress in understanding the mechanisms by which the drugs alter myosin mechanochemistry, and we provide an appraisal of the results from clinical trials of these drugs, with consideration for the importance of disease heterogeneity and genetic etiology for predicting treatment benefit.

Recent advances in bacterial biosensing and bioremediation of cadmium pollution: a mini-review.

Abstract: Cadmium (Cd) pollution has become a global environmental issue because Cd gets easily accumulated and translocated in the food chain, threatening human health. Considering the detrimental effects and non-biodegradability of environmental Cd, this is an urgent issue that needs to be addressed through the development of robust, cost-effective, and eco-friendly green routes for monitoring and remediating toxic levels of Cd. This article attempts to review various bacterial approaches toward biosensing and bioremediation of Cd in the environment. This review focuses on the recent development of bacterial cell-based biosensors for the detection of bioavailable Cd and the bioremediation of toxic Cd by natural or genetically-engineered bacteria. The present limitations and future perspectives of these available bacterial approaches are outlined. New trends for integrating synthetic biology and metabolic engineering into the design of bacterial biosensors and bioadsorbers are additionally highlighted.