Cyanobacteria blooms induced precipitation of calcium carbonate and dissolution of silica in a subtropical lagoon, Florida Bay, USA.

In recent decades, annual cyanobacteria blooms in Florida Bay displayed spatial and temporal patterns that are consistent with changes in alkalinity and dissolved silicon in water. In early summer, the blooms developed in the north-central bay and spread southward in fall. The blooms drew down dissolved inorganic carbon and increased water pH, causing in situ precipitation of calcium carbonate. Dissolved silicon concentrations in these waters were at minimum in spring (20-60 µM), increased during summer, and reached an annual maximum (100-200 µM) during late summer. The dissolution of silica as a result of high pH in bloom water was first observed in this study. During the peak of blooms, silica dissolution in Florida Bay varied from 0.9 × 107 to 6.9 × 107 mol per month over the study period, depending on the extent of cyanobacteria blooms in a given year. Concurrent calcium carbonate precipitations in the cyanobacteria bloom region are between 0.9 × 108 and 2.6 × 108 mol per month. It is estimated that 30-70% of atmospheric CO2 uptake in bloom waters was precipitated as calcium carbonate mineral and remainders of CO2 influx were used for the production of biomass.

Why is calcite a strong phosphorus sink in freshwater? Investigating the adsorption mechanism using batch experiments and surface complexation modeling.

One of the primary drivers of Phosphorus (P) limitation in aquatic systems is P adsorption to sediments. Sediments adsorb more P in freshwater compared to other natural solutions, but the mechanism driving this difference is poorly understood. To provide insights into the mechanism, we conducted batch experiments of P adsorption to calcite in freshwater and seawater, and used computer software to develop complexation models. Our simulations revealed three main reasons that, combining together, may explain the greater P adsorption to calcite in freshwater vs. seawater. First, aqueous speciation of P makes a difference. The ion pair CaPO4- is much more abundant in freshwater; although seawater has more Ca2+ ions, MgHPO40 and NaHPO40 are more thermodynamically favored. Second, the adsorbing species of P make a difference. The ion pair CaPO4- (the preferred adsorbate in freshwater) is able to access adsorption sites that are not available to HPO42- (the preferred adsorbate in seawater), thereby raising the maximum concentration of P that can adsorb to the calcite surface in freshwater. Third, water chemistry affects the competition among ions for surface sites. Other ions (including P) compete more effectively against CO32- when immersed in freshwater vs. seawater, even when the concentration of HCO3-/CO32- is higher in freshwater vs. seawater. In addition, we found that under oligotrophic conditions, P adsorption is driven by the higher energy adsorption sites, and by the lower energy sites in eutrophic conditions. This study is the first to model P adsorption mechanisms to calcite in freshwater and seawater.

Small-world effects in a modified epidemiological model with mutation and permanent immune mechanism.

Pandemic with mutation and permanent immune spreading in a small-world network described is studied by a modified SIR model, with consideration of mutation-immune mechanism. First, a novel mutation-immune model is proposed to modify the classical SIR model to simulate the transmission of mutable viruses that can be permanently immunized in small-world networks. Then, the influences of the size, coordination number and disorder parameter of the small-world network on the spread of the epidemic are analyzed in detail. Finally, the influences of mutation cycle and infection rate on epidemic transmission in small-world network are investigated further. The results show that the structure of the small-world network and the virus mutation cycle have an important impact on the spread of the epidemic. For viruses that can be permanently immunized, virus mutation is equivalent to making the immune cycle of human beings from infinite to finite. The dynamical behavior of the modified SIR epidemic model changes from an irregular, low-amplitude evolution at small disorder parameter to a spontaneous state of wide amplitude oscillations at large disorder parameter. Moreover, similar transition can also be found in increasing mutation cycle parameter. The maximum valid variation mutation decreases with the increase of disorder parameter and coordination number, but increase with respect to system size. In addition above, as the infection rate increases, the fraction of the infected increases and then decreases. As the mutation cycle increases, the time-average fraction of the infected and the infection rate corresponding to the maximum time-average fraction of the infected also decrease. As one conclusion, the results could give a deep understanding Pandemic with mutation and permanent immune spreading, from viewpoint of small-world network.

Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aß deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

A Route to Chaotic Behavior of Single Neuron Exposed to External Electromagnetic Radiation.

Non-linear behaviors of a single neuron described by Fitzhugh-Nagumo (FHN) neuron model, with external electromagnetic radiation considered, is investigated. It is discovered that with external electromagnetic radiation in form of a cosine function, the mode selection of membrane potential occurs among periodic, quasi-periodic, and chaotic motions as increasing the frequency of external transmembrane current, which is selected as a sinusoidal function. When the frequency is small or large enough, periodic, and quasi-periodic motions are captured alternatively. Otherwise, when frequency is in interval 0.778 < ω < 2.208, chaotic motion characterizes the main behavior type. The mechanism of mode transition from quasi-periodic to chaotic motion is also observed when varying the amplitude of external electromagnetic radiation. The frequency apparently plays a more important role in determining the system behavior.

An estimate of diapycnal nutrient fluxes to the euphotic zone in the Florida Straits.

A recent hydrographic survey of the Florida Current at 27°N revealed an enhanced upward flux of nutrients along the Florida coast. Geostrophic flow of the Gulf Stream through the narrow Florida Straits causes an uplift of the nutricline toward its western edge, shoaling the mixed layers into the base of the euphotic zone. At a nearshore station, nitrate, phosphate, and silicate concentrations reached 19, 1.4, and 10 µM, respectively, at a water depth of 27 m. Furthermore, nutrient vertical gradients below the mixed layer increased with decreasing seafloor depth toward the Florida coast. The estimated vertical eddy diffusive nutrient fluxes across diapycnal surfaces reached 0.40-83.7, 0.03-6.24, and 0.24-45.5 mmol m-2 d-1 for nitrate, phosphate, and silicate, respectively, along the shore. Estimated fluxes span a wide range due to the range of diffusivity measured. The lower end of estimated fluxes are comparable to open ocean values, but higher end of estimates are two orders of magnitude greater than those observed in open ocean. The diapycnal nutrient fluxes declined rapidly offshore as a result of decreasing vertical gradients of nutrient concentration.

Spike-like solitary waves in incompressible boundary layers driven by a travelling wave.

Nonlinear waves produced in an incompressible boundary layer driven by a travelling wave are investigated, with damping considered as well. As one of the typical nonlinear waves, the spike-like wave is governed by the driven-damped Benjamin-Ono equation. The wave field enters a completely irregular state beyond a critical time, increasing the amplitude of the driving wave continuously. On the other hand, the number of spikes of solitary waves increases through multiplication of the wave pattern. The wave energy grows in a sequence of sharp steps, and hysteresis loops are found in the system. The wave energy jumps to different levels with multiplication of the wave, which is described by winding number bifurcation of phase trajectories. Also, the phenomenon of multiplication and hysteresis steps is found when varying the speed of driving wave as well. Moreover, the nature of the change of wave pattern and its energy is the stability loss of the wave caused by saddle-node bifurcation.

Growth and Optical Spectra of Tb³âº/Sm³âº/Ce³âº Triply Doped LiYF4Single Crystals for White-Light LEDs.

The Tb³âº/Sm³âº/Ce³âº triply doped LiYF4 single crystals were grown by a modified Bridgman method. The absorption spectra, excitation spectra, and fluorescence spectra of Tb³âº/Sm³âº/Ce³âº ions in LiYF4 crystals were measured. The fluorescence spectra of several bands, mainly located at purplish blue ~413 nm (5D3 --> 7F5), yellowish green ~542 nm (5D4 --> 7F5), and red ~643 nm (4G5/2 --> 6H9/2), were observed under excitation of ultraviolet light. White light could be generated by the mixture of the multicolor lights. The luminous intensities varied slightly with the excitation wavelength from 300 nm to 400 nm and doping Tb³âº/Sm³âº/Ce³âº ion concentration. The chromatic- ity coordinates of the crystal could be modified by changing the excitation wavelengths and the concentrations of Tb³âº/Sm³âº/Ce³âº ions. A near-ideal white light emission could be obtained from 1.25 mol% Tb³âº, 1.98 mol% Sm³âº, 0.44 mol% Ce³âº triply doped LiYF4 single crystal with chro- maticity coordinates of x = 0.3090, y = 0.3223, color temperature Tc = 6777 K, color rendering index Ra = 77 and color quality scale Qa = 76 under the excitation of a 374 nm light.

Energy Transfer and 1.8 µm Emission in Tm³âº/Yb³âº Co-Doped LiYF4Crystal.

LiYF4 single crystals co-doped with various Tm³âº/Yb³âº concentrations were grown using the Bridg- man method. The luminescent properties of the crystals were investigated through emission spectra, emission cross section, and decay curves under excitation by 980 nm. Compared with the Tm³âº single-doped LiYF4 crystal, an enhanced emission band from 1600 to 2150 nm was observed upon excitation of a 980 nm laser diode. The energy transfer from Yb³âº to Tm³âº and the optimum fluo- rescence emission around 1.80 µm of Tm³âº ion were investigated. The maximum emission cross section at 1.8 µm was calculated to be 1.48 x 10⁻²° cm² according to the measured absorption spectrum. The high energy transfer efficiency of 86.5% from Yb³âº to Tm³âº ion demonstrate that the Yb³âº ions can efficiently sensitize the Tm³âº ions.

Highly Efficient LiYF4:Yb(3+), Er(3+) Upconversion Single Crystal under Solar Cell Spectrum Excitation and Photovoltaic Application.

Luminescent upconversion is a promising way to harvest near-infrared (NIR) sunlight and transforms it into visible light that can be directly absorbed by active materials of solar cells and improve their power conversion efficiency (PCE). However, it is still a great challenge to effectively improve the PCE of solar cells with the assistance of upconversion. In this work, we demonstrate the application of the transparent LiYF4:Yb(3+), Er(3+) single crystal as an independent luminescent upconverter to improve the PCE of perovskite solar cells. The LiYF4:Yb(3+), Er(3+) single crystal is prepared by an improved Bridgman method, and its internal quantum efficiency approached to 5.72% under 6.2 W cm(-2) 980 nm excitation. The power-dependent upconversion luminescence indicated that under the excitation of simulated sunlight the (4)F(9/2)-(4)I(15/2) red emission originally results from the cooperation of a 1540 nm photon and a 980 nm photon. Furthermore, when the single crystal is placed in front of the perovskite solar cells, the PCE is enhanced by 7.9% under the irradiation of simulated sunlight by 7-8 solar constants. This work implies the upconverter not only can serve as proof of principle for improving PCE of solar cells but also is helpful to practical application.

RAF inhibitors that evade paradoxical MAPK pathway activation.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.

UNLABELLED: Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has been frequently implicated in TKI resistance. The molecular underpinnings of gatekeeper mutation-mediated resistance are incompletely understood. We report the first cocrystal structure of FLT3 with the TKI quizartinib, which demonstrates that quizartinib binding relies on essential edge-to-face aromatic interactions with the gatekeeper F691 residue, and F830 within the highly conserved Asp-Phe-Gly motif in the activation loop. This reliance makes quizartinib critically vulnerable to gatekeeper and activation loop substitutions while minimizing the impact of mutations elsewhere. Moreover, we identify PLX3397, a novel FLT3 inhibitor that retains activity against the F691L mutant due to a binding mode that depends less vitally on specific interactions with the gatekeeper position. SIGNIFICANCE: We report the first cocrystal structure of FLT3 with a kinase inhibitor, elucidating the structural mechanism of resistance due to the gatekeeper F691L mutation. PLX3397 is a novel FLT3 inhibitor with in vitro activity against this mutation but is vulnerable to kinase domain mutations in the FLT3 activation loop.

Carbon dynamics of Florida Bay: spatiotemporal patterns and biological control.

Carbon dynamics of Florida Bay is manifested by wide ranges of pH (7.65-8.61), dissolved inorganic carbon (DIC, 929-3223 µM) and partial pressure of CO2 (pCO2, 50-1313 µatm) observed over seven years. Despite the seasonal variation, a decline of -0.0066 pH per year was observed as a result of ocean acidification and the spatiotemporal patterns were consistent with known biological processes in the bay. Microbial respiration of organic matter produced high pCO2, resulting in Florida Bay being a CO2 source to the atmosphere during winter and spring. In summer, cyanobacteria blooms developed in the north central bay drew down pCO2, causing bloom waters to become a CO2 sink while the nonbloom waters shrunk but remained a CO2 source. The maxima local CO2 fluxes were 36.4 ± 10.5 and -14.0 ± 5.6 mmol m(-2) d(-1) for the source and sink region, respectively. Cyanobacteria blooms modulated the interannual variation in bay-wide CO2 net flux, which averaged 7.96 × 10(9) ± 1.84 × 10(9) mol yr(-1). Extensive cyanobacteria blooms in 2009 resulted in a 50% reduction in the net CO2 flux as compared with 2010 when a minimal cyanobacteria bloom occurred.

A portable analyser for the measurement of ammonium in marine waters.

A portable ammonium analyser was developed and used to measure in situ ammonium in the marine environment. The analyser incorporates an improved LED photodiode-based fluorescence detector (LPFD). This system is more sensitive and considerably smaller than previous systems and incorporates a pre-filtering subsystem enabling measurements in turbid, sediment-laden waters. Over the typical range for ammonium in marine waters (0­10 mM), the response is linear (r(2) = 0.9930) with a limit of detection (S/N ratio > 3) of 10 nM. The working range for marine waters is 0.05­10 mM. Repeatability is 0.3% (n =10) at an ammonium level of 2 mM. Results from automated operation in 15 min cycles over 16 days had good overall precision (RSD = 3%, n = 660). The system was field tested at three shallow South Florida sites. Diurnal cycles and possibly a tidal influence were expressed in the concentration variability observed.

Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.

Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.

Vemurafenib: the first drug approved for BRAF-mutant cancer.

The identification of driver oncogenes has provided important targets for drugs that can change the landscape of cancer therapies. One such example is the BRAF oncogene, which is found in about half of all melanomas as well as several other cancers. As a druggable kinase, oncogenic BRAF has become a crucial target of small-molecule drug discovery efforts. Following a rapid clinical development path, vemurafenib (Zelboraf; Plexxikon/Roche) was approved for the treatment of BRAF-mutated metastatic melanoma in the United States in August 2011 and the European Union in February 2012. This Review describes the underlying biology of BRAF, the technology used to identify vemurafenib and its clinical development milestones, along with future prospects based on lessons learned during its development.

Phosphorus sorption on marine carbonate sediment: phosphonate as model organic compounds.

Organophosphonate, characterized by the presence of a stable, covalent, carbon to phosphorus (C-P) bond, is a group of synthetic or biogenic organophosphorus compounds. The fate of these organic phosphorus compounds in the environment is not well studied. This study presents the first investigation on the sorption of phosphorus (P) in the presence of two model phosphonate compounds, 2-aminothylphosphonoic acid (2-AEP) and phosphonoformic acid (PFA), on marine carbonate sediments. In contrast to other organic P compounds, no significant inorganic phosphate exchange was observed in seawater. P was found to adsorb on the sediment only in the presence of PFA, not 2-AEP. This indicated that sorption of P from phosphonate on marine sediment was compound specific. Compared with inorganic phosphate sorption on the same sediments, P sorption from organic phosphorus is much less in the marine environment. Further study is needed to understand the potential role of the organophosphonate compounds in biogeochemical cycle of phosphorus in the environment.