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Intratumoral heterogeneity poses a significant hurdle for cancer treatment, yet is under-characterized in the context of tumor invasion. Cancer cells from solid tumors can invade through two predominant modes: collective invasion, whereby cancer cells invade in multi-cellular packs or streams marked by intact cell-cell junctions; and single-cell invasion, whereby cells invade independently without intercellular adhesion. We have observed that collective and single-cell invasion co-occur within the same tumor microenvironment in triple-negative breast cancer, suggesting that invasive heterogeneity supports cooperative behavior between tumor subpopulations. To test this, we used a novel, published technique developed by the lab (SaGA) to isolate pure subpopulations of 4T1 cells that collectively invade (collectives) or single cells that invade alone (singles). 3-D spheroids of SaGA-purified collectives and singles exhibited almost exclusively collective and single-cell invasion, respectively, and these invasive phenotypes were retained over multiple passages. Integration of RNA sequencing and methylation array data obtained from RNA and DNA isolates, respectively, of collectives and singles revealed that collectives exhibit drastic overexpression and promoter hypomethylation of two laminin genes that form the laminin-332 complex, Lama3 and Lamc2. Additionally, an unbiased proteomic analysis of secreted proteins also revealed an overabundance of these laminins in collectives media. We found that singles have increased expression of integrin α6 and β4, which together have been found to specifically bind to laminin-332 to activate the Rac1 GTPase. Interestingly, our RNA sequencing data revealed a binary overexpression of a Rac1 GTPase, Prex1 in singles, suggesting that singles have enhanced Rac1 activation when compared to collectives with the potential for hyperactivation upon laminin-332 binding. Indeed, laminin-332 resulted in higher GTP-bound Rac1 in singles and subsequently increased invasion of singles in 3-D models. Additionally, laminin-332 induced cell elongation at the leading edge of singles spheroids, which was reversable by treatment with a Rac1 inhibitor. Together, our data suggests that distinct subpopulations amidst a heterogeneous tumor cooperate via laminin-332 and Rac1 to facilitate tumor invasion in metastatic triple-negative breast cancer. Citation Format: Sung Bo (Joseph) Yoon, Janna Mouw, Luxiao Chen, Hao Wu, Adam Marcus. Invasively distinct subpopulations cooperate via a laminin-332/Rac1 axis in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-01.

Liver kinase B1 (LKB1)–inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77–1726, inhibits dihydroorotate dehydrogenase, which is essential for de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor–derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G1 cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.

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Experiments have recently placed stringent constraints on the most natural incarnations of weakly interacting massive particles (WIMPs), which motivates exploring alternative dark matter (DM) candidates. One interesting possibility is that DM has mass at the MeV scale. Indirect detection of gamma rays produced in its self-annihilations is a particularly timely subject since proposed telescopes such as e-ASTROGAM are poised to revolutionize our understanding of the MeV gamma ray spectrum.This thesis presents a comprehensive analysis of how existing and future gamma ray detectors can probe three realistic simplified models of MeV DM. After employing chiral perturbation theory to write down effective Lagrangians for the DM's interactions with mesons, the relevant strongly interacting degrees of freedom at the MeV scale, the gamma-ray spectra for DM annihilation are computed in detail. The final state radiation from annihilation into leptons and charged pions is calculated exactly, and contributions to the charged pion decay spectrum are accounted for at each step of the decay chain. The electron and positron spectra are also determined in these models and used to derive accurate cosmic microwave background (CMB) constraints. A common concern is that CMB constraints rule out the possibility of detecting photons from MeV DM. This is found not to be the case over most of the parameter space of the simplified models, with e-ASTROGAM providing stronger constraints even when the DM annihilates in an s-wave. For p-wave DM, e-ASTROGAM will place bounds approaching the thermal relic cross section.

Cuboctahedral coordination cages of the general formula [Pd12L24]24+ (L = low-symmetry ligand) were analyzed theoretically and experimentally. With 350 696 potential isomers, the structural space of these assemblies is vast. Orientational self-sorting refers to the preferential formation of particular isomers within the pool of potential structures. Geometric and computational analyses predict the preferred formation of cages with a cis arrangement at the metal centers. This prediction was corroborated experimentally by synthesizing a [Pd12L24]24+ cage with a bridging 3-(4-(pyridin-4-yl)phenyl)pyridine ligand. A crystallographic analysis of this assembly showed exclusive cis coordination of the 3- and the 4-pyridyl donor groups at the Pd2+ ions.

The accuracy of data-driven predictive mineral prospectivity models relies heavily on the training datasets used. These models are usually trained using data for “known” deposit locations as well as “non-deposit” locations that are based on randomly generated point patterns. In this study, data related to the Seabridge Gold Inc Iskut project, an epithermal Au deposit in northwestern British Columbia (BC), Canada, are used to test the utility of data-driven mineral prospectivity modeling. The input spatial dataset is comprised mostly of publicly available data. Data for 18 vein and epithermal Au known mineral occurrences (KMO) are obtained from the BC Geological Survey’s MINFILE repository and selected as training deposit locations. A total of eleven sets of non-deposit locations (NDL) were also created, including one set of selected non-prospective KMO for Au deposits from the MINFILE and ten sets of random point patterns. Given the scale of this study, most of the KMO recorded on the property are of the epithermal deposit type. Hence, they could not be used as a selection criterion. Data-driven mineral potential models are generated using the random forest (RF) algorithm and trained on multiple data sets. The comparison of RF models demonstrated that using non-prospective KMO generates more accurate predictions than the random point pattern. The produced mineral prospectivity maps delineated multiple areas with higher discovery potential, which matched viable targets for the Au-Cu epithermal-porphyry system identified through previous Seabridge Gold Inc. (Toronto, ON, Canada) field reconnaissance and drilling programs.

Objective Identify key features of an enduring group exercise program for people with Parkinson’s disease (PD) by exploring experiences of participants, student assistants and the exercise instructor through a convergent mixed methods design. Methods Fourteen people with PD (modified Hoehn & Yahr: 1–3.5) who regularly participated in a group exercise program (≥ 50% of classes for ≥ 1 year) were interviewed to explore their perceptions of the program. The exercise instructor was also interviewed and weekly written reflections were collected from 18 undergraduate student assistants. Using a grounded theory approach, interviews and written reflections were thematically analyzed via qualitative content analysis. Quantitative data from the Physical Fitness and Exercise Activity Levels of Older Adults Scale were used as part of a convergent mixed-methods design to move towards theory formation. Results Thematic analysis of the PD participant interviews revealed 4 themes: 1) Quality of the program, 2) Social interactions, 3) Facilitators to exercise, 4) Barriers to exercise. The exercise instructor interview revealed 2 themes: individualization and functionality of exercises, and creating a nurturing atmosphere. Themes from students’ data included student learning, and positive in-class experiences. Means (sd) were 1.6 (0.5) for facilitators and 3.0 (0.5) for barriers subscales (1=strongly agree to 4=strongly disagree). Conclusion These varied sources of data converge to identify and characterize key features of an enduring group exercise program for people with PD: a positive and nurturing environment, varied and individually tailored exercise content, and the importance of social cohesion. These findings also highlight the critical role of multiple stakeholders in fostering an environment that facilitates long-term adherence to group exercise.

We prove that there exist bipartite Ramanujan graphs of every degree and every number of vertices. The proof is based on analyzing the expected characteristic polynomial of a union of random perfect matchings, and involves three ingredients: (1) a formula for the expected characteristic polynomial of the sum of a regular graph with a random permutation of another regular graph, (2) a proof that this expected polynomial is real rooted and that the family of polynomials considered in this sum is an interlacing family, and (3) strong bounds on the roots of the expected characteristic polynomial of a union of random perfect matchings, established using the framework of finite free convolutions we recently introduced.

More than 20 papers about COVID-19 have been retracted at the time of this writing. It is premature, however, to conclude that such work is being retracted at higher rates than the rest of the literature.

This paper describes a series of research seminars investigating the contemporary capacities of architectural ornamentation in the context of computational design and digital fabrication technologies. The pedagogy explores potential overlaps between ornamental systems and logics of performance-driven design, challenging students to formulate a critical agenda vis-a-vis the relationship between the two. How can material assemblies produce innovative, symbolic, or communicative visual effects while also addressing specific performance criteria? What kinds of new aesthetic, figural, representational, expressive, and spatial qualities can emerge from such a synthetic approach?

We sharpen the constant in the KS 2 {\mathrm{KS}_{2}} Conjecture of Weaver [31] that was given by Marcus, Spielman and Srivastava [28] in their solution of the Kadison–Singer problem. We then apply this result to prove optimal asymptotic bounds on the size of partitions in the Feichtinger Conjecture.

Crowdsourcing refers to solving large problems by involving human workers that solve component sub-problems or tasks. In data crowdsourcing, the problem involves data acquisition, management, and analysis. In this paper, we provide an overview of data crowdsourcing, giving examples of problems that the authors have tackled, and presenting the key design steps involved in implementing a crowdsourced solution. We also discuss some of the open challenges that remain to be solved.

Previous studies have shown that sodium bicarbonate ingestion may enhance intense exercise performance, but may also cause severe gastrointestinal distress. The purpose of this study was to determine whether a modified sodium bicarbonate (SB) ingestion protocol would elevate serum bicarbonate concentration more than previous methods without causing gastrointestinal distress. In randomized order, seven (5 men, 2 women) elite middle-distance runners ingested either placebo, Modified SB (600 mg·kg− 1 over 19.5 h), or Acute SB (300 mg·kg− 1) in opaque gelatin capsules. Baseline and post-ingestion blood samples were analyzed for bicarbonate, pH, sodium, hematocrit, and lactate. Repeated measures ANOVA (2 time points × 3 conditions) were analyzed to determine differences in serum bicarbonate, lactate, sodium, blood pH, and hematocrit. Gastrointestinal distress was assessed via self-report on a Likert scale of 1–10. Simple (condition) and repeated (time) within-participant contrasts were used to determine the location of any statistically significant main and interaction effects (p ≤ 0.05). Both Modified SB (7.6 mmol·L− 1, p

As people increasingly work different jobs, the respon-sibility of building long-term career satisfaction and stability increasingly falls more on the workers rather than individual employers. With technologies playing a central role in how people choose and access employ-ment opportunities, it is necessary to understand how online technologies are shaping career development. We bring together leading human-computer interaction researchers, industry members, and community organ-izers, who have worked with systems and people across the socio-economic spectrum during the career devel-opment process. We will discuss research on the role of online technologies in career development, including but not limited to topics in crowd work, social media sites, and freelance work sites.

These lecture notes are meant to accompany two lectures given at the CDM 2016 conference, about the Kadison-Singer Problem. They are meant to complement the survey by the same authors (along with Spielman) which appeared at the 2014 ICM. In the first part of this survey we will introduce the Kadison-Singer problem from two perspectives ($C^*$ algebras and spectral graph theory) and present some examples showing where the difficulties in solving it lie. In the second part we will develop the framework of interlacing families of polynomials, and show how it is used to solve the problem. None of the results are new, but we have added annotations and examples which we hope are of pedagogical value.

OBJECT Over the last decade, image guidance systems have been widely adopted in neurosurgery. Nonetheless, the evidence supporting the use of these systems in surgery remains limited. The aim of this study was to compare simultaneously the effectiveness and safety of various image guidance systems against that of standard surgery. METHODS In this preclinical, randomized study, 50 novice surgeons were allocated to one of the following groups: 1) no image guidance, 2) triplanar display, 3) always-on solid overlay, 4) always-on wire mesh overlay, and 5) on-demand inverse realism overlay. Each participant was asked to identify a basilar tip aneurysm in a validated model head. The primary outcomes were time to task completion (in seconds) and tool path length (in mm). The secondary outcomes were recognition of an unexpected finding (i.e., a surgical clip) and subjective depth perception using a Likert scale. RESULTS The time to task completion and tool path length were significantly lower when using any form of image guidance compared with no image guidance (p < 0.001 and p = 0.003, respectively). The tool path distance was also lower in groups using augmented reality compared with triplanar display (p = 0.010). Always-on solid overlay resulted in the greatest inattentional blindness (20% recognition of unexpected finding). Wire mesh and on-demand overlays mitigated, but did not negate, inattentional blindness and were comparable to triplanar display (40% recognition of unexpected finding in all groups). Wire mesh and inverse realism overlays also resulted in better subjective depth perception than always-on solid overlay (p = 0.031 and p = 0.008, respectively). CONCLUSIONS New augmented reality platforms may improve performance in less-experienced surgeons. However, all image display modalities, including existing triplanar displays, carry a risk of inattentional blindness.

Three operations on eigenvalues of real/complex/quaternion (corresponding to β=1,2,4⁠) matrices, obtained from cutting out principal corners, adding, and multiplying matrices, can be extrapolated to general values of β>0 through associated special functions. We show that the β→∞ limit for these operations leads to the finite free projection, additive convolution, and multiplicative convolution, respectively. The limit is the most transparent for cutting out the corners, where the joint distribution of the eigenvalues of principal corners of a uniformly-random general β self-adjoint matrix with fixed eigenvalues is known as the β-corners process. We show that as β→∞ these eigenvalues crystallize on an irregular lattice consisting of the roots of derivatives of a single polynomial. In the second order, we observe a version of the discrete Gaussian Free Field put on top of this lattice, which provides a new explanation as to why the (continuous) Gaussian Free Field governs the global asymptotics of random matrix ensembles. ©2020, NSF (Grant DMS-1407562), NSF (Grant DMS-1664619)

Buoyant Ecologies is a collaborative research platform that brings together architects, marine ecologists, and fabricators to address the implications of sea level rise through innovative approaches to designing and constructing resilient waterfront structures. This paper describes how the project’s unique collaborative structure incorporates expertise from ecological researchers and industry manufacturers to promote recursive, interdisciplinary feedback loops between speculative thinking and pragmatic knowledge.

The Courageous Lake Greenstone Belt (CLGB) is hosted in the Yellowknife Supergroup of the Central Slave Province, NWT, Canada: a fertile gold district that includes the former Giant, Con and Lupin orogenic gold mines. The largest deposit in the CLGB is the FAT deposit, which has a proven and probable reserve of 91MT at 2.20gpt gold owned by Seabridge Gold Inc. The FAT deposit differs from other gold deposits in the Yellowknife Supergroup in that deformation and shear textures are intermittent, and where present, deformation does not correlate spatially with mineralisation. The CLGB formed as a volcanic succession that was deposited on a 3218 Ma sodic granitoid gneissic complex. Periodic volcanism commencing at 2660 Ma formed an extrusive cycle of mafic flows to rhyolitic tuffs. The felsic units reach a maximum (post compression) thickness of 1800m proximal to the FAT deposit. Volcanic textures of the rocks hosting the FAT deposit are well preserved sub-aerial lapilli and lesser amounts of ash and bomb tuff. There is periodic intercalation with aqeuously reworked beds. These are overlain by greywacke turbiditic rocks. Three distinct structural/metamorphic events have affected the Courageous Lake Greenstone Belt: 1. compression and vertical tilting of stratigraphy and associated regional dynamothermal metamorphism to mid-greenschist facies commencing at 2592Ma; 2. concurrent discreet thermal metamorphism associated with local granitic intrusions; and 3. late retrograde hydrothermal alteration. Gold is refractory within acicular and rhombic arsenopyrite. Petrography, SIMS, EMP and LA-ICP-MS analysis have defined three arsenopyrite styles of distinct crystal habit with distinct inclusion abundance, Au enrichment and zoning and trace element zoning. The greatest enrichment is in the earliest type of arsenopyrite, attributed to hydrothermal events associated with volcanism. Later, heterogeneous, less enriched arsenopyrite is a result of metamorphic recrystalisation. A strataform quartz body with arsenopyrite and sulphate in textural equilibrium has sulphur isotopes indicative of an Archean ocean sinter. Terraspec and EMP analysis identify sericite mineralogy to be dominantly end-member muscovite. Early sericite associated with syn-volcanic arsenopyrite is Mg-rich compared to late, metamorphic Al-rich sericite.

Microblogs such as Twitter provide a valuable stream of diverse user-generated data. While the data extracted from Twitter is generally timely and accurate, the process by which developers extract structured data from the tweet stream is ad-hoc and requires reimplementation of common data manipulation primitives. In this paper, we present two systems for querying and extracting structure from Twitter-embedded data. The first, TweeQL, provides a streaming SQL-like interface to the Twitter API, making common tweet processing tasks simpler. The second, TwitInfo, shows how end-users can interact with and understand aggregated data from the tweet stream, in addition to showcasing the power of the TweeQL language. Together these systems show the richness of content that can be extracted from Twitter.