Soil phosphorus dynamics following land application of unsaturated and partially saturated red mud and water treatment residuals.

The secondary use of P-sorbing industrial by-products as a fertilizer or soil conditioner is gaining increased attention, particularly in light of diminishing reserves of rock phosphate traditionally used to manufacture P fertilizer. This study examined applications of red mud (RM) and water treatment residuals (WTR) at two levels of P saturation (i.e. 'as received' and partially saturated) in a soil incubation and runoff plot study. When incubated with soils ranging in texture and initial P concentration, P-sorbing residuals that were less enriched with P decreased water-extractable soil P (WEP) concentration to a greater extent than more P saturated residuals. In contrast to WTR treatments, not all of the RM applications decreased soil WEP concentrations below those of the control soils. The runoff study investigated soil P dynamics when partially P-saturated RM and WTR's were surface applied to grass plots at 2 t ha-1 on Day 0, followed by three rainfall simulations (7 cm h-1 for 30 min, Days 2, 7 and 28) and at 3 t ha-1 on Day 70 followed by two more rainfall simulations (Days 77 and 96). Application of residuals at these rates did not significantly increase dissolved reactive P (DRP) in runoff compared with unamended controls during the study. Forage cuttings taken 90 days after the first rainfall simulation indicated that nutrient uptake was not compromised by the application of the residuals. Overall results indicate that WTRs may be a more suitable soil amendment than RM residuals given their greater ability to reduce soil WEP across a range of soils without simultaneously increasing Mehlich-3 extractable soil P concentrations above the upper threshold limit (150 mg P kg-1), and their minimal impact on plant nutrient uptake.

Hypofractionated Concomitant Chemoradiation in Inoperable Locally Advanced Non-small Cell Lung Cancer: A Report on 100 Patients and a Systematic Review.

AIMS: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. MATERIALS AND METHODS: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. RESULTS: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. CONCLUSION: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial.

Social touch during development: Long-term effects on brain and behavior.

In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and "natural experiments", such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.

Chronic Intranasal Oxytocin has Dose-dependent Effects on Central Oxytocin and Vasopressin Systems in Prairie Voles (Microtus ochrogaster).

Oxytocin (Oxt) is a neuropeptide with many functions, including modulation of social behavior(s) and anxiety. Due to its notable pro-social effects, it has been proposed as a treatment in the management of neuropsychiatric disorders, such as autism spectrum disorder (ASD), schizophrenia, and social anxiety; however, effects of long-term daily treatment are still being explored. Previously, we have shown that in male prairie voles (Microtus ochrogaster) exposure to Oxt during the peri-adolescent period impaired adult pair bonding in a dose-dependent fashion. In females, the medium dose used (0.8 IU/kg) appeared to facilitate pair bonding, and the low and medium doses were associated with fewer lines crossed in the open field. In this study, we examined central receptor binding and immunoreactive (IR) protein for Oxt and vasopressin (Avp), a closely related peptide. Voles were treated with saline vehicle, or one of three doses of Oxt (0.08, 0.8, 8.0 IU/kg) for three weeks from postnatal days 21 to 42, and euthanized as adults. We used autoradiography to examine Oxt and Avp receptor binding and immunohistochemistry to examine Oxt and Avp - IR cells in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. Females that received the medium dose of Oxt had higher Oxt receptor binding in the nucleus accumbens shell (NAS), while males that received the medium dose had lower Avp-IR cells in the PVN. In summary, we found sex-specific effects of long-term exposure to intranasal Oxt on the Oxt and Avp systems at the weight-adjusted dose currently being used in clinical trials in humans.

Structural and electronic determinants of lytic polysaccharide monooxygenase reactivity on polysaccharide substrates.

Lytic polysaccharide monooxygenases (LPMOs) are industrially important copper-dependent enzymes that oxidatively cleave polysaccharides. Here we present a functional and structural characterization of two closely related AA9-family LPMOs from Lentinus similis (LsAA9A) and Collariella virescens (CvAA9A). LsAA9A and CvAA9A cleave a range of polysaccharides, including cellulose, xyloglucan, mixed-linkage glucan and glucomannan. LsAA9A additionally cleaves isolated xylan substrates. The structures of CvAA9A and of LsAA9A bound to cellulosic and non-cellulosic oligosaccharides provide insight into the molecular determinants of their specificity. Spectroscopic measurements reveal differences in copper co-ordination upon the binding of xylan and glucans. LsAA9A activity is less sensitive to the reducing agent potential when cleaving xylan, suggesting that distinct catalytic mechanisms exist for xylan and glucan cleavage. Overall, these data show that AA9 LPMOs can display different apparent substrate specificities dependent upon both productive protein-carbohydrate interactions across a binding surface and also electronic considerations at the copper active site.

A Critical Review of All Known Published Records for Water Mite (Acari: Hydrachnidiae) and Mosquito (Diptera: Culicidae) Parasitic Associations From 1975 to Present.

All published records of water mite-mosquito parasitic associations since Gary R. Mullen's comprehensive review in the 1970s of the literature were critiqued to provide an up-to-date account on the identity of water mites parasitizing mosquitoes and their geographic distribution. In total, 321 records in 62 sources were identified, with each record representing an association specific to a state, province, or region within a country. The greatest number of records were from the United States (120), followed by India (106) and Canada (40). In all, 105 species of mosquitoes were parasitized, with the majority belonging to the genera Aedes sensu lato (30), Anopheles (30), and Culex (21). Records were biased toward mosquito genera with the greatest number of freshwater species and medical importance. Most water mites belonged to the genus Arrenurus, or were Parathyas barbigera (Viets 1908). Arrenurus water mites were often not identified to species, but 15 different Arrenurus species were determined in 119 records. All but one of the species (i.e., Arrenurus madaraszi Daday 1898) were only reported from Canada, Germany, or the United States. Although a greater proportion of sources reviewed by us compared with Mullen's review identified water mites down to the level of genus, to better understand the biological significance of mite and mosquito interactions, more of an effort is needed to identify the species of water mites. The availability of molecular techniques such as DNA barcoding will make this goal more attainable.

Decision tree analysis as a supplementary tool to enhance histomorphological differentiation when distinguishing human from non-human cranial bone in both burnt and unburnt states: A feasibility study.

This feasibility study was undertaken to describe and record the histological characteristics of burnt and unburnt cranial bone fragments from human and non-human bones. Reference series of fully mineralized, transverse sections of cranial bone, from all variables and specimen states, were prepared by manual cutting and semi-automated grinding and polishing methods. A photomicrograph catalogue reflecting differences in burnt and unburnt bone from human and non-humans was recorded and qualitative analysis was performed using an established classification system based on primary bone characteristics. The histomorphology associated with human and non-human samples was, for the main part, preserved following burning at high temperature. Clearly, fibro-lamellar complex tissue subtypes, such as plexiform or laminar primary bone, were only present in non-human bones. A decision tree analysis based on histological features provided a definitive identification key for distinguishing human from non-human bone, with an accuracy of 100%. The decision tree for samples where burning was unknown was 96% accurate, and multi-step classification to taxon was possible with 100% accuracy. The results of this feasibility study strongly suggest that histology remains a viable alternative technique if fragments of cranial bone require forensic examination in both burnt and unburnt states. The decision tree analysis may provide an additional but vital tool to enhance data interpretation. Further studies are needed to assess variation in histomorphology taking into account other cranial bones, ontogeny, species and burning conditions.

Seasonal Activity, Density, and Collection Efficiency of the Blacklegged Tick (Ixodes scapularis) (Acari: Ixodidae) in Mid-Western Pennsylvania.

Although Pennsylvania has recently reported the greatest number of Lyme disease cases in the United States, with the largest increase for PA occurring in its western region, the population biology of the blacklegged tick (Ixodes scapularis Say) has not been adequately characterized in western PA. We studied the seasonal activity of host-seeking I. scapularis larvae, nymphs, and adults in mid-western PA over the course of a year, including a severe winter, and determined their absolute densities and collection efficiencies using replicated mark-release-recapture or removal methods. Our results are compared to those from similar studies conducted in the highly Lyme disease endemic Hudson Valley region of southeastern New York State. The seasonal activity of I. scapularis was intermediate between patterns observed in the coastal northeastern and upper Midwestern United States. Only one peak of larval activity was observed, which was later than the major peak in the Midwest, but earlier than in the northeast. Seasonal synchrony of larvae and nymphs was similar to the northeast, but the activity peaks were much closer together, although not completely overlapping as in the Midwest. Pre- and postwinter relative densities of questing adult I. scapularis were not significantly different from one another. The absolute densities and collection efficiencies of larvae, nymphs, and adults were comparable to results from classic research conducted at the Louis Calder Center in Westchester County, NY. We conclude that the population biology of I. scapularis in mid-western PA is similar to southeastern NYS contributing to a high acarological Lyme disease risk.

Prevalence Rates of Borrelia burgdorferi (Spirochaetales: Spirochaetaceae), Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae), and Babesia microti (Piroplasmida: Babesiidae) in Host-Seeking Ixodes scapularis (Acari: Ixodidae) from Pennsylvania.

The etiological agents responsible for Lyme disease (Borrelia burgdorferi), human granulocytic anaplasmosis (Anaplasma phagocytophilum), and babesiosis (Babesia microti) are primarily transmitted by the blacklegged tick, Ixodes scapularis Say. Despite Pennsylvania having in recent years reported the highest number of Lyme disease cases in the United States, relatively little is known regarding the geographic distribution of the vector and its pathogens in the state. Previous attempts at climate-based predictive modeling of I. scapularis occurrence have not coincided with the high human incidence rates in parts of the state. To elucidate the distribution and pathogen infection rates of I. scapularis, we collected and tested 1,855 adult ticks statewide from 2012 to 2014. The presence of I. scapularis and B. burgdorferi was confirmed from all 67 Pennsylvania counties. Analyses were performed on 1,363 ticks collected in the fall of 2013 to avoid temporal bias across years. Infection rates were highest for B. burgdorferi (47.4%), followed by Ba. microti (3.5%) and A. phagocytophilum (3.3%). Coinfections included B. burgdorferi+Ba. microti (2.0%), B. burgdorferi+A. phagocytophilum (1.5%) and one tick positive for A. phagocytophilum+Ba. microti. Infection rates for B. burgdorferi were lower in the western region of the state. Our findings substantiate that Lyme disease risk is high throughout Pennsylvania.

Selective roles of E2Fs for ErbB2- and Myc-mediated mammary tumorigenesis.

Previous studies have demonstrated that cyclin D1, an upstream regulator of the Rb/E2F pathway, is an essential component of the ErbB2/Ras (but not the Wnt/Myc) oncogenic pathway in the mammary epithelium. However, the role of specific E2fs for ErbB2/Ras-mediated mammary tumorigenesis remains unknown. Here, we show that in the majority of mouse and human primary mammary carcinomas with ErbB2/HER2 overexpression, E2f3a is up-regulated, raising the possibility that E2F3a is a critical effector of the ErbB2 oncogenic signaling pathway in the mammary gland. We examined the consequence of ablating individual E2fs in mice on ErbB2-triggered mammary tumorigenesis in comparison to a comparable Myc-driven mammary tumor model. We found that loss of E2f1 or E2f3 led to a significant delay in tumor onset in both oncogenic models, whereas loss of E2f2 accelerated mammary tumorigenesis driven by Myc-overexpression. Furthermore, southern blot analysis of final tumors derived from conditionally deleted E2f3(-/loxP) mammary glands revealed that there is a selection against E2f3(-/-) cells from developing mammary carcinomas, and that such selection pressure is higher in the presence of ErbB2 activation than in the presence of Myc activation. Taken together, our data suggest oncogenic activities of E2F1 and E2F3 in ErbB2- or Myc-triggered mammary tumorigenesis, and a tumor suppressor role of E2F2 in Myc-mediated mammary tumorigenesis.

Composite polysaccharide fibers prepared by electrospinning and coating.

Composite polysaccharide fibers composed two oppositely charged natural polysaccharides, chitosan and hyaluronic acid, were prepared by electrospinning and subsequent coating. The fiber size distribution was characterized by scanning electron microscopy. Chitosan/hyaluronic acid composite fibers were stable in water but showed controlled release of hyaluronic acid into phosphate buffered saline, and the presence of 3-wt% hyaluronic acid coating improved the swelling ratio to 30%. The resulting composite polysaccharide fibers have a number of potential biomedical applications in wound healing applications and in drug delivery systems.

Biomimetic assembly and activation of [FeFe]-hydrogenases.

Hydrogenases are the most active molecular catalysts for hydrogen production and uptake, and could therefore facilitate the development of new types of fuel cell. In [FeFe]-hydrogenases, catalysis takes place at a unique di-iron centre (the [2Fe] subsite), which contains a bridging dithiolate ligand, three CO ligands and two CN(-) ligands. Through a complex multienzymatic biosynthetic process, this [2Fe] subsite is first assembled on a maturation enzyme, HydF, and then delivered to the apo-hydrogenase for activation. Synthetic chemistry has been used to prepare remarkably similar mimics of that subsite, but it has failed to reproduce the natural enzymatic activities thus far. Here we show that three synthetic mimics (containing different bridging dithiolate ligands) can be loaded onto bacterial Thermotoga maritima HydF and then transferred to apo-HydA1, one of the hydrogenases of Chlamydomonas reinhardtii algae. Full activation of HydA1 was achieved only when using the HydF hybrid protein containing the mimic with an azadithiolate bridge, confirming the presence of this ligand in the active site of native [FeFe]-hydrogenases. This is an example of controlled metalloenzyme activation using the combination of a specific protein scaffold and active-site synthetic analogues. This simple methodology provides both new mechanistic and structural insight into hydrogenase maturation and a unique tool for producing recombinant wild-type and variant [FeFe]-hydrogenases, with no requirement for the complete maturation machinery.

Forebrain glucocorticoid receptor overexpression increases environmental reactivity and produces a stress-induced spatial discrimination deficit.

Reactivity to environmental stressors influences vulnerability to neurological and psychiatric illnesses, but little is known about molecular mechanisms that control this reactivity. Since mice with forebrain-specific glucocorticoid receptor overexpression (GRov mice) display anxiety-like behaviors in novel environments and have difficulty adjusting to change in memory tasks, we hypothesized that these may be facets of a broader phenotype of altered reactivity to environmental demands. Male GRov and wild-type mice were tested in a multiple-trial object interaction test comprising environmental and object habituation and spatial and object novelty trials. Half the mice received restraint stress before testing. GRov mice exhibited more locomotor activity and, without stress, more object interaction than wild-type mice. Following acute stress, GRov mice no longer showed increased object exploration. While stress dampened responses to object novelty in both groups, GRov mice were particularly impaired in discrimination of spatial novelty post-stress. These data demonstrate that GRov leads to increased environmental reactivity, responsiveness to salience, and vulnerability to stress-induced cognitive deficits. They implicate forebrain glucocorticoid receptor (GR) in fine-tuning interactions with the environment and the interplay of emotional salience, coping abilities, and cognitive function.

Desmethoxymajusculamide C, a cyanobacterial depsipeptide with potent cytotoxicity in both cyclic and ring-opened forms.

Cytotoxicity-guided fractionation of the organic extract from a Fijian Lyngbya majuscula led to the discovery of desmethoxymajusculamide C (DMMC) as the active metabolite. Spectroscopic analysis including 1D and 2D NMR, MS/MS, and chemical degradation and derivatization protocols were used to assign the planar structure and stereoconfiguration of this new cyclic depsipeptide. DMMC demonstrated potent and selective anti-solid tumor activity with an IC(50) = 20 nM against the HCT-116 human colon carcinoma cell line via disruption of cellular microfilament networks. A linear form of DMMC was generated by base hydrolysis, and the amino acid sequence was confirmed by mass spectrometry. Linearized DMMC was also evaluated in the biological assays and found to maintain potent actin depolymerization characteristics while displaying solid tumor selectivity equivalent to DMMC in the disk diffusion assay. A clonogenic assay assessing cytotoxicity to HCT-116 cells as a function of exposure duration showed that greater than 24 h of constant drug treatment was required to yield significant cell killing. Therapeutic studies with HCT-116 bearing SCID mice demonstrated efficacy at the highest dose used (%T/C = 60% at 0.62 mg/kg daily for 5 days).

Viridamides A and B, lipodepsipeptides with antiprotozoal activity from the marine cyanobacterium Oscillatoria nigro-viridis.

Parallel chemical and phylogenetic investigation of a marine cyanobacterium from Panama led to the isolation of two new PKS-NRPS-derived compounds, viridamides A and B. Their structures were determined by NMR and mass spectroscopic methods, and the absolute configurations assigned by Marfey's method and chiral HPLC analysis. In addition to six standard, N-methylated amino and hydroxy acids, these metabolites contained the structurally novel 5-methoxydec-9-ynoic acid moiety and an unusual proline methyl ester terminus. Morphologically, this cyanobacterium was identified as Oscillatoria nigro-viridis, and its 16S rDNA sequence is reported here for the first time. Phylogenetic analysis of these sequence data has identified O. nigro-viridis strain OSC3L to be closely related to two other marine cyanobacterial genera, Trichodesmium and Blennothrix. Viridamide A showed antitrypanosomal activity with an IC50 of 1.1 microM and antileishmanial activity with an IC50 of 1.5 microM.

Biosynthetic origin of natural products isolated from marine microorganism-invertebrate assemblages.

In all probability, natural selection began as ancient marine microorganisms were required to compete for limited resources. These pressures resulted in the evolution of diverse genetically encoded small molecules with a variety of ecological and metabolic roles. Remarkably, many of these same biologically active molecules have potential utility in modern medicine and biomedical research. The most promising of these natural products often derive from organisms richly populated by associated microorganisms (e.g., marine sponges and ascidians), and often there is great uncertainty about which organism in these assemblages is making these intriguing metabolites. To use the molecular machinery responsible for the biosynthesis of potential drug-lead natural products, new tools must be applied to delineate their genetic and enzymatic origins. The aim of this perspective is to highlight both traditional and emerging techniques for the localization of metabolic pathways within complex marine environments. Examples are given from the literature as well as recent proof-of-concept experiments from the authors' laboratories.

Marine natural products as anticancer drugs.

The chemical and biological diversity of the marine environment is immeasurable and therefore is an extraordinary resource for the discovery of new anticancer drugs. Recent technological and methodologic advances in structure elucidation, organic synthesis, and biological assay have resulted in the isolation and clinical evaluation of various novel anticancer agents. These compounds range in structural class from simple linear peptides, such as dolastatin 10, to complex macrocyclic polyethers, such as halichondrin B; equally as diverse are the molecular modes of action by which these molecules impart their biological activity. This review highlights several marine natural products and their synthetic derivatives that are currently undergoing clinical evaluation as anticancer drugs.

Poly(phenyllactide): synthesis, characterization, and hydrolytic degradation.

Poly(phenyllactide) was synthesized via the ring-opening polymerization of phenyllactide, the dimer of phenyllactic acid. Phenyllactide was synthesized by two methods, the solution phase condensation of L-phenyllactic acid and by thermal cracking of low molecular weight phenyllactic acid oligomers. The poor solubility of the monomer limited solution polymerizations of phenyllactide to low yields and low molecular weights, but melt polymerization of phenyllactide with Sn(Oct)2/tert-butylbenzyl alcohol at 180 degrees C gave high molecular weight polymers in high yields. The resulting polymers were amorphous due to epimerization of approximately 10% of the stereocenters during polymerization. Poly(phenyllactide) has a glass transition temperature of 50 degrees C and degrades to monomer at 320 degrees C. Experiments run at 55 degrees C at pH 7.4 show that poly(phenyllactide) degrades at approximately 1/5 the rate of rac-polylactide.

Undergraduate environmental health education: preparing for the future.

Attendees indicated that the workshop was beneficial and that the opportunity to communicate with faculty representing 23 programs accredited by EHAC and nine programs not accredited by EHAC was extremely useful. There was general agreement on a number of points: There is a need for undergraduate environmental health programs to collaborate on matters related to distance learning. Topics related to women, gender, diversity, ethics, and international environmental health should be incorporated into the environmental health curriculum. There are no major problems with current EHAC curricular guidelines, but the guidelines should be evaluated on a regular basis. Field experience or internship is an essential component in the academic preparation of undergraduate environmental health students. There is a significant need for increased funding for undergraduate environmental health programs. There is a need to increase the visibility and recognition of environmental health programs. There is a need to solidify ties with traditional partners and to establish new linkages at the local, regional, and national levels in the government, community, and private sector. It is essential that undergraduate faculty communicate with each other on matters relating to the preparation of environment health practitioners. There is a need for an association of undergraduate academic programs to provide leadership and a focal point for identification and resolution of issues common to all. The establishment of an association was viewed as the most practical and effective way to address these issues and to pursue related opportunities.

Bizarre parosteal osteochondromatous proliferation: case report and review of the literature.

Bizarre parosteal osteochondromatous proliferation of bone (BPOP) is a benign lesion that is occasionally misinterpreted as a malignant process. The original reports described lesions exclusively in the hands and feet. However, subsequent reports have included additional sites in the long bones, skull, and maxilla. The differential diagnosis of BPOP includes numerous benign and malignant lesions. The benign differential diagnosis includes osteochondroma and reactive processes. The most important malignant differential diagnosis is parosteal osteosarcoma. We present a case of an 11-year-old boy with recurrent BPOP and review the literature. We discuss the differential diagnosis and pathogenesis of the lesion.