Modeling and estimating the feedback mechanisms among depression, rumination, and stressors in adolescents

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The systemic interactions among depressive symptoms, rumination, and stress are important to understanding depression but have not yet been quantified. In this article, we present a system dynamics simulation model of depression that captures the reciprocal relationships among stressors, rumination, and depression. Building on the response styles theory, this model formalizes three interdependent mechanisms: 1) Rumination contributes to 'keeping stressors alive'; 2) Rumination has a direct impact on depressive symptoms; and 3) Both 'stressors kept alive' and current depressive symptoms contribute to rumination. The strength of these mechanisms is estimated using data from 661 adolescents (353 girls and 308 boys) from two middle schools (grades 6-8). These estimates indicate that rumination contributes to depression by keeping stressors 'alive'-and the individual activated- even after the stressor has ended. This mechanism is stronger among girls than boys, increasing their vulnerability to a rumination reinforcing loop. Different profiles of depression emerge over time depending on initial levels of depressive symptoms, rumination, and stressors as well as the occurrence rate for stressors; levels of rumination and occurrence of stressors are stronger contributors to long-term depression. Our systems model is a steppingstone towards a more comprehensive understanding of depression in which reinforcing feedback mechanisms play a significant role. Future research is needed to expand this simulation model to incorporate other drivers of depression and provide a more holistic tool forstudying depression.National Institutes of Health (U.S.) (Award R21MH100515)National Institute of Mental Health (U.S.) (Award R21MH100515

Outlook for tuberculosis elimination in California: An individual-based stochastic model.

RationaleAs part of the End TB Strategy, the World Health Organization calls for low-tuberculosis (TB) incidence settings to achieve pre-elimination (<10 cases per million) and elimination (<1 case per million) by 2035 and 2050, respectively. These targets require testing and treatment for latent tuberculosis infection (LTBI).ObjectivesTo estimate the ability and costs of testing and treatment for LTBI to reach pre-elimination and elimination targets in California.MethodsWe created an individual-based epidemic model of TB, calibrated to historical cases. We evaluated the effects of increased testing (QuantiFERON-TB Gold) and treatment (three months of isoniazid and rifapentine). We analyzed four test and treat targeting strategies: (1) individuals with medical risk factors (MRF), (2) non-USB, (3) both non-USB and MRF, and (4) all Californians. For each strategy, we estimated the effects of increasing test and treat by a factor of 2, 4, or 10 from the base case. We estimated the number of TB cases occurring and prevented, and net and incremental costs from 2017 to 2065 in 2015 U.S. dollars. Efficacy, costs, adverse events, and treatment dropout were estimated from published data. We estimated the cost per case averted and per quality-adjusted life year (QALY) gained.Measurements and main resultsIn the base case, 106,000 TB cases are predicted to 2065. Pre-elimination was achieved by 2065 in three scenarios: a 10-fold increase in the non-USB and persons with MRF (by 2052), and 4- or 10-fold increase in all Californians (by 2058 and 2035, respectively). TB elimination was not achieved by any intervention scenario. The most aggressive strategy, 10-fold in all Californians, achieved a case rate of 8 (95% UI 4-16) per million by 2050. Of scenarios that reached pre-elimination, the incremental net cost was $20 billion (non-USB and MRF) to$48 billion. These had an incremental cost per QALY of $657,000 to$3.1 million. A more efficient but somewhat less effective single-lifetime test strategy reached as low as $80,000 per QALY.ConclusionsSubstantial gains can be made in TB control in coming years by scaling-up current testing and treatment in non-USB and those with medical risks

Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease.

UnlabelledCryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1's specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.ImportanceCryptococcus neoformans is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For C. neoformans to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of C. neoformans across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis

Optical characterization of the PALM-3000 3388-actuator deformable mirror

We describe the lab characterization of the new 3,388-actuator deformable mirror (DM3388) produced by Xinetics, Inc. for the PALM-3000 adaptive optics (AO) system1 under development by Jet Propulsion Laboratory and Caltech Optical Observatories. This square grid 66-by-66 actuator mirror has the largest number of actuators of any deformable mirror currently available and will enable high-contrast imaging for direct exoplanet imaging science at the Palomar 200" diameter Hale Telescope. We present optical measurements of the powered and unpowered mirror surface, influence functions, linearity of the actuators, and creep of the actuators. We also quantify the effect of changes in humidity

Emerging Leadership in Nonprofit Organizations: Myths, Meaning and Motivations

This report contributes to the understanding of, and conversation about, how to develop emerging leaders in the nonprofit sector. It provides recommendations for various stakeholders of the sector, including funders. A bibliography is included

Demonstration of on sky contrast improvement using the Modified Gerchberg-Saxton algorithm at the Palomar Observatory

We have successfully demonstrated significant improvements in the high contrast detection limit of the Well-Corrected Subaperture (WCS) using a number of steps aimed at reducing non-common path (NCP) wavefront errors, including the Autonomous Phase Retrieval Calibration (APRC) software package developed at the Jet Propulsion Laboratory (JPL) for the Palomar adaptive optics instrument (PALAO). APRC utilizes the Modified Gerchberg-Saxton (MGS) wavefront sensing algorithm, also developed at JPL. The WCS delivers such excellent correction of the atmosphere that NCP wavefront errors not sensed by PALAO but present at the coronagraphic image plane begin to factor heavily as a limit to contrast. The APRC program was implemented to reduce these NCP wavefront errors from 110 nm to 35 nm (rms) in the lab, and now these exceptional results have been extended to targets on the sky for the first time, leading to a significant suppression of speckle noise. Consequently we now report a contrast level of very nearly 1×10^(-4) at separations of 2λ/D before the data is post processed, and 1×10^(-5) after post processing. We describe here the major components of our instrument, the work done to improve the NCP wavefront errors, and the ensuing excellent on sky results, including the detection of the three exoplanets orbiting the star HR8799

Electric Field Conjugation with the Project 1640 coronagraph

The Project 1640 instrument on the 200-inch Hale telescope at Palomar Observatory is a coronagraphic instrument with an integral field spectrograph at the back end, designed to find young, self-luminous planets around nearby stars. To reach the necessary contrast for this, the PALM-3000 adaptive optics system corrects for fast atmospheric speckles, while CAL, a phase-shifting interferometer in a Mach-Zehnder configuration, measures the quasistatic components of the complex electric field in the pupil plane following the coronagraphic stop. Two additional sensors measure and control low-order modes. These field measurements may then be combined with a system model and data taken separately using a white-light source internal to the AO system to correct for both phase and amplitude aberrations. Here, we discuss and demonstrate the procedure to maintain a half-plane dark hole in the image plane while the spectrograph is taking data, including initial on-sky performance.Comment: 9 pages, 7 figures, in Proceedings of SPIE, 8864-19 (2013