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Our understanding of cancer and the key pathways that drive cancer survival has expanded rapidly over the past several decades. However, there are still important challenges that continue to impair patient survival, including our inability to target cancer stem cells (CSCs), metastasis, and drug resistance. The transcription factor p63 is a p53 family member with multiple isoforms that carry out a wide array of functions. Here, we discuss the critical importance of the ΔNp63α isoform in cancer and potential therapeutic strategies to target ΔNp63α expression to impair the CSC population, as well as to prevent metastasis and drug resistance to improve patient survival. ΔNp63α is a p63 isoform in the p53 family that is a master regulator of epithelial stemness in normal tissue. In cancer, ΔNp63α regulates a number of key aspects of cancer progression, including cancer stem cell (CSC) maintenance, metastasis, and drug resistance, through regulation of several downstream pathways. ΔNp63α is difficult to target directly, but multiple pathways upstream of ΔNp63α with druggable targets have been identified that represent potential therapeutic opportunities in cancer. Many pathways upstream of ΔNp63α are involved in crosstalk with the tumor microenvironment. With growing interest in targeting the tumor niche, further investigation into how ΔNp63α is involved in crosstalk with the microenvironment represents an exciting area of future investigation. [ABSTRACT FROM AUTHOR]

• Tocilizumab was not associated with significantly reduced mortality in mechanically ventilated patients with COVID-19 pneumonia. • Patients who received tocilizumab were younger, presented with higher fever on the day of intubation, and had significantly fewer comorbidities than controls. • Elevated interleukin-6 was associated with greater mortality risk; interleukin-6 levels were similar in the treatment and control group. The purpose of this study is to evaluate clinical outcomes in patients with critical COVID-19 pneumonia requiring invasive mechanical ventilation who were treated with tocilizumab Single-center retrospective cohort study Stony Brook University Hospital, a 600-bed academic tertiary medical center in Suffolk County, New York Consecutive patients with COVID-19 confirmed by nasopharyngeal polymerase chain reaction (PCR) who were admitted to Stony Brook University Hospital between March 10 and April 2 2020 and required mechanical ventilation in any intensive care unit during their hospitalization Treatment with tocilizumab while intubated Overall mortality 30 days from the date of intubation Forty-five patients received tocilizumab compared to seventy controls. Baseline demographic characteristics, inflammatory markers, treatment with corticosteroids, and sequential organ failure assessment (SOFA) scores were similar between the two cohorts. Patients who received tocilizumab had significantly lower Charlson co-morbidity index (2.0 vs 3.0, P = 0.01) than controls. There was a trend towards younger mean age in the tocilizumab exposed group (56.2 vs 60.6; P = 0.09). In logistic regression analysis there was no reduction in mortality associated with receipt of tocilizumab (odds ratio (OR) 1.04; 95% CI, 0.27–3.75). There was no observed increased risk of secondary infection in patients given tocilizumab (28.9 vs 25.7; OR 1.17; 95% CI, 0.51–2.71). When controlling for age, severity of illness, and co-morbidities, tocilizumab was not associated with reduction in mortality in this retrospective cohort study of mechanically ventilated patients with COVID-19 pneumonia. Further studies are needed to determine the role of tocilizumab in the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Azole resistance is a concern for the management of diseases caused by Aspergillus fumigatus in humans. Azole fungicide use in the environment has been identified as a possible cause for development of resistance, which increases the complexity and number of stakeholders involved in this emerging problem. A workshop was held in Amsterdam early 2019 in which stakeholders, including medical and agricultural researchers, representatives from the government, public health, fungicide producers and end-users, reviewed the current evidence supporting environmental selection for resistance and to discuss which research and measures are needed to retain the effectiveness of the azole class for environmental and medical applications. This paper provides an overview of the latest insights and understanding of azole resistance development in the clinical setting and the wider environment. A One Health problem approach was undertaken to list and prioritize which research will be needed to provide missing evidence and to enable preventive interventions. • Environmental azole resistance selection in A. fumigatus threatens medical therapy. • Certain azole fungicide applications have a low risk of resistance selection. • Hotspots involve A. fumigatus growth in plant waste containing azole residues. • Environmental resistance burden may be reduced through a One-Health approach. • AMR research and action plans should include fungal resistance. [ABSTRACT FROM AUTHOR]

• Candida auris is a newly identified and globally emerging fungal infection. • C. auris shows extensive innate and acquired resistance to antifungal drugs. • The fungus is intrinsically resistant to widely used hospital disinfectants leading to high rates of nosocomial transmission. • Research into virulence and treatment of C. auris in susceptible patients is urgently needed. The discovery in 2009 of a new species of yeast, Candida auris , heralded the arrival of a novel emerging human infectious disease. This review highlights the unique characteristics of C. auris that have lled to it being of public health concern worldwide, namely public health concern, namely its global emergence, its ability to cause nosocomial outbreaks in healthcare settings, its innate and emerging resistance to multiple antifungal drugs and its resilience in the face of hygiene and infection control measures. Genomic epidemiology has identified four emergences of C. auris marked by four clades of the pathogen. These clades of C. auris are genetically dissimilar and are associated with differential resistance to antifungal drugs, suggesting that they will continue to phenotypically diverge into the future. The global emergence of C. auris testifies to the unmapped nature of Kingdom Fungi, and represents a new nosocomial threat that will require enhanced infection control across diverse healthcare and community settings. [ABSTRACT FROM AUTHOR]

Melt electrowriting (MEW) is an additive manufacturing technique that has the potential to create fibrous scaffolds that reproduce the scale and organization of collagen fiber networks in musculoskeletal soft tissues. For musculoskeletal soft tissue engineering, it is useful for scaffolds to have a high aspect ratio (length to width ratio of 5:1 or higher). However, the relationship between MEW process variables and the structural and mechanical properties of such scaffolds is not well understood. In addition, prior studies have cut samples from larger MEW structures, resulting in test specimens with discontinuous fibers. In this study, MEW scaffolds with low (square, 12 mm × 12 mm) and high aspect ratio (rectangular, 35 mm × 5 mm) macroscale geometries were fabricated at varying stage translation speeds or melt extrusion temperatures. Fiber morphology in both geometries and mechanical properties of the continuous rectangular structures were then quantified. Fiber diameter in both square and rectangular scaffolds generally decreased with increasing stage speed, but increased with melt temperature, though the effect of the latter was greater in square scaffolds. Interfiber spacing in both geometries was closer to the intended value as stage speed increased. Spacing became less accurate in square scaffolds with increasing melt temperature but changed little in rectangular scaffolds. Transverse fiber angle in rectangular scaffolds improved with increasing stage speed and had a median value within 1.4% of the intended angle at all temperatures. Finally, apparent tensile modulus in rectangular scaffolds decreased with increasing speed and temperature. These findings highlight the need to tailor MEW process parameters in scaffolds with high aspect ratio geometry in order to consistently generate specific structural and mechanical properties. Because of the potential to reproduce the structural anisotropy, fiber size, and mechanical properties of collagenous extracellular matrix, MEW structures are promising as musculoskeletal soft tissue scaffolds. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 infection can spread rapidly among residents and staff of a long term care facility. • Vaccinations against SARS-CoV-2 is of paramount importance to save lives in US long term care facilities. • Breakthrough SARS-CoV-2 infections in vaccinated long term care facility residents is possible, but a favorable outcome is more likely. An outbreak of SARS-CoV-2 involving four residents of a United States Veterans Affairs long term care facility occurred following administration of the first dose of the mRNA-1273 vaccine (Moderna) to thirty out of 33 residents. Three out of 4 positive cases were partially vaccinated and remained asymptomatic. One of 2 partially vaccinated patients who were tested for anti-spike protein antibodies had detectable levels at the time of diagnosis. The mortality rate was lower compared to a prior outbreak reported in this facility. [ABSTRACT FROM AUTHOR]

Forensic DNA testing is grounded in molecular biology and population genetics. The technologies that were the basis of restriction length polymorphism testing (RFLP) have given way to PCR based technologies. While PCR has been the pillar of short tandem repeat (STR) methods and will continue to be used as DNA sequencing and analysis of single nucleotide polymorphisms (SNPs) are introduced into human identification, the molecular biology techniques in use today represent significant advances since the introduction of STR testing. Large forensic laboratories with dedicated research teams and forensic laboratories which are part of academic institutions have the resources to keep track of advances which can then be considered for further research or incorporated into current testing methods. However, many laboratories have limited ability to keep up with research advances outside of the immediate area of forensic science and may not have access to a large university library systems. This review focuses on filling this gap with respect to areas of research that intersect with selected methods used in forensic biology. The review summarizes information collected from several areas of the scientific literature where advances in molecular biology have produced information relevant to DNA analysis of sexual assault evidence and methods used in presumptive and confirmatory identification of semen. Older information from the literature is also included where this information may not be commonly known and is relevant to current methods. The topics selected highlight (1) information from applications of proteomics to sperm biology and human reproduction, (2) seminal fluid proteins and prostate cancer diagnostics, (3) developmental biology of sperm from the fertility literature and (4) areas where methods are common to forensic analysis and research in contraceptive use and monitoring. Information and progress made in these areas coincide with the research interests of forensic biology and cross-talk between these disciplines may benefit both. [ABSTRACT FROM AUTHOR]

Despite advances in tissue engineering for the knee meniscus, it remains a challenge to match the complex macroscopic and microscopic structural features of native tissue, including the circumferentially and radially aligned collagen bundles essential for mechanical function. To mimic this structural hierarchy, this study developed multi-lamellar mesenchymal stem cell (MSC)-seeded nanofibrous constructs. Bovine MSCs were seeded onto nanofibrous scaffolds comprised of poly(e-caprolactone) with fibers aligned in a single direction (0° or 90° to the scaffold long axis) or circumferentially aligned (C). Multi-layer groups (0°/0°/0°, 90°/90°/90°, 0°/90°/0°, 90°/0°/90°, and C/C/C) were created and cultured for a total of 6 weeks under conditions favoring fibrocartilaginous tissue formation. Tensile testing showed that 0° and C single layer constructs had stiffness values several fold higher than 90° constructs. For multi-layer groups, the stiffness of 0°/0°/0° constructs was higher than all other groups, while 90°/90°/90° constructs had the lowest values. Data for collagen content showed a general positive interactive effect for multi-layers relative to single layer constructs, while a positive interaction for stiffness was found only for the C/C/C group. Collagen content and cell infiltration occurred independent of scaffold alignment, and newly formed collagenous matrix followed the scaffold fiber direction. Structural hierarchies within multi-lamellar constructs dictated biomechanical properties, and only the C/C/C constructs with non-orthogonal alignment within layers featured positive mechanical reinforcement as a consequence of the layered construction. These multi-layer constructs may serve as functional substitutes for the meniscus as well as test beds to understand the complex mechanical principles that enable meniscus function. [ABSTRACT FROM AUTHOR]

The success of stem cell-based cartilage repair requires that the regenerate tissue reach a stable state. To investigate the long-term stability of tissue engineered cartilage constructs, we assessed the develop-ment of compressive mechanical properties of chondrocyte and mesenchymal stem cell (MSC)-laden three dimensional agarose constructs cultured in a well defined chondrogenic in vitro environment through 112 days. Consistent with previous reports, in the presence of TGF-ß, chondrocytes outperformed MSCs through day 56, under both free swelling and dynamic culture conditions, with MSC-laden constructs reaching a plateau in mechanical properties between days 28 and 56. Extending cultures through day 112 revealed that MSCs did not simply experience a lag in chondrogenesis, but rather that construct mechanical properties never matched those of chondrocyte-laden constructs. After 56 days, MSC-laden constructs underwent a marked reversal in their growth trajectory, with significant declines in glycosaminoglycan content and mechanical properties. Quantification of viability showed marked differences in cell health between chondrocytes and MSCs throughout the culture period, with MSC-laden construct cell viability falling to very low levels at these extended time points. These results were not dependent on the material environment, as similar findings were observed in a photocrosslinkable hyaluronic acid (HA) hydrogel system that is highly supportive of MSC chondrogenesis. These data suggest that, even within a controlled in vitro environment that is conducive to chondrogenesis, there may be an innate instability in the MSC phenotype that is independent of scaffold composition, and may ultimately limit their application in functional cartilage repair. [ABSTRACT FROM AUTHOR]

Abstract: Pythium insidiosum is an aquatic fungus-like organism in the kingdom Stramenopila that causes pythiosis in both humans and animals. Human pythiosis occurs in ocular, localized granulomatous subcutaneous and systemic or vascular forms. Individuals whose occupations involve exposure to aquatic habitats have an elevated risk of contracting pythiosis. Previously, we reported the first successful isolation of Pythium insidiosum from aquatic environmental samples by culture including confirmation using molecular methods. In this study, we show that P. insidiosum inhabitats moist soil environments in agricultural areas. A total of 303 soil samples were collected from 25 irrigation sources in the areas nearby the recorded home addresses of pythiosis patients residing in northern provinces of Thailand. P. insidiosum DNA was identified directly from each soil extract by using a nested PCR assay and subsequent phylogenetic analysis of the ribosomal intragenic spacer region. P. insidiosum DNA could be detected from 16 of the 25 soil sources (64%). Conventional culture methods were also performed, however all samples exhibited negative culture results. We conclude that both irrigation water and soil are the natural reservoirs of P. insidiosum. In endemic areas, the exposure to these environmental reservoirs should be considered a risk factor for hosts susceptible to pythiosis. [Copyright &y& Elsevier]

Abstract: Given the limitations of current surgical approaches to treat articular cartilage injuries, tissue engineering (TE) approaches have been aggressively pursued. Despite reproduction of key mechanical attributes of native tissue, the ability of TE cartilage constructs to integrate with native tissue must also be optimized for clinical success. In this paper, we propose a “trajectory-based” tissue engineering (TB-TE) approach, based on the hypothesis that time-dependent increases in construct maturation in-vitro prior to implantation (i.e. positive rates) may provide a reliable predictor of in-vivo success. As an example TE system, we utilized hyaluronic acid hydrogels laden with mesenchymal stem cells. We first modeled the maturation of these constructs in-vitro to capture time-dependent changes. We then performed a sensitivity analysis of the model to optimize the timing and amount of data collection. Finally, we showed that integration to cartilage in-vitro is not correlated to the maturation state of TE constructs, but rather their maturation rate, providing a proof-of-concept for the use of TB-TE to enhance treatment outcomes following cartilage injury. This new approach challenges the traditional TE paradigm of matching only native state parameters of maturity and emphasizes the importance of also establishing an in-vitro trajectory in constructs in order to improve the chance of in-vivo success. [Copyright &y& Elsevier]

Abstract: Penicillium chrysogenum is a ubiquitous airborne fungus detected in every sampled region of the Earth. Owing to its role in Alexander Fleming's serendipitous discovery of Penicillin in 1928, the fungus has generated widespread scientific interest; however its natural history is not well understood. Research has demonstrated speciation within P. chrysogenum, describing the existence of four cryptic species. To discriminate the four species, we developed protocols for species-specific diagnostic PCR directly from fungal conidia. 430 Penicillium isolates were collected to apply our rapid diagnostic tool and explore the distribution of these fungi across the London Underground rail transport system revealing significant differences between Underground lines. Phylogenetic analysis of multiple type isolates confirms that the ‘Fleming species’ should be named Penicillium rubens and that divergence of the four ‘Chrysogenum complex’ fungi occurred about 0.75 million yr ago. Finally, the formal naming of two new species, Penicillium floreyi and Penicillium chainii, is performed. [Copyright &y& Elsevier]

Abstract: Endogenous repair of fibrous connective tissues is limited, and there exist few successful strategies to improve healing after injury. As such, new methods that advance repair by promoting cell growth, extracellular matrix (ECM) production, and tissue integration would represent a marked clinical advance. Using the meniscus as a test platform, we sought to develop an enzyme-releasing scaffold that enhances integrative repair. We hypothesized that the high ECM density and low cellularity of native tissue present physical and biological barriers to endogenous healing, and that localized collagenase treatment might expedite cell migration to the wound edge and tissue remodeling. To test this hypothesis, we fabricated a delivery system in which collagenase was stored inside electrospun poly(ethylene oxide) (PEO) nanofibers and released upon hydration. In vitro results showed that partial digestion of the wound interface improved repair by creating a microenvironment that facilitated cell migration, proliferation and matrix deposition. Specifically, treatment with high-dose collagenase led to a 2-fold increase in cell density at the wound margin and a 2-fold increase in integrative tissue compared to untreated controls at 4weeks (P ⩽0.05). Furthermore, when composite scaffolds containing both collagenase-releasing and structural fiber fractions were placed inside meniscal tears in vitro, enzyme release acted locally and resulted in a positive cellular response similar to that of global treatment with aqueous collagenase. This innovative approach to targeted enzyme delivery may aid the many patients that exhibit meniscal tears by promoting integration of the defect, thereby circumventing the pathologic consequences of partial meniscus removal, and may find widespread application in the treatment of injuries to a variety of dense connective tissues. [Copyright &y& Elsevier]

Abstract: The menisci are crescent-shaped fibrocartilaginous tissues whose structural organization consists of dense collagen bundles that are locally aligned but show a continuous change in macroscopic directionality. This circumferential patterning is necessary for load transmission across the knee joint and is a key design parameter for tissue engineered constructs. To address this issue we developed a novel electrospinning method to produce scaffolds composed of circumferentially aligned (CircAl) nanofibers, quantified their structure and mechanics, and compared them with traditional linearly aligned (LinAl) scaffolds. Fibers were locally oriented in CircAl scaffolds, but their orientation varied considerably as a function of position (P <0.05). LinAl fibers did not change in orientation over a similar length scale (P >0.05). Cell seeding of CircAl scaffolds resulted in a similar cellular directionality. Mechanical analysis of CircAl scaffolds revealed significant interactions between scaffold length and region (P <0.05), with the tensile modulus near the edge of the scaffolds decreasing with increasing scaffold length. No such differences were detected in LinAl specimens (P >0.05). Simulation of the fiber deposition process produced “theoretical” fiber populations that matched the fiber organization and mechanical properties observed experimentally. These novel scaffolds, with spatially varying local orientations and mechanics, will enable the formation of functional anatomic meniscus constructs. [Copyright &y& Elsevier]

Abstract: The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy. [Copyright &y& Elsevier]

Abstract: This article highlights some of the more notable persistent fungal diseases of our times. It draws attention to the emergence of new fungal pathotypes infecting food staple crops, due largely to modern agricultural practices, and to nascent fungal diseases decimating frog populations worldwide and killing hibernating bats in Northern USA. We invoke use of the basic disease triangle concept to highlight the “missing” data, with regards to pathogen and host biology and to the various environmental parameters which may dictate disease spread. Given these data “voids” we comment on the implementation of policy. We conclude with a series of recommendations for improved disease surveillance and reporting, the need for greater public awareness of these issues and a call for greater funding for fungal research. In so doing, we have exploited Magnaporthe oryzae and Batrachochytrium dendrobatidis as exemplar emerging infectious fungi. Our aim is to highlight the impact of emerging and emergent fungi on food security and, more broadly, ecosystem health. [Copyright &y& Elsevier]

Abstract: Functional tissue engineering (FTE) approaches have shown promise in healing an injured anterior cruciate ligament (ACL) of the knee. Nevertheless, additional mechanical augmentation is needed to maintain joint stability and appropriate loading of the joint while the ACL heals. The objective of this study was to quantitatively evaluate how mechanical augmentation using sutures restores the joint kinematics as well as the distribution of loading among the ACL, medial collateral ligament, and medial meniscus (MM) in response to externally applied loads. Eight goat stifle joints were tested on a robotic/universal force–moment sensor testing system under two loading conditions: (1) a 67N anterior tibial load (ATL) and (2) a 67N ATL with 100N axial compression. For each joint, four experimental conditions were tested at 30°, 60°, and 90° of flexion: the (1) intact and (2) ACL-deficient joint, as well as following (3) suture repair of the transected ACL, and (4) augmentation using sutures passed from the femur to the tibia. Under the 67N ATL, suture augmentation could restore the anterior tibial translation (ATT) to within 3mm of the intact joint (p>0.05), representing a 54–76% improvement over suture repair (p<0.05). With the additional axial compression, the ATT and in-situ forces of the sutures following suture augmentation remained 2–3 times closer to normal (p<0.05). Also, the in-situ forces in the MM were 58–73% lower (p<0.05). Thus, suture augmentation may be helpful in combination with FTE approaches for ACL healing by providing the needed initial joint stability while lowering the loads on the MM. [Copyright &y& Elsevier]

Abstract: Extracellular matrix (ECM) bioscaffolds, such as porcine small intestine submucosa (SIS) and urinary bladder matrix (UBM), have been successfully used to improve soft tissue healing. Yet they contain plenty of galactose α1,3 galactose (αGal) epitopes, which cause rejection responses in pig organ transplantation to human. Recently, ECM bioscaffolds derived from genetically modified pigs that are αGal-deficient (αGal(−)) have become available. To ensure that the ECM bioscaffolds from these pigs can be used as alternatives, we examined their morphological, bioactive and biomechanical properties and compared them with those from the wild-type pigs (n =5 per group). Morphologically, the αGal(−) ECMs were found to be similar to the wild-type ECMs in gross observation and matrix appearance with hematoxylin and eosin staining. Growth factors commonly known to be present in ECM bioscaffolds, including FGF-2, TGF-β1, VEGF, IGF-1 and PDGF-BB, also showed no significant differences in terms of quantity (p >0.05) and distribution in tissue from the results of enzyme-linked immunosorbent assay, Western blot analysis and immunohistochemistry. Furthermore, a bromodeoxyuridine cell proliferation assay confirmed the bioactivity of the extracts from the αGal(−) bioscaffolds to be similar to the wild-type bioscaffolds. Under uniaxial tensile testing, no significant differences were found between the αGal(−) and wild-type bioscaffolds in terms of their viscoelastic and mechanical properties (p >0.05). These multidisciplinary results suggest that genetic modification to eliminate the αGal epitopes in the ECM bioscaffolds had not altered the properties of these ECM bioscaffolds and, as such, they should retain their performance in tissue engineering in humans. [Copyright &y& Elsevier]

Abstract: The GABAA receptors are ligand-gated chloride channels which are the targets for many clinically used sedatives, including the barbiturates. The barbiturate pentobarbital acts through multiple sites on the GABAA receptor. At low concentrations (μM), it acts as a positive allosteric modulator while at higher concentrations it can directly activate the receptor. This agonist action is influenced by the subunit composition of the receptor, and pentobarbital is a more effective agonist than GABA only at receptors containing an α6 subunit. The conformational change that translates GABA binding into channel opening is known to involve a lysine residue located in an extracellular domain between the 2nd and 3rd transmembrane domains. Mutations of this residue disrupt activation of the channel by GABA and have been linked to inherited epilepsy. Pentobarbital binds to the receptor at a different agonist site than GABA, but could use a common signal transduction mechanism to gate the channel. To address this question, we compared the effect of a mutating the homologous lysine residue in the α1 or α6 subunits (K278 or K277, respectively) to methionine on direct activation of recombinant GABAA receptors by GABA or pentobarbital. We found that this mutation reduced GABA sensitivity for both α1 and α6 subunits, but affected pentobarbital sensitivity only for the α1 subunit. This suggests that pentobarbital acts through a distinct signal transduction pathway at the α6 subunit, which may account for its greater efficacy compared to GABA at receptors containing this subunit. [Copyright &y& Elsevier]

Abstract: Penicillium marneffei is an endemic mycosis of humans in southeast Asia. Epidemiological data have shown that exposure to soil and season increase the risk of infection, and it is assumed that the main environmental reservoir is in soil. We sampled soils from a P. marneffei - endemic region of Thailand and confirmed by quantitative PCR and sequencing that P. marneffei DNA can be detected, a finding that we replicated over three sampling seasons. P. marneffei-positive and -negative sampling locations can be viewed using a dynamic browser located at www.spatialepidemiology.net/pmarneffei. We subsequently examined the hypothesis that P. marneffei isolates representing the two major phylogeographic clades of this species can grow in: (i) soil and (ii) competition against the closely related species, Talaromyces stipitatus, in a model soil environment. P. marneffei was not detected in non-sterile soil microcosms 14d post inoculation, showing that the pathogen is unable to compete against complete soil fauna under our laboratory conditions. However, both isolates of P. marneffei persisted and increased in biomass when inoculated into sterile soil. P. marneffei stably co-existed with T. stipitatus, and that the main competitive interaction was the inhibition of T. stipitatus growth at low spore application by the ‘Eastern’ isolate of P. marneffei. We conclude that P. marneffei is present in soils within endemic regions, and is able to grow in soil under certain conditions. More research is required to ascertain the specific conditions that regulate the growth of P. marneffei in soils in natural environments. [Copyright &y& Elsevier]

Abstract: Graphene’s honeycomb lattice structure underlies much of the remarkable physics inherent in this material, most strikingly through the formation of two “flavors” of Dirac cones for each spin. In the quantum Hall regime, the resulting flavor degree of freedom leads to an interesting problem when a Landau level is partially occupied. Namely, while Zeeman splitting clearly favors polarizing spins along the field, precisely how the states for each flavor are occupied can become quite delicate. Here we focus on clean graphene sheets in the regime of quantum Hall ferromagnetism, and discuss how subtler lattice-scale physics, arising either from interactions or disorder, resolves this ambiguity to measurable consequence. Interestingly, such lattice-scale physics favors microscopic symmetry-breaking order coexisting with the usual liquid-like quantum Hall physics emerging on long length scales. The current experimental situation is briefly reviewed in light of our discussion. [Copyright &y& Elsevier]

Abstract: Chytridiomycosis is an emerging infectious disease of amphibians caused by the chytrid Batrachochytrium dendrobatidis. The disease has been associated with global amphibian declines and species extinctions, however the principle drivers that underly the emergence of chytridiomycosis remain unclear. Current evidence suggests that the world trade in amphibians is implicated in the emergence of chytridiomycosis. Here, we review the evidence that the amphibian trade is driving the emergence of chytridiomycosis by (1) spreading infected animals worldwide, (2) introducing non-native infected animals into naïve populations and (3) amplifying infection of amphibians by co-housing, followed by untreated discharge of infectious zoospores into water supplies. We conclude that the evidence that the amphibian trade is contributing to the spread of Batrachochytrium dendrobatidis is strong, and that specific actions are necessary to prevent the introduction of the pathogen into thus-far uninfected areas. Specifically, we recommend the development of national risk-abatement plans, focused on firstly preventing introduction of Bd into disease free areas, and secondly, decreasing the impact of the disease on populations that are currently infected. [Copyright &y& Elsevier]

Abstract: Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active. [Copyright &y& Elsevier]

Abstract: Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1. [Copyright &y& Elsevier]

Multilocus sequence typing uses nucleotide sequence from several genes to identify individual microbial pathogens. The data obtained for multilocus sequence typing can be used to recognize fungal species and to determine if the fungi are purely clonal, or if they also recombine. Genetic regions with more polymorphisms and microsatellites might be used to recognize populations within species and are well suited to Bayesian methods of assigning unknown individuals to populations of origin. Knowledge of species, populations and reproductive mode can help answer questions common to all emerging diseases: is the disease due to the recent spread of a pathogen, to the emergence of a virulent strain of an existing pathogen, or to a change in the environment that promotes disease? [Copyright &y& Elsevier]

Abstract: The purpose of this in vitro study was to compare the bond strength of various obturation materials to root canal dentin by using a push-out test design. Twenty-five single-rooted extracted human teeth were used in this study. The crowns were removed, and root canal instrumentation was completed by using Endogel-coated 0.06 EndoSequence rotary files (Brasseler, Savannah, GA) and appropriate irrigation with 5.25% NaOCl and a final rinse with 17% EDTA. After instrumentation, the roots were randomly divided into five single-matched cone obturation groups (n = 5 roots/group), as follows: group 1, gutta percha with Kerr EWT (Kerr Corp, Romulus, MI); group 2, gutta percha with AH Plus (Dentsply, DeTrey, Germany); group 3, Resilon (Pentron Clinical Technologies, Wallingford, CT) and Epiphany (Pentron); group 4, Activ GP (Brasseler) obturation system; and group 5, EndoREZ obturation system (Ultradent, South Jordan, UT). The obturated roots were cut perpendicular to the long access to create 1-mm thick slices from the apical, middle, and coronal thirds. The bond strength was measured for each test slice with a push-out testing machine. Statistical analysis was completed by using a two-way analysis of variance and the post hoc Tukeys test with significance set at p < 0.05. Group 2 showed a significantly (p < 0.05) greater bond strength compared with all other groups. Also, groups 1 and 4 had significantly (p < 0.05) higher bond strengths compared with groups 3 and 5. [Copyright &y& Elsevier]

Next generation telecommunications infrastructure is expanding and supporting rapid growth of broadband technologies and a digital economy. In this context, digital information and communications technologies (ICTs) are of increasing importance as a means for people to gain access to health or social services, employment opportunities, information and social networks. In this article we draw on our recent case study research to examine the policy (and politics) shaping implementation of Australia's National Broadband Network (NBN) and its likely effects on equity of access to high speed broadband (HSB) services. We monitored NBN policy and implementation from 2015 to 2018 through policy documents, reports, and media. To assess likely effects of NBN policy on implementation and subsequently on equity of access to HSB we: a) applied a framework defining four elements of equity of access; and b) analysed stakeholder views drawn from media articles and 22 interviews with experts on NBN policy including politicians, government staff, and industry representatives. We found that equity considerations competed with political and commercial imperatives during the rollout of the NBN. This resulted in positive and negative consequences for equity of access to HSB, with a change in policy and implementation in 2013 bringing greater risks to equity of access. The case study provides a framework for considering equity in the implementation of next generation telecommunications infrastructure and highlights the importance of considering equity in the evaluation of telecommunications infrastructure. • We examine the role of ICT infrastructure as a determinant of health equity. • We use policy theory to explain how politics shaped Australia's broadband network. • Implementation of Australia's NBN has affected equity of access and quality. • How governments can implement equitable ICT infrastructure policies. [ABSTRACT FROM AUTHOR]

Abstract: The articulation of strong evidence and moral arguments about the importance of social determinants of health (SDH) and health equity has not led to commensurate action to address them. Policy windows open when, simultaneously, an issue is recognised as a problem, policy formulation and refinement happens and the political will for action is present. We report on qualitative interviews with 20 former Australian Federal, State or Territory health ministers conducted between September 2011 and January 2012 concerning their views about how and why the windows of policy opportunity on the SDH did or did not open during their tenure. Almost all ex-health ministers were aware of the existence of health inequalities and SDH but their complexity meant that this awareness rarely crystalised into a clear problem other than as a focus on high needs groups, especially Aboriginal people. Formulation of policies about SDH was assisted by cross-portfolio structures, policy entrepreneurs, and evidence from reviews and reports. It was hindered by the complexity of SDH policy, the dominance of medical power and paradigms and the weakness of the policy community advocating for SDH. The political stream was enabling when the general ideological climate was supportive of redistributive policies, the health care sector was not perceived to be in crisis, there was support for action from the head of government and cabinet colleagues, and no opposition from powerful lobby groups. There have been instances of Australian health policy which addressed the SDH over the past twenty five years but they are rare and the windows of opportunity that made them possible did not stay open for long. [ABSTRACT FROM AUTHOR]

Abstract: In this work we studied the functional differences between the microcirculation of murine tumours that express only single isoforms of vascular endothelial growth factor-A (VEGF), namely VEGF120 and VEGF188, and the effect of VEGF receptor tyrosine kinase (VEGF-R TK) inhibition on their functional response to the vascular disrupting agent, combretastatin A-4 phosphate (CA-4-P), using measurement of red blood cell (RBC) velocity by a ‘keyhole’ tracking algorithm. RBC velocities in VEGF188 tumours were unaffected by chronic treatment with a VEGF-R tyrosine kinase inhibitor, SU5416, whereas RBC velocities in VEGF120 tumours were significantly increased compared to control VEGF120 tumours. This effect was accompanied by a reduced tumour vascularisation. Pre-treatment of VEGF120 tumours with SU5416 made them much more resistant to CA-4-P treatment, with a RBC velocity response that was very similar to that of the more mature vasculature of the VEGF188 tumours. This study shows that vascular normalisation following anti-angiogenic treatment with a VEGF-R tyrosine kinase inhibitor reduced the response of a previously sensitive tumour line to CA-4-P. [Copyright &y& Elsevier]

Abstract: Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R. [Copyright &y& Elsevier]

Public policy plays a central role in creating and distributing resources and conditions of daily life that matter for health equity. Policy agendas have tended to focus on health care delivery and individualised interventions. Asking why there is a lack of policy action on structural drivers of health inequities raises questions about power inequities in policy systems that maintain the status quo. In this paper we investigate the power dynamics shaping public policy and implications for health equity. Using a Health Equity Power Framework (HEPF), we examined data from 158 qualitative interviews with government, industry and civil society actors across seven policy case studies covering areas of macroeconomics, employment, social protection, welfare reform, health care, infrastructure and land use planning. The influence of structures of capitalism, neoliberalism, sexism, colonisation, racism and biomedicalism were widely evident, manifested through the ideologies, behaviours and discourses of state, market, and civil actors and the institutional spaces they occupied. Structurally less powerful public interest actors made creative use of existing or new institutional spaces, and used network, discursive and moral power to influence policy, with some success in moderating inequities in structural and institutional forms of power. Our hope is that the methodological advancement and empirical data presented here helps to illuminate how public interest actors can navigate structural power inequities in the policy system in order to disrupt the status quo and advance a comprehensive policy agenda on the social determinants of health equity. However, this analysis highlights the unrealistic expectation of turning health inequities around in a short time given the long-term embedded power dynamics and inequities within policy systems under late capitalism. Achieving health equity is a power-saturated long game. • Public policy creates and distributes resources that matter for health equity. • There is policy inaction on the structural drivers of health inequities. • The Health Equity Power Framework reveals key power inequities in policy systems. • Achieving health equity is a power-saturated long game. [ABSTRACT FROM AUTHOR]

EP 4 is a prostaglandin E 2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP 4 antagonists which reverses PGE 2 -induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound ( 6 ) has been selected for potential clinical studies. EP 4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included. [ABSTRACT FROM AUTHOR]

Application of an acid-catalyzed thioamidation of β-amino-acrylonitriles to the corresponding β-amino-thioacrylamides toward the synthesis of 3,4-substituted-5-amino-isothiazoles is described. The greatest yields were observed for examples with electron rich aromatic systems. This method uses inexpensive and easily handled reagents. [ABSTRACT FROM AUTHOR]