The comparative biology of skeletal metastasis

Bone metastasis, a very common sequelae of cancer, is often associated with great morbidity. Understanding the biology of bone metastases may lead to therapeutic interventions to target the metastases. In addition to replacing bone marrow elements, the presence of tumour cells in bone modulates the normal bone remodelling process. Some tumours result in primarily osteolytic bone lesions, whereas others are associated with osteoblastic bone lesions. In either case, the resulting changes in the bone structure result in weakened bone that induces pain and is predisposed to fracture. The mechanisms through which cancer cells modulate bone remodelling are not clearly defined, but ongoing research using a variety of animal models will hopefully provide clues to prevent or slow the progress of bone metastases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73390/1/j.1476-5829.2003.00023.x.pd

RNA and RNA Binding Proteins in Neurodegenerative Tauopathies

Tau aggregates are insoluble, fibrillar accumulations of microtubule associated protein tau (MAPT) that are observed in the brains of patients with more than 20 different neurodegenerative diseases including Alzheimer&rsquo;s disease (AD) and subtypes of frontotemporal dementia. How these fibrils form in patients and how they alter neuronal function are both unknown. In vitro, RNA promotes the conversion of tau from a soluble form to an insoluble fibrillar aggregate. RNA and RNA binding proteins are also sequestered into tau aggregates in the brains of patients. I set out to better understand the role that of RNA and RNA binding proteins play in tauopathies and this led to new insights into the composition, origin, and cellular effects of tau aggregates. Specifically, I isolated and sequenced RNA from tau aggregates in two model systems and found enrichment of small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). As a result, I investigated tau&rsquo;s interaction with nuclear membraneless organelles that contains a high concentration of snRNAs, known as splicing speckles. I found that tau aggregates localize to splicing speckles and alter their composition, organization, and dynamics. Consistent with these observations, I also found that inducing tau aggregation is sufficient to alter RNA splicing. Unexpectedly, multiple splicing speckle components mislocalized from the nucleus to cytoplasmic tau aggregates. I chose one of these proteins, SRRM2, to investigate further and found it mislocalized to cytoplasmic tau aggregates in three different human tauopathies, including AD. Using CRISPR, I then mapped the domains of SRRM2 and found that poly-serine repeats in its C-terminus are both necessary and sufficient for its interaction with tau aggregates. Further, I also discovered that tau aggregates can merge with and nucleate from the surface of SRRM2 positive cytoplasmic assemblies. I hope that these insights will lead to a better understanding of how tau aggregates form, their role in disease, and lead to therapeutics that can help patients and their families suffering from these devastating neurologic conditions.</p

The Impossibility of a Perfectly Competitive Labor Market

Using the institutional theory of transaction cost, I demonstrate that the assumptions of the competitive labor market model are internally contradictory and lead to the conclusion that on purely theoretical grounds a perfectly competitive labor market is a logical impossibility. By extension, the familiar diagram of wage determination by supply and demand is also a logical impossibility and the neoclassical labor demand curve is not a well-defined construct. The reason is that the perfectly competitive market model presumes zero transaction cost and with zero transaction cost all labor is hired as independent contractors, implying multi-person firms, the employment relationship, and labor market disappear. With positive transaction cost, on the other hand, employment contracts are incomplete and the labor supply curve to the firm is upward sloping, again causing the labor demand curve to be ill-defined. As a result, theory suggests that wage rates are always and everywhere an amalgam of an administered and bargained price. Working Paper 06-0

Test sensitivity is secondary to frequency and turnaround time for COVID-19 screening

The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with presymptomatic, symptomatic, and asymptomatic infections, the reopening of societies and the control of virus spread will be facilitated by robust population screening, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are too low to detect, followed by exponential viral growth, leading to peak viral load and infectiousness and ending with declining titers and clearance. Given the pattern of viral load kinetics, we model the effectiveness of repeated population screening considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective screening depends largely on frequency of testing and speed of reporting and is only marginally improved by high test sensitivity. We therefore conclude that screening should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary. &nbsp;</p

Earth's ion upflow associated with polar cap patches: global and in-situ observations

We report simultaneous global monitoring of a patch of ionization and in situ observation of ion upflow at the center of the polar cap region during a geomagnetic storm. Our observations indicate strong fluxes of upwelling O+ ions originating from frictional heating produced by rapid antisunward flow of the plasma patch. The statistical results from the crossings of the central polar cap region by Defense Meteorological Satellite Program F16–F18 from 2010 to 2013 confirm that the field-aligned flow can turn upward when rapid antisunward flows appear, with consequent significant frictional heating of the ions, which overcomes the gravity effect. We suggest that such rapidly moving patches can provide an important source of upwelling ions in a region where downward flows are usually expected. These observations give new insight into the processes of ionosphere-magnetosphere coupling

Minimum Wage Channels of Adjustment

Industrial Relations, forthcoming Abstract: The effects of minimum wage increases in 2007-2009 are analyzed using a sample of restaurants from Georgia/Alabama. Store-level payroll records provide precise measures of compliance costs. Examined are multiple adjustment channels. Exploiting variation in compliance costs across restaurants, we find employment and hours responses to be variable and in most cases statistically insignificant. Channels of adjustment to wage increases and to changes in non-labor costs include prices, profits, wage compression, turnover, and performance standards

The Non-existence of the Labor Demand/Supply Diagram, and Other Theorems of Institutional Economics

The most famous and influential diagram in modern (neoclassical) labor economics is the model of wage determination by supply and demand. Using concepts and ideas from institutional economics, I argue that the theory of a perfectly competitive labor market is logically contradictory and, hence, the demand/supply diagram cannot exist on the plane of pure theory. Four other fundamental theorems concerning labor markets are also derived, as are implications about the theoretical foundation of the field of industrial relations and the economic evaluation of labor and employment policy. In this article I accomplish four things of significance. The first is to demonstrate that the core diagram of neoclassical labor economics - the diagram of wage determination by demand and supply (D/S) - does not have logical coherence and thus has no existence on the plane of pure theory. The second is to deduce this conclusion using a core concept of institutional economics (i.e., transaction cost), thus demonstrating that the institutional approach to labor economics has theoretical explanatory power. The third is to use the transaction cost idea to also deduce four fundamental theorems concerning labor markets and wage determination. The fourth is to identify the core theoretical foundation of the field of industrial relations. This discussion also yields important implications for the economic evaluation of labor and employment policy, as well as interesting insights on the history of thought in labor economics. Working Paper 07-2

TESS Discovery of Twin Planets near 2:1 Resonance around Early M-Dwarf TOI 4342

With data from the Transiting Exoplanet Survey Satellite (TESS), we showcase improvements to the MIT Quick-Look Pipeline (QLP) through the discovery and validation of a multi-planet system around M-dwarf TOI 4342 ($T_{mag}=11.032$, $M_* = 0.63 M_\odot$, $R_* = 0.60 R_\odot$, $T_{eff} = 3900$ K, $d = 61.54$ pc). With updates to QLP, including a new multi-planet search, as well as faster cadence data from TESS' First Extended Mission, we discovered two sub-Neptunes ($R_b = 2.266_{-0.038}^{+0.038} R_\oplus$ and $R_c = 2.415_{-0.040}^{+0.043} R_\oplus$; $P_b$ = 5.538 days and $P_c$ = 10.689 days) and validated them with ground-based photometry, spectra, and speckle imaging. Both planets notably have high transmission spectroscopy metrics (TSMs) of 36 and 32, making TOI 4342 one of the best systems for comparative atmospheric studies. This system demonstrates how improvements to QLP, along with faster cadence Full-Frame Images (FFIs), can lead to the discovery of new multi-planet systems.Comment: accepted for publication in A

Polar cap patch transportation beyond the classic scenario

We report the continuous monitoring of a polar cap patch, encompassing its creation, and a subsequent evolution that differs from the classic behavior. The patch was formed from the storm-enhanced density plume, by segmentation associated with a subauroral polarization stream generated by a substorm. Its initial antisunward motion was halted due to a rapidly changing of interplanetary magnetic field (IMF) conditions from strong southward to strong eastward with weaker northward components, and the patch subsequently very slowly evolved behind the duskside of a lobe reverse convection cell in afternoon sectors, associated with high-latitude lobe reconnection, much of it fading rapidly due to an enhancement of the ionization recombination rate. This differs from the classic scenario where polar cap patches are transported across the polar cap along the streamlines of twin-cell convection pattern from day to night. This observation provides us new important insights into patch formation and control by the IMF, which has to be taken into account in F region transport models and space weather forecasts