Decomposing the Sources of Earnings Inequality: Assessing the Role of Reallocation

This paper exploits longitudinal employer-employee matched data from the U.S. Census Bureau to investigate the contribution of worker and firm reallocation to changes in earnings inequality within and across industries between 1992 and 2003. We find that factors that cannot be measured using standard cross-sectional data, including the entry and exit of firms and the sorting of workers across firms, are important sources of changes in earnings distributions over time. Our results also suggest that the dynamics driving changes in earnings inequality are heterogeneous across industries.inequality, linked employer-employee data, sorting

Decomposing the Sources of Earnings Inequality Assessing the Role of Reallocation

This paper uses matched employer-employee data from the Longitudinal Employer Household Dynamics database to investigate the contribution of worker and firm reallocation to within industry changes in wage inequality between 1992 and 2003. We find that the entry and exit of firms and the sorting of workers and firms based on underlying worker "skills" are important determinants of changes in industry earnings distributions over time. Our results suggest that the underlying dynamics of earnings inequality are complex and are due to factors that cannot be measured in standard crosssectional data.

Novel Use of Folate-Targeted Intraoperative Fluorescence, OTL38, in Robot-Assisted Laparoscopic Partial Nephrectomy: Report of the First Three Cases

Partial nephrectomy is now the preferred surgical option for small renal tumors because it allows nephron preservation without compromising oncologic clearance. Its outcomes depend on the surgeon's ability to continuously identify the edges of the tumor during resection, thus leaving an adequate margin around the tumor without excessive removal of normal parenchyma, as well as keeping a short ischemic time. Folate receptors are highly abundant in the normal kidney, and there is a difference in folate receptor expression between malignant and normal renal tissues. Thus, the use of fluorescent agents that target folate receptors should result in differential fluorescence between the tumor and surrounding parenchyma during partial nephrectomy, which, in turn, helps tumor demarcation for identification and resection. A phase 2 study on the novel use of OTL38 in robot-assisted laparoscopic partial nephrectomy is currently in progress in our institution. The outcomes of the first three cases have shown the possible advantages of OTL38 in intraoperative tumor identification before resection and recognition of residual disease in the surrounding parenchyma after resection. The tumors typically appeared dark while the surrounding parenchyma showed brighter fluorescence. Immediately after tumor resection, the margins of all the specimens appeared to have a uniformly bright fluorescence, suggestive of an intact margin of normal renal parenchyma along the plane of excision. The pattern of intraoperative fluorescence correlates well with immunohistochemistry. No OTL38-related adverse effects have been seen among these three patients. We present the outcomes of these three cases, illustrated with intraoperative and immunohistochemistry images

Pattern formation and localization in the forced-damped FPU lattice

We study spatial pattern formation and energy localization in the dynamics of an anharmonic chain with quadratic and quartic intersite potential subject to an optical, sinusoidally oscillating field and a weak damping. The zone-boundary mode is stable and locked to the driving field below a critical forcing that we determine analytically using an approximate model which describes mode interactions. Above such a forcing, a standing modulated wave forms for driving frequencies below the band-edge, while a ``multibreather'' state develops at higher frequencies. Of the former, we give an explicit approximate analytical expression which compares well with numerical data. At higher forcing space-time chaotic patterns are observed.Comment: submitted to Phys.Rev.

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Blocking HIF signaling via novel inhibitors of CA9 and APE1/Ref-1 dramatically affects pancreatic cancer cell survival

Abstract Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifunctional protein with redox signaling activity that converts certain oxidized transcription factors to a reduced state, enabling them to upregulate tumor-promoting genes. Our studies evaluate PDAC hypoxia responses and APE1/Ref-1 redox signaling contributions to HIF-1α-mediated CA9 transcription. Our previous studies implicated this pathway in PDAC cell survival under hypoxia. We expand those studies, comparing drug responses using patient-derived PDAC cells displaying differential hypoxic responses in 3D spheroid tumor-stroma models to characterize second generation APE1/Ref-1 redox signaling and CA9 inhibitors. Our data demonstrates that HIF-1α-mediated CA9 induction differs between patient-derived PDAC cells and that APE1/Ref-1 redox inhibition attenuates this induction by decreasing hypoxia-induced HIF-1 DNA binding. Dual-targeting of APE1/Ref-1 and CA9 in 3D spheroids demonstrated that this combination effectively kills PDAC tumor cells displaying drastically different levels of CA9. New APE1/Ref-1 and CA9 inhibitors were significantly more potent alone and in combination, highlighting the potential of combination therapy targeting the APE1-Ref-1 signaling axis with significant clinical potential

Optical creation of vibrational intrinsic localized modes in anharmonic lattices with realistic interatomic potentials

Using an efficient optimal control scheme to determine the exciting fields, we theoretically demonstrate the optical creation of vibrational intrinsic localized modes (ILMs) in anharmonic perfect lattices with realistic interatomic potentials. For systems with finite size, we show that ILMs can be excited directly by applying a sequence of femtosecond visible laser pulses at THz repetition rates. For periodic lattices, ILMs can be created indirectly via decay of an unstable extended lattice mode which is excited optically either by a sequence of pulses as described above or by a single picosecond far-infrared laser pulse with linearly chirped frequency. In light of recent advances in experimental laser pulse shaping capabilities, the approach is experimentally promising.Comment: 20 pages, 7 eps figures. Accepted, Phys. Rev.

Stepwise quantum decay of self-localized solitons

The two-phonon decay of self-localized soliton in a one-dimensional monatomic anharmonic lattice caused by cubic anharmonicity is considered. It is shown that the decay takes place with emission of phonon bursts. The average rate of emission of phonons is of the order of vibrational quantum per vibrational period. Characteristic time of the relaxation is determined by the quantum anharmonicity parameter; this time may vary from a few (quantum lattices, large anharmonicity) to thousands (ordinary lattices, small anharmonicity) of vibrational periods.Comment: 6 pages, 3 figure

Discrete breathers in dissipative lattices

We study the properties of discrete breathers, also known as intrinsic localized modes, in the one-dimensional Frenkel-Kontorova lattice of oscillators subject to damping and external force. The system is studied in the whole range of values of the coupling parameter, from C=0 (uncoupled limit) up to values close to the continuum limit (forced and damped sine-Gordon model). As this parameter is varied, the existence of different bifurcations is investigated numerically. Using Floquet spectral analysis, we give a complete characterization of the most relevant bifurcations, and we find (spatial) symmetry-breaking bifurcations which are linked to breather mobility, just as it was found in Hamiltonian systems by other authors. In this way moving breathers are shown to exist even at remarkably high levels of discreteness. We study mobile breathers and characterize them in terms of the phonon radiation they emit, which explains successfully the way in which they interact. For instance, it is possible to form ``bound states'' of moving breathers, through the interaction of their phonon tails. Over all, both stationary and moving breathers are found to be generic localized states over large values of $C$, and they are shown to be robust against low temperature fluctuations.Comment: To be published in Physical Review