The nucleation of C-S-H via prenucleation clusters.

The nucleation and growth of calcium-silicate-hydrate (C-S-H) is of fundamental importance for the strength development and durability of the concrete. However, the nucleation process of C-S-H is still not fully understood. The present work investigates how C-S-H nucleates by analyzing the aqueous phase of hydrating tricalcium silicate (C3S) by applying inductively coupled plasma-optical emission spectroscopy as well as analytical ultracentrifugation. The results show that the C-S-H formation follows non-classical nucleation pathways associated with the formation of prenucleation clusters (PNCs) of two types. Those PNCs are detected with high accuracy and reproducibility and are two species of the 10 in total, from which the ions (with associated water molecules) are the majority of the species. The evaluation of the density and molar mass of the species shows that the PNCs are much larger than ions, but the nucleation of C-S-H starts with the formation of liquid precursor C-S-H (droplets) with low density and high water content. The growth of these C-S-H droplets is associated with a release of water molecules and a reduction in size. The study gives experimental data on the size, density, molecular mass, and shape and outlines possible aggregation processes of the detected species.

Fusarium mirum sp. nov, intertwining Fusarium madaense and Fusarium andiyazi, pathogens of tropical grasses.

Many species in the Fusarium fujikuroi Species Complex (FFSC) have an affinity for grass species, with whom they live in an endophytic association or cause disease. We recovered isolates of Fusarium from agriculturally important grasses in Africa and Brazil, and characterized them with morphological markers, mating type, and Amplified Fragment Length Polymorphisms (AFLPs). We also conducted multi-locus phylogenetic analyses based on partial DNA sequences of translation elongation factor-1α (TEF1), ß-tubulin (TUB), and the second largest subunit of RNA polymerase (RPB2) gene regions. Sexual cross fertility was used to test the biological species concept and the sexual stage of F. madaense is described. A novel species within the FFSC, Fusarium mirum, that is different from the other known species in the complex, was formally described. Fusarium mirum, F. madaense, and Fusarium andiyazi are a tightly intertwined species trio that are morphologically identical, but phylogenetically distinguishable, and amongst whom interspecific genetic exchange may still occur. These three species are so close that they cannot be reliably distinguished if only sequences of the TEF1 gene are used. In pathogenicity tests, all tested isolates of F. madaense from sugarcane, sorghum, maize, millet and Brachiaria could induce stalk rot in sorghum, maize and millet, and pokkah boeng in sugarcane. This study increases our understanding of the diversity of species within the FFSC that cause disease in tropical grasses or act as endophytes, and their geographic distributions. The genetically close relationship between F. mirum, F. madaense, and F. andiyazi provides an opportunity to study and identify factors underlying their limited inter-specific cross-fertility and sympatric speciation.

Charge regulated solid-liquid interfaces interacting on the nanoscale: Benchmarking of a generalized speciation code (SINFONIA).

Surface chemistry of mineral phases in aqueous environments generates the electrostatic forces involved in particle-particle interactions. However, few models directly take into account the influence of surface speciation and changes in solution speciation when the diffuse layer potential profiles of approaching particles overlap and affect each other. These electrostatic interactions can be quantified, ideally, through charge regulation, considering solution and surface speciation changes upon particle approach by coupling state-of-the-art surface complexation models for the two particle surfaces with a Poisson-Boltzmann type distribution of electrostatic potential and ions in the inter-particle space. These models greatly improve the accuracy of inter-particle force calculations at small inter-particle separations compared to constant charge and constant potential approaches. This work aims at advancing charge regulation calculations by including full chemical speciation and advanced surface complexation models (Basic Stern-, three-, or four plane models and charge distribution concepts), for cases of similar and dissimilar surfaces involving the numerical solution of the Poisson-Boltzmann equation for arbitrary electrolytes. The concept was implemented as a Python-based code and in COMSOL. The flexibility and precision of both, concept and implementations are demonstrated in several benchmark calculations testing the new codes against published results or simulations using established speciation codes, including aqueous speciation, surface complexation and various interaction force examples. Due to the flexibility in terms of aqueous chemistry and surface complexation models for various geometries, a large variety of potential applications can be tackled with the developed codes including industrial, biological, and environmental systems, from colloidal suspensions to gas bubbles, emulsions, slurries like cement paste, as well as new possibilities to assess the chemistry in nano-confined systems.

Fusarium fujikuroi species complex in Brazilian rice: Unveiling increased phylogenetic diversity and toxigenic potential.

Fusarium fujikuroi species complex (FFSC) species are commonly encountered infecting rice, but knowledge of the diversity and toxigenic potential of the species is lacking in Brazil, the largest rice-producing country outside Asia. One hundred FFSC isolates obtained from national rice were identified using morphology and phylogeny of TEF, CAL and TUB genes. Eight previously known and one novel Fusarium species were identified. Three species accounted for around 60% of the strains: F. fujikuroi (n = 23), F. proliferatum (n = 22) and F. verticillioides (n = 16). The less frequent species were F. volatile (n = 8), F. anthophilum (n = 6), F. pseudocircinatum (n = 4), F. sterilihyphosum (n = 2) and F. begoniae (n = 1). The novel Fusarium species was represented by 18 isolates. All species produced at least one of the analyzed mycotoxins [beauvericin (BEA), fumonisins (FBs), moniliformin (MON) and enniatins (ENNs)]. BEA was produced by all species but F. verticillioides. The FBs (mainly FB1) were produced mostly by F. fujikuroi, F. proliferatum and F. verticillioides. F. begoniae and F. verticillioides did not produce ENNs and F. sterilihyphosum and F. begoniae did not produce MON, while the other species produced MON and ENNs. Our results add new knowledge of the diversity, geographical distribution and host range of FFSC species.

Hydrocephalus shunt therapy: current titanium shunt valve implants obstructed by internal tissue proliferations identified as extracellular matrix membranes.

PURPOSE: Shunt valves, required for treatment of hydrocephalus, demand for high performance rates and lifelong excellent function. To overcome problems with traditional silicone materials, adjustable and gravity-adapted titanium valves were developed. Even modern shunt valve systems are still subject to occlusion. The aim of the present study was to investigate dysfunctional silicone and titanium valves for presence of cellular and proteinous materials inside the housings by means of histopathology. METHODS: A total of 19 explanted shunt valves from children between 2 and 182 months of age were investigated following dysfunction. After fixation in formalin and embedding in hard resin, slices were ground to a thickness of 5-30 µ. Besides standard histology, immunohistochemistry was performed using antibodies with markers for microglia, astrocytes, platelets, monocytes, and the proteins laminin, fibronectin, and collagen IV. RESULTS: Traces, layers, and plaques could be demonstrated in every investigated silicone or titanium valve with an implantation time of more than 6 days. Most of the tissue was found adjacent to silicone and titanium surfaces of the inner housing, the adjustment rotor, and ball-in-cone core. Markers for micro and astroglia stained positive in 40-60% of the specimen, mostly demonstrating a proteinous layer positive for laminin (80%), fibronectin (30%), and collagen IV (30%). CONCLUSIONS: Tissue reactions with formation of cellular and proteinous matrix components are common in obstructed silicone and titanium shunt valves. The tissue mimics astrocytic repair mechanisms genuine for basilar membrane matrix. The knowledge of these typical arachnoid patterns of colonization is a prerequisite for developing future shunt devices.

Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: Modulation by the immunotherapeutic LNFPIII.

Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6 J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethyl-methylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-HT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.

Fusarium incarnatum-equiseti species complex associated with Brazilian rice: Phylogeny, morphology and toxigenic potential.

Fusarium incarnatum-equiseti species complex (FIESC) is commonly detected in Brazilian rice, but knowledge of the species limits and their toxigenic potential is lacking. Seventy strains morphologically identified as FIESC-like, isolated from the major rice-growing regions of Brazil, were subjected to sequencing of EF-1α gene. Among them, 18 strains were selected and analyzed for their RPB2 gene sequences. Nine phylogenetic species were identified, among which eight matched the previously reported FIESC 4 (F. lacertarum), 6, 16, 17 (F. pernambucanum), 20 (F. caatingaense), 24, 26 and 29. One new phylogenetic species was identified, and named FIESC 38. Five strains formed new singleton lineages. The most dominant species were FIESC 26 (22/70 strains) and FIESC 38 (21/70), the newly identified species. The incarnatum morphotype was dominant (10 phylogenetic species) over the equiseti (4 species). Among 46 strains selected to represent all species, only 16 strains produced detectable levels of mycotoxins in vitro. FIESC 26 produced ZEA and FIESC 38 produced both ZEA and DON. ZEA was produced by nine isolates of three other species, among which few isolates produced trichothecenes: DON (5/46), NIV (3/46), 4-ANIV (2/46), 15-ADON (1/46) and 3-ADON (1/46). The T-2 and HT-2 mycotoxins were not detected. Our results contribute novel information on species limits and mycotoxin production within cereal-infecting FIESC in the southern hemisphere and provide baseline data for further exploring morphological differences among the species.

Epidemiology of Exobasidium Leaf and Fruit Spot of Rabbiteye Blueberry: Pathogen Overwintering, Primary Infection, and Disease Progression on Leaves and Fruit.

Epidemiological field studies utilizing disease monitoring, spore trapping, and trap plants were conducted on rabbiteye blueberry (Vaccinium virgatum) between 2014 and 2017 to shed light on the epidemiology of Exobasidium leaf and fruit spot, an emerging disease in the southeastern United States caused by the fungus Exobasidium maculosum. Wash plating of field-collected blueberry tissue from the late dormant season through bud expansion showed that the pathogen overwintered epiphytically on blueberry plants in the field, most likely in its yeast-like conidial stage. Agrichemical applications during the dormant season altered epiphytic populations of the pathogen, which correlated directly with leaf spot incidence later in the spring. Disease monitoring of field plants and weekly exposure of potted trap plants revealed that young leaves at the mouse-ear stage were most susceptible to infection, that disease incidence on leaves progressed monocyclically, and that infection periods were associated with rainfall variables such as the number of days per week with ≥1.0 mm of rain or cumulative weekly rainfall. Weekly spore trapping with an Andersen sampler showed that airborne inoculum was detected only after sporulating leaf lesions producing basidiospores were present in the field, suggesting that the primary inoculum is not airborne. The first symptoms on young, green fruit were observed soon after petal fall (requiring removal of the waxy fruit layer to visualize lesions), and visible disease progress on fruit was delayed by 1 to 3 weeks relative to that on leaves. Fruit infection of field plants and trap plants occurred before airborne propagules were detected by spore trapping and before sporulating leaf lesions were present in the field. Hence, this study showed that fruit infections are initiated by the same initial inoculum as leaf infections but it was not possible to conclusively exclude the possibility of a contribution of basidiospore inoculum from leaf lesions to disease progress on later developing fruit. This is one of only a few studies addressing the epidemiology and disease cycle of an Exobasidium sp. in a pathosystem where artificial inoculation has not been possible to date.

Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension.

BACKGROUND: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. METHODS: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs. RESULTS: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. CONCLUSIONS: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions.

Differential metabolism of diastereoisomeric diterpenes by Preussia minima, found as endophytic fungus in Cupressus lusitanica.

The plant diastereoisomeric diterpenes ent-pimara-8(14)-15-dien-19-oic acid, obtained from Viguiera arenaria, and isopimara-8(14)-15-dien-18-oic acid, isolated from Cupressus lusitanica, were distinctly functionalized by the enzymes produced in whole cell cultures of the fungus Preussia minima, isolated from surface sterilized stems of C. lusitanica. The ent-pimaradienoic acid was transformed into the known 7ß-hydroxy-ent-pimara-8(14)-15-dien-19-oic acid, and into the novel diterpenes 7-oxo-8 ß-hydroxy-ent-pimara-8(14)-15-dien-19-oic and 7-oxo-9ß-hydroxy-ent-pimara-8(14)-15-dien-19-oic acids. Isopimara-8(14)-15-dien-18-oic acid was converted into novel diterpenes 11α-hydroxyisopimara-8(14)-15-dien-18-oic acid, 7ß,11α-dihydroxyisopimara-8(14)-15-dien-18-oic acid, and 1ß,11α-dihydroxyisopimara-8(14)-15-dien-18-oic acid, along with the known 7ß-hydroxyisopimara-8(14)-15-dien-18-oic acid. All compounds were isolated and fully characterized by 1D and 2D NMR, especially 13C NMR. The diterpene bioproduct 7-oxo-9ß-hydroxy-ent-pimara-8(14)-15-dien-19-oic acid is an isomer of sphaeropsidin C, a phytotoxin that affects cypress trees produced by Shaeropsis sapinea, one of the main phytopathogen of Cupressus. The differential metabolism of the diterpene isomers used as substrates for biotransformation was interpreted with the help of computational molecular docking calculations, considering as target enzymes those of cytochrome P450 group.

Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel.

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment.

Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after ⩾2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomide-exposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit-risk profile and should be considered an appropriate treatment option for patients with 1 or ⩾2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.

Efficacy and safety of carfilzomib regimens in multiple myeloma patients relapsing after autologous stem cell transplant: ASPIRE and ENDEAVOR outcomes.

Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib-lenalidomide-dexamethasone; ENDEAVOR, carfilzomib-dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide-dexamethasone; ENDEAVOR, bortezomib-dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

Lactone Derivatives Produced by a Phaeoacremonium sp., an Endophytic Fungus from Senna spectabilis.

Three new isoaigialones, A, B, and C (1-3), along with aigialone (4), were isolated from the crude EtOAc extract of a Phaeoacremonium sp., an endophytic fungus obtained from the leaves of Senna spectabilis. The structures of these compounds were elucidated based on the analysis of spectroscopic data. Compounds 2 and 4 were active against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum. This is the first report of metabolites produced by an Phaeoacremonium sp., associated with S. spectabilis.