Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse

Receptor-ligand couples in the cell-cell contact interface between a T cell and an antigen-presenting cell form distinct geometric patterns and undergo spatial rearrangement within the contact interface. Spatial segregation of the antigen and adhesion receptors occurs within seconds of contact, central aggregation of the antigen receptor then occurring over 1-5 min. This structure, called the immunological synapse, is becoming a paradigm for localized signaling. However, the mechanisms driving its formation, in particular spatial segregation, are currently not understood. With a reaction diffusion model incorporating thermodynamics, elasticity, and reaction kinetics, we examine the hypothesis that differing bond lengths (extracellular domain size) is the driving force behind molecular segregation. We derive two key conditions necessary for segregation: a thermodynamic criterion on the effective bond elasticity and a requirement for the seeding/nucleation of domains. Domains have a minimum length scale and will only spontaneously coalesce/aggregate if the contact area is small or the membrane relaxation distance large. Otherwise, differential attachment of receptors to the cytoskeleton is required for central aggregation. Our analysis indicates that differential bond lengths have a significant effect on synapse dynamics, i.e., there is a significant contribution to the free energy of the interaction, suggesting that segregation by differential bond length is important in cell-cell contact interfaces and the immunological synapse

New Cross-Bridged Cyclam Ligands and Their Transition Metal Complexes as CXCR4 Antagonists

CXCR4 is a co-receptor on the surface of immune cells that has been proven to facilitate the entry of HIV into the cells. Within the last 15 years the CXCR4 and CCR5 coreceptors have influenced new therapeutic approaches to the treatment of HIV via fusion inhibitor drugs that target these receptors. Our aim is to develop new antagonists for the CXCR4 coreceptor. Specifically, the goal was the synthesis of Propyl Cross-Bridged, linked analogues of the known CXCR4 antagonist AMD-3100

Conformations of closed DNA

We examine the conformations of a model for a short segment of closed DNA. The molecule is represented as a cylindrically symmetric elastic rod with a constraint corresponding to a specification of the linking number. We obtain analytic expressions leading to the spatial configuration of a family of solutions representing distortions that interpolate between the circular form of DNA and a figure-eight form that represents the onset of interwinding. We are also able to generate knotted loops. We suggest ways to use our approach to produce other configurations relevant to studies of DNA structure. The stability of the distorted configurations is assessed, along with the effects of fluctuations on the free energy of the various configurations.Comment: 39 pages in REVTEX with 14 eps figures. Submitted to Phys. Rev. E. This manuscript updates, expands and revises, to a considerable extent, a previously posted manuscript, entitled "Conformations of Circular DNA," which appeared as cond-mat/970104

Gaps in Patient Education on Safe Handling and Disposal of Oral Chemotherapy Drugs: A Pilot Prospective Cohort Survey Study

Background Oral anticancer chemotherapy (OC) has been misperceived as being safer than intravenous chemotherapy, leading to its increased risk of improper handling and disposal. This survey study assessed the knowledge, practices and attitudes of pharmacists and patients regarding OC handling and disposal, gaps in knowledge and barriers to patient education. Methods Surveys were developed based on literature review and pilot study validation results. Patients completed a 33-item paper or electronic survey whereas pharmacists completed a 38-item electronic survey. Descriptive statistics and Fisher’s exact test computed using the R Project were used for analyses. Results Pharmacist group (16/25, 62.5%) and patient group (14/29, 48.3%) believed that the oral route is safer than IV. Average overall correct response rates for pharmacist and patient groups were 78.3% and 61.9%, respectively. Significant gaps in knowledge between groups were observed in three sections (p \u3c 0.05). Common barriers to providing patient education were insufficient training (70.8%) and insufficient time (50%). Conclusion Pharmacist and patient knowledge, awareness and practices of OC safe handling and disposal are suboptimal. Areas of knowledge gaps and barriers to patient education were identified. Enhanced supports are needed to empower pharmacists to assume an active role in patient education on safe handling and disposal of OC

Brivaracetam to Treat Partial Onset Seizures in Adults.

PURPOSE OF REVIEW: Seizures are a hyperexcitable, and hypersynchronous imbalance between excitatory and inhibitory factors (E/I imbalance) in neurotransmission, and epilepsy is the recurrent manifestation of seizures within a reasonable time frame and without being attributable to a reversible cause. Brivaracetam is a derivative of the antiepileptic agent, levetiracetam, that is used as adjuvant therapy for focal onset seizures. It was approved by the FDA in 2016 and has shown promising results with minimal adverse effect reactions in clinical trials. RECENT FINDINGS: Brivaracetam has been used in multiple clinical trials at various dosages in adults that have partial-onset seizures refractory to conventional treatment. A meta-analysis in 2016 showed that brivaracetam as adjunctive therapy was statically significant in its reduction of adults with drug-refractory seizure frequency. CONCLUSION: The treatment of epilepsy with pharmacologic agents is a difficult task due to balancing the efficacy of the drug with the side effect profile that will allow for the best quality of life for the patient. There are approximately 30 antiepileptic agents for clinicians to choose from. Brivaracetam is a novel antiepileptic agent that was approved for use by the FDA in 2016 and is showing promising results as monotherapy and adjunctive therapy in individuals with drug-refractory focal seizures while minimizing adverse drug reactions

Temporal resolution of protein–protein interactions in the live-cell plasma membrane

We have recently devised a method to quantify interactions between a membrane protein (“bait”) and a fluorophore-labeled protein (“prey”) directly in the live-cell plasma membrane (Schwarzenbacher et al. Nature Methods 5:1053–1060 2008). The idea is to seed cells on surfaces containing micro-patterned antibodies against the exoplasmic domain of the bait, and monitor the co-patterning of the fluorescent prey via fluorescence microscopy. Here, we characterized the time course of bait and prey micropattern formation upon seeding the cells onto the micro-biochip. Patterns were formed immediately after contact of the cells with the surface. Cells were able to migrate over the chip surface without affecting the micropattern contrast, which remained constant over hours. On single cells, bait contrast may be subject to fluctuations, indicating that the bait can be released from and recaptured on the micropatterns. We conclude that interaction studies can be performed at any time-point ranging from 5 min to several hours post seeding. Monitoring interactions with time opens up the possibility for new assays, which are briefly sketched in the discussion section

Highly variable iron content modulates iceberg-ocean fertilisation and potential carbon export

Marine phytoplankton growth at high latitudes is extensively limited by iron availability. Icebergs are a vector transporting the bioessential micronutrient iron into polar oceans. Therefore, increasing iceberg fluxes due to global warming have the potential to increase marine productivity and carbon export, creating a negative climate feedback. However, the magnitude of the iceberg iron flux, the subsequent fertilization effect and the resultant carbon export have not been quantified. Using a global analysis of iceberg samples, we reveal that iceberg iron concentrations vary over 6 orders of magnitude. Our results demonstrate that, whilst icebergs are the largest source of iron to the polar oceans, the heterogeneous iron distribution within ice moderates iron delivery to offshore waters and likely also affects the subsequent ocean iron enrichment. Future marine productivity may therefore be not only sensitive to increasing total iceberg fluxes, but also to changing iceberg properties, internal sediment distribution and melt dynamics

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected