Oxidative stress, malaria, sickle cell disease, and innate immunity

This work was supported by the Wellcome Trust (grant 094847).Peer reviewedPostprin

Market Access Analysis of Biologics and Small-Molecule Inhibitors for Inflammatory Bowel Disease Among US Health Insurance Policies.

BACKGROUND AND AIMS:Treatment pathways for ulcerative colitis (UC) and Crohn's disease (CD) are shifting to a more individualized, risk-stratified approach. The perception is that insurance policies may not have implemented this paradigm shift, particularly regarding access to newer agents. We evaluated patient access to advanced therapies by analyzing policy information from the Managed Markets Insight and Technology database. METHODS:Coverage status as of December 2018 for all US lives was queried for adalimumab, infliximab, infliximab-dyyb, tofacitinib, ustekinumab, and vedolizumab by indication (UC and/or CD) and medical or pharmacy coverage benefit. Coverage status was classified by the number of biologic steps before access to specified drug as "No Biologic," "1 Prior Biologic," "2+ Prior Biologics," "Not Covered." Unknown lives were excluded from the analyses. RESULTS:Coverage analysis was available for approximately 302 million lives under each medical and pharmacy benefit. Our analysis indicates that approximately half of covered lives had access to all agents (except tofacitinib) as first-line therapy; two-thirds had access after one biologic exposure. Among newer agents, vedolizumab had the widest coverage. For indications of UC and CD, 81% of known lives had access to vedolizumab with no prior biologic exposure required ("No Biologic"), 95% after "No Biologic" + "1 prior Biologic." Geographic variations were identified for coverage patterns. CONCLUSIONS:This US-based healthcare policy analysis points to an increased access to advanced therapies for UC and CD. An individualized, risk-stratified treatment approach integrating advanced therapies, including those recently approved, into treatment pathways for UC and CD is feasible

Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca²⁺ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 13-17 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (≥ 2 µM) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca²⁺ dynamics causing an immediate but transient elevation of neuronal intracellular Ca²⁺ followed by decreased frequency of Ca²⁺ oscillations but greater peak amplitude. The effect on Ca²⁺ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca²⁺ dynamics requires activation of N-methyl-D-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca²⁺ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca²⁺ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1 µM) and allopregnanolone (0.1 µM), when administered together, were highly effective in suppressing TETS-induced alterations in Ca²⁺ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication

Photoluminescence modification by high-order photonic band with abnormal dispersion in ZnO inverse opal

We measured the angle- and polarization-resolved reflection and photoluminescence spectra of ZnO inverse opals. Significant enhancement of spontaneous emission is observed. The enhanced emission not only has good directionality but also can be linearly polarized. A detailed theoretical analysis and numerical simulation reveal that such enhancement is caused by the abnormal dispersion of a high-order photonic band. The frozen mode at a stationary inflection point of a dispersion curve can strongly modify the intensity, directionality and polarization of spontaneous emission.Comment: 22 pages, 11 figures, figures modified, references added, more explanation adde

Going the distance for protein function prediction: a new distance metric for protein interaction networks

Due to an error introduced in the production process, the x-axes in the first panels of Figure 1 and Figure 7 are not formatted correctly. The correct Figure 1 can be viewed here: http://dx.doi.org/10.1371/annotation/343bf260-f6ff-48a2-93b2-3cc79af518a9In protein-protein interaction (PPI) networks, functional similarity is often inferred based on the function of directly interacting proteins, or more generally, some notion of interaction network proximity among proteins in a local neighborhood. Prior methods typically measure proximity as the shortest-path distance in the network, but this has only a limited ability to capture fine-grained neighborhood distinctions, because most proteins are close to each other, and there are many ties in proximity. We introduce diffusion state distance (DSD), a new metric based on a graph diffusion property, designed to capture finer-grained distinctions in proximity for transfer of functional annotation in PPI networks. We present a tool that, when input a PPI network, will output the DSD distances between every pair of proteins. We show that replacing the shortest-path metric by DSD improves the performance of classical function prediction methods across the board.MC, HZ, NMD and LJC were supported in part by National Institutes of Health (NIH) R01 grant GM080330. JP was supported in part by NIH grant R01 HD058880. This material is based upon work supported by the National Science Foundation under grant numbers CNS-0905565, CNS-1018266, CNS-1012910, and CNS-1117039, and supported by the Army Research Office under grant W911NF-11-1-0227 (to MEC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Using Multiple-case Studies to Investigate Relationships among Knowledge Management Systems, Business Process and Business Performance: A Task Technology Fit Perspective

In the face of heighted competition, organizations need to continuously improve their competitive advantage. Both knowledge management (KM) and knowledge management systems (KMS) play a pivotal role in helping organizations to stay competitive. There is much research in KMS, however very little is known about how they affect individual and organizational performance. Drawing on task-technology fit theory (Goodhue and Thompson, 1995), this study explores the fit or alignment between business process (task) and KMS (technology) and its impact on KMS utilization based on multiple case studies. Subsequently, the impacts of both the task-technology fit and KMS utilization on individual and business performance are investigated. This paper contributes to the KM literature in several ways. First, it applies task-technology fit theory to an important context, that of KM. Second, it characterizes task as business processes which have the potential to help explain KMS success on business performance. Third, the paper explores the positive impact of task-technology fit on KMS utilization and business performance. Fourth, the study provides insight into the future development of KMS which are better aligned with managerial purpose