Biofilms: Five-Star Accommodations for the Aerobically Challenged

SummaryThe human microbiome contains a diverse array of microbes that affect human health. A recent study finds that fungal biofilms are capable of supporting growth of anaerobic bacteria, suggesting that these fungi can promote bacterial growth in otherwise toxic environments

Regulation of Sterol Biosynthesis in the Human Fungal Pathogen Aspergillus Fumigatus: Opportunities for Therapeutic Development

Sterols are a major component of eukaryotic cell membranes. For human fungal infections caused by the filamentous fungus Aspergillus fumigatus, antifungal drugs that target sterol biosynthesis and/or function remain the standard of care. Yet, an understanding of A. fumigatus sterol biosynthesis regulatory mechanisms remains an under developed therapeutic target. The critical role of sterol biosynthesis regulation and its interactions with clinically relevant azole drugs is highlighted by the basic helix loop helix (bHLH) class of transcription factors known as Sterol Regulatory Element Binding Proteins (SREBPs). SREBPs regulate transcription of key ergosterol biosynthesis genes in fungi including A. fumigatus. In addition, other emerging regulatory pathways and target genes involved in sterol biosynthesis and drug interactions provide additional opportunities including the unfolded protein response, iron responsive transcriptional networks, and chaperone proteins such as Hsp90. Thus, targeting molecular pathways critical for sterol biosynthesis regulation presents an opportunity to improve therapeutic options for the collection of diseases termed aspergillosis. This mini-review summarizes our current understanding of sterol biosynthesis regulation with a focus on mechanisms of transcriptional regulation by the SREBP family of transcription factors

Stakeholders

The stakeholder concept derives from a simple premise: organizations and technologies exist in constellations of relationships. Organizations operate in a network of market and nonmarket relationships with other organizations, groups, and individuals. Likewise technologies emerge and exist in a network of suppliers, end users, and others who bear the impact of the technology. Generally with reference to both organizations and technologies, these related parties are termed stakeholders, meaning that they hold a stake in the outcomes of the organization or technology

Stakeholder Orientation, Managerial Discretion and Nexus Rents

A firm\u27s orientation toward its stakeholders determines how it will use the discretion accorded to it by external and internal circumstances. The interaction between these two factors affects a firm\u27s ability to create value in the short term and influences the level of discretion available to the firm in the long term. We argue that the interplay of discretion and orientation create a vicious (or virtuous) cycle, in which the firm either creates or destroys goodwill with stakeholders, thereby making it more or less likely that stakeholders will grant discretion in the future. This argument suggests an account of stakeholder management that is sensitive to variation in managerial discretion, an account that is more constrained than typical moral and instrumental prescriptions about how firms should treat stakeholders and less constrained than descriptions premised on more deterministic theories

Age and features of movement influence motor overflow.

OBJECTIVES:To measure the magnitude and prevalence of motor overflow to the arm at rest during attempted unilateral arm movements. DESIGN:Cross-sectional assessment. SETTING:Motor physiology laboratory. PARTICIPANTS:Healthy young (n=20) and elderly (n=20) adult subjects. MEASUREMENTS:Surface electromyography (EMG) was obtained from bilateral forearm muscles during performance of 12 different unilateral finger-tapping tasks. RESULTS:For all subjects, faster movement rate (F=2.56-3.30, P<.05), cognitive distraction (F=4.09, P<.05), and fatigue (F=15.15, P<.001) were each associated with a significant increase in the magnitude of EMG in the arm intended to be at rest. In elderly subjects, tapping at maximum rate and fatigue were each associated with a further increase in motor overflow across the midline. In addition, better left hand dexterity correlated with greater motor overflow to the right hand during rapid left hand tapping (r=0.63, P<.005). Prevalence of motor overflow was also higher in older subjects for some tasks, for example during 1 Hz tapping by the right index finger (motor overflow present in 45%, vs 15% young subjects, P<.05). CONCLUSION:Several behavioral variables increase motor overflow across the midline in young and elderly adults. Motor overflow was even greater in elderly subjects with the most demanding tasks and was greater in those with better motor status, suggesting that this form of motor system change is a compensatory event of normal aging rather than age-related dysfunction. The results support the hypotheses that healthy aging is associated with an increase in the degree to which brain function is bilaterally organized

Transcriptomic and proteomic analyses of the Aspergillus fumigatus hypoxia response using an oxygen-controlled fermenter

<p>Abstract</p> <p>Background</p> <p><it>Aspergillus fumigatus </it>is a mold responsible for the majority of cases of aspergillosis in humans. To survive in the human body, <it>A. fumigatus </it>must adapt to microenvironments that are often characterized by low nutrient and oxygen availability. Recent research suggests that the ability of <it>A. fumigatus </it>and other pathogenic fungi to adapt to hypoxia contributes to their virulence. However, molecular mechanisms of <it>A. fumigatus </it>hypoxia adaptation are poorly understood. Thus, to better understand how <it>A. fumigatus </it>adapts to hypoxic microenvironments found <it>in vivo </it>during human fungal pathogenesis, the dynamic changes of the fungal transcriptome and proteome in hypoxia were investigated over a period of 24 hours utilizing an oxygen-controlled fermenter system.</p> <p>Results</p> <p>Significant increases in transcripts associated with iron and sterol metabolism, the cell wall, the GABA shunt, and transcriptional regulators were observed in response to hypoxia. A concomitant reduction in transcripts was observed with ribosome and terpenoid backbone biosynthesis, TCA cycle, amino acid metabolism and RNA degradation. Analysis of changes in transcription factor mRNA abundance shows that hypoxia induces significant positive and negative changes that may be important for regulating the hypoxia response in this pathogenic mold. Growth in hypoxia resulted in changes in the protein levels of several glycolytic enzymes, but these changes were not always reflected by the corresponding transcriptional profiling data. However, a good correlation overall (R²= 0.2, p < 0.05) existed between the transcriptomic and proteomics datasets for all time points. The lack of correlation between some transcript levels and their subsequent protein levels suggests another regulatory layer of the hypoxia response in <it>A. fumigatus</it>.</p> <p>Conclusions</p> <p>Taken together, our data suggest a robust cellular response that is likely regulated both at the transcriptional and post-transcriptional level in response to hypoxia by the human pathogenic mold <it>A. fumigatus</it>. As with other pathogenic fungi, the induction of glycolysis and transcriptional down-regulation of the TCA cycle and oxidative phosphorylation appear to major components of the hypoxia response in this pathogenic mold. In addition, a significant induction of the transcripts involved in ergosterol biosynthesis is consistent with previous observations in the pathogenic yeasts <it>Candida albicans </it>and <it>Cryptococcus neoformans </it>indicating conservation of this response to hypoxia in pathogenic fungi. Because ergosterol biosynthesis enzymes also require iron as a co-factor, the increase in iron uptake transcripts is consistent with an increased need for iron under hypoxia. However, unlike <it>C. albicans </it>and <it>C. neoformans</it>, the GABA shunt appears to play an important role in reducing NADH levels in response to hypoxia in <it>A. fumigatus </it>and it will be intriguing to determine whether this is critical for fungal virulence. Overall, regulatory mechanisms of the <it>A. fumigatus </it>hypoxia response appear to involve both transcriptional and post-transcriptional control of transcript and protein levels and thus provide candidate genes for future analysis of their role in hypoxia adaptation and fungal virulence.</p

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

Trehalose biosynthesis is found in fungi but not humans. Proteins involved in trehalose biosynthesis are essential for fungal pathogen virulence in humans and plants through multiple mechanisms. Loss of canonical trehalose biosynthesis genes in the human pathogen Aspergillus fumigatus significantly alters cell wall structure and integrity, though the mechanistic link between these virulence-associated pathways remains enigmatic. Here we characterize genes, called tslAand tslB, which encode proteins that contain domains similar to those corresponding to trehalose-6-phosphate phosphatase but lack critical catalytic residues for phosphatase activity. Loss of tslA reduces trehalose content in both conidia and mycelia, impairs cell wall integrity, and significantly alters cell wall structure. To gain mechanistic insights into the role that TslA plays in cell wall homeostasis, immunoprecipitation assays coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to reveal a direct interaction between TslA and CsmA, a type V chitin synthase enzyme. TslA regulates not only chitin synthase activity but also CsmA sub-cellular localization. Loss of TslA impacts the immunopathogenesis of murine invasive pulmonary aspergillosis through altering cytokine production and immune cell recruitment. In conclusion, our data provide a novel model whereby proteins in the trehalose pathway play a direct role in fungal cell wall homeostasis and consequently impact fungus-host interactions

Mental disorders as networks of problems:A review of recent insights

Purpose: The network perspective on psychopathology understands mental disorders as complex networks of interacting symptoms. Despite its recent debut, with conceptual foundations in 2008 and empirical foundations in 2010, the framework has received considerable attention and recognition in the last years. Methods: This paper provides a review of all empirical network studies published between 2010 and 2016 and discusses them according to three main themes: comorbidity, prediction, and clinical intervention. Results: Pertaining to comorbidity, the network approach provides a powerful new framework to explain why certain disorders may co-occur more often than others. For prediction, studies have consistently found that symptom networks of people with mental disorders show different characteristics than that of healthy individuals, and preliminary evidence suggests that networks of healthy people show early warning signals before shifting into disordered states. For intervention, centrality—a metric that measures how connected and clinically relevant a symptom is in a network—is the most commonly studied topic, and numerous studies have suggested that targeting the most central symptoms may offer novel therapeutic strategies. Conclusions: We sketch future directions for the network approach pertaining to both clinical and methodological research, and conclude that network analysis has yielded important insights and may provide an important inroad towards personalized medicine by investigating the network structures of individual patients

Quantum harmonic oscillator systems with disorder

We study many-body properties of quantum harmonic oscillator lattices with disorder. A sufficient condition for dynamical localization, expressed as a zero-velocity Lieb-Robinson bound, is formulated in terms of the decay of the eigenfunction correlators for an effective one-particle Hamiltonian. We show how state-of-the-art techniques for proving Anderson localization can be used to prove that these properties hold in a number of standard models. We also derive bounds on the static and dynamic correlation functions at both zero and positive temperature in terms of one-particle eigenfunction correlators. In particular, we show that static correlations decay exponentially fast if the corresponding effective one-particle Hamiltonian exhibits localization at low energies, regardless of whether there is a gap in the spectrum above the ground state or not. Our results apply to finite as well as to infinite oscillator systems. The eigenfunction correlators that appear are more general than those previously studied in the literature. In particular, we must allow for functions of the Hamiltonian that have a singularity at the bottom of the spectrum. We prove exponential bounds for such correlators for some of the standard models

Incentivizing appropriate prescribing in primary care:Development and first results of an electronic health record-based pay-for-performance scheme

Objective Part of the funding of Dutch General Practitioners (GPs) care is based on pay-for-performance, including an incentive for appropriate prescribing according to guidelines in national formularies. Aim of this paper is to describe the development of an indicator and an infrastructure based on prescription data from GP Electronic Health Records (EHR), to assess the level of adherence to formularies and the effects of the pay-for-performance scheme, thereby assessing the usefulness of the infrastructure and the indicator. Methods Adherence to formularies was calculated as the percentage of first prescriptions by the GP for medications that were included in one of the national formularies used by the GP, based on prescription data from EHRs. Adherence scores were collected quarterly for 2018 and 2019 and subsequently sent to health insurance companies for the pay-for-performance scheme. Adherence scores were used to monitor the effect of the pay-for-performance scheme. Results 75% (2018) and 83% (2019) of all GP practicesparticipated. Adherence to formularies was around 85% or 95%, depending on the formulary used. Adherence improved significantly, especially for practices that scored lowest in 2018. Discussion We found high levels of adherence to national formularies, with small improvements after one year. The infrastructure will be used to further stimulate formulary-based prescribing by implementing more actionable and relevant indicators on adherence scores for GPs