University Leadership for Innovation in Global Health and HIV/AIDS Diagnostics

Medical products used in the developed world often fail to adequately serve resource-limited settings where electricity, transportation and health care workers are not readily available. We suggest that the problem is not only a lack of coordinated financial resources to purchase existing medical products, but also a lack of products that are specifically designed for resource-limited settings. While donor organisations with a focus on global health are increasingly willing to bear the additional financial risk for the research and development of such high-impact medical products, corporations are still reluctant to take their best scientists and engineers away from more commercially attractive projects. Universities, on the other hand, given their teaching and research missions, are well positioned to engage in such high-risk development projects. A group of biomedical, engineering, business and social science researchers at Northwestern University (NU) propose a creative model to address significant social and health needs. The team's initial product focus is a rapid test for diagnosing infants with HIV. The NU model aligns the incentives and expertise of industry, donors and academia to innovate medical products, such as the infant HIV diagnostic test, for resource-limited settings

Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes

Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes

CMBPol Mission Concept Study: Prospects for polarized foreground removal

In this report we discuss the impact of polarized foregrounds on a future CMBPol satellite mission. We review our current knowledge of Galactic polarized emission at microwave frequencies, including synchrotron and thermal dust emission. We use existing data and our understanding of the physical behavior of the sources of foreground emission to generate sky templates, and start to assess how well primordial gravitational wave signals can be separated from foreground contaminants for a CMBPol mission. At the estimated foreground minimum of ~100 GHz, the polarized foregrounds are expected to be lower than a primordial polarization signal with tensor-to-scalar ratio r=0.01, in a small patch (~1%) of the sky known to have low Galactic emission. Over 75% of the sky we expect the foreground amplitude to exceed the primordial signal by about a factor of eight at the foreground minimum and on scales of two degrees. Only on the largest scales does the polarized foreground amplitude exceed the primordial signal by a larger factor of about 20. The prospects for detecting an r=0.01 signal including degree-scale measurements appear promising, with 5 sigma_r ~0.003 forecast from multiple methods. A mission that observes a range of scales offers better prospects from the foregrounds perspective than one targeting only the lowest few multipoles. We begin to explore how optimizing the composition of frequency channels in the focal plane can maximize our ability to perform component separation, with a range of typically 40 < nu < 300 GHz preferred for ten channels. Foreground cleaning methods are already in place to tackle a CMBPol mission data set, and further investigation of the optimization and detectability of the primordial signal will be useful for mission design.Comment: 42 pages, 14 figures, Foreground Removal Working Group contribution to the CMBPol Mission Concept Study, v2, matches AIP versio

Pallidal low‐frequency activity in dystonia after cessation of long‐term deep brain stimulation

Objective: This study investigates the association between pallidal low-frequency activity and motor sign severity in dystonia after chronic deep brain stimulation for several months. Methods: Local field potentials were recorded in 9 dystonia patients at 5 timepoints (T1–T5) during an OFF-stimulation period of 5 to 7 hours in parallel with clinical assessment using Burke-Fahn-Marsden Dystonia Rating Scale. A linear mixed effects model was used to investigate the potential association of motor signs with local field potential activity in the low frequency (3–12 Hz) and beta range (13–30 Hz). Results: A significant association of Burke-Fahn-Marsden Dystonia Rating Scale scores with low-frequency activity (3–12 Hz; b = 4.4; standard error = 1.5, degrees of freedom = 43, P = 0.006, 95% confidence interval, 1.3–7.5), but not beta activity (13–30 Hz) was revealed within participants across timepoints. Conclusion: Low-frequency activity is associated with dystonic motor sign severity, even months after chronic deep brain stimulation. Our findings corroborate the pathophysiological role of low-frequency activity in dystonia and highlight the potential utility as a biomarker for adaptive neuromodulation

Tracing Sub-Structure in the European American Population with PCA-Informative Markers

Genetic structure in the European American population reflects waves of migration and recent gene flow among different populations. This complex structure can introduce bias in genetic association studies. Using Principal Components Analysis (PCA), we analyze the structure of two independent European American datasets (1,521 individuals–307,315 autosomal SNPs). Individual variation lies across a continuum with some individuals showing high degrees of admixture with non-European populations, as demonstrated through joint analysis with HapMap data. The CEPH Europeans only represent a small fraction of the variation encountered in the larger European American datasets we studied. We interpret the first eigenvector of this data as correlated with ancestry, and we apply an algorithm that we have previously described to select PCA-informative markers (PCAIMs) that can reproduce this structure. Importantly, we develop a novel method that can remove redundancy from the selected SNP panels and show that we can effectively remove correlated markers, thus increasing genotyping savings. Only 150–200 PCAIMs suffice to accurately predict fine structure in European American datasets, as identified by PCA. Simulating association studies, we couple our method with a PCA-based stratification correction tool and demonstrate that a small number of PCAIMs can efficiently remove false correlations with almost no loss in power. The structure informative SNPs that we propose are an important resource for genetic association studies of European Americans. Furthermore, our redundancy removal algorithm can be applied on sets of ancestry informative markers selected with any method in order to select the most uncorrelated SNPs, and significantly decreases genotyping costs

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy.

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p &lt; 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization

A global biophysical typology of mangroves and its relevance for ecosystem structure and deforestation

Mangrove forests provide many ecosystem services but are among the world's most threatened ecosystems. Mangroves vary substantially according to their geomorphic and sedimentary setting; while several conceptual frameworks describe these settings, their spatial distribution has not been quantified. Here, we present a new global mangrove biophysical typology and show that, based on their 2016 extent, 40.5% (54,972 km2) of mangrove systems were deltaic, 27.5% (37,411 km2) were estuarine and 21.0% (28,493 km2) were open coast, with lagoonal mangroves the least abundant (11.0%, 14,993 km2). Mangroves were also classified based on their sedimentary setting, with carbonate mangroves being less abundant than terrigenous, representing just 9.6% of global coverage. Our typology provides a basis for future research to incorporate geomorphic and sedimentary setting in analyses. We present two examples of such applications. Firstly, based on change in extent between 1996 and 2016, we show while all types exhibited considerable declines in area, losses of lagoonal mangroves (- 6.9%) were nearly twice that of other types. Secondly, we quantify differences in aboveground biomass between mangroves of different types, with it being significantly lower in lagoonal mangroves. Overall, our biophysical typology provides a baseline for assessing restoration potential and for quantifying mangrove ecosystem service provision