418 research outputs found
Genome wide analysis of the complete GlnR nitrogen-response regulon in Mycobacterium smegmatis
BACKGROUND: Nitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms. RESULTS: We investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding. CONCLUSIONS: We have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions
Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration
Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35?mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration
The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles
Tissue factor (TF) is critical for the activation of blood coagulation. TF function is regulated by the amount of externalised phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the surface of the cell in which it is expressed. We investigated the role PS and PE in fibroblast TF function. Fibroblasts expressed 6â9 x 104 TF molecules/cell but had low specific activity for FXa generation. We confirmed that this was associated with minimal externalized PS and PE and characterised for the first time the molecular species of PS/PE demonstrating that these differed from those found in platelets. Mechanical damage of fibroblasts, used to simulate vascular injury, increased externalized PS/PE and led to a 7-fold increase in FXa generation that was inhibited by annexin V and an anti-TF antibody. Platelet-derived extracellular vesicles (EVs), that did not express TF, supported minimal FVIIa-dependent FXa generation but substantially increased fibroblast TF activity. This enhancement in fibroblast TF activity could also be achieved using synthetic liposomes comprising 10% PS without TF. In conclusion, despite high levels of surface TF expression, healthy fibroblasts express low levels of external-facing PS and PE limiting their ability to generate FXa. Addition of platelet-derived TF-negative EVs or artificial liposomes enhanced fibroblast TF activity in a PS dependent manner. These findings contribute information about the mechanisms that control TF function in the fibroblast membrane
An RNAi screen of the kinome in epithelial follicle cells of the Drosophila melanogaster ovary reveals genes required for proper germline death and clearance
Programmed cell death and cell corpse clearance are an essential part of organismal health and development. Cell corpses are often cleared away by professional phagocytes such as macrophages. However, in certain tissues, neighboring cells known as nonprofessional phagocytes can also carry out clearance functions. Here, we use the Drosophila melanogaster ovary to identify novel genes required for clearance by nonprofessional phagocytes. In the Drosophila ovary, germline cells can die at multiple time points. As death proceeds, the epithelial follicle cells act as phagocytes to facilitate the clearance of these cells. We performed an unbiased kinase screen to identify novel proteins and pathways involved in cell clearance during two death events. Of 224 genes examined, 18 demonstrated severe phenotypes during developmental death and clearance while 12 demonstrated severe phenotypes during starvation-induced cell death and clearance, representing a number of pathways not previously implicated in phagocytosis. Interestingly, it was found that several genes not only affected the clearance process in the phagocytes, but also non-autonomously affected the process by which germline cells died. This kinase screen has revealed new avenues for further exploration and investigation.R01 GM060574 - NIGMS NIH HHS; R35 GM127338 - NIGMS NIH HHS; 5R35GM127338-05 REVISED - NIH/National Institute of General Medical Scienceshttps://academic.oup.com/g3journal/article/11/2/jkaa066/6080751?login=truePublished versio
Planetary Candidates Observed by Kepler V: Planet Sample from Q1-Q12 (36 Months)
The Kepler mission discovered 2842 exoplanet candidates with 2 years of data.
We provide updates to the Kepler planet candidate sample based upon 3 years
(Q1-Q12) of data. Through a series of tests to exclude false-positives,
primarily caused by eclipsing binary stars and instrumental systematics, 855
additional planetary candidates have been discovered, bringing the total number
known to 3697. We provide revised transit parameters and accompanying posterior
distributions based on a Markov Chain Monte Carlo algorithm for the cumulative
catalogue of Kepler Objects of Interest. There are now 130 candidates in the
cumulative catalogue that receive less than twice the flux the Earth receives
and more than 1100 have a radius less than 1.5 Rearth. There are now a dozen
candidates meeting both criteria, roughly doubling the number of candidate
Earth analogs. A majority of planetary candidates have a high probability of
being bonafide planets, however, there are populations of likely
false-positives. We discuss and suggest additional cuts that can be easily
applied to the catalogue to produce a set of planetary candidates with good
fidelity. The full catalogue is publicly available at the NASA Exoplanet
Archive.Comment: Accepted for publication, ApJ
Beyond Accommodations: Supporting Autistic Professionals in Education. Practice based guide for employers and employees
This guide is intended to support neurodivergent people working by providing
information and practical suggestions based upon the views and preferences
of neurodivergent adults.
Autistic people can have poor employment outcomes, are under-represented in the
workforce, and often experience discrimination and poor mental health (Buckley
et al., 2021; Bury et al., 2021; Wood et al., 2022). Employment is often precarious (short term, part-time, low paid) and individuals are underemployed or overqualified for
their current roles. Although, as not all autistic people are diagnosed or choose to
share their autistic identity, the literature may not reflect the true picture.
It is therefore important that we increase our understanding of the challenges
facing autistic people not only in gaining employment but within the workforce.
This study draws on the experience of autistic professionals working in health and
education because professionals working within health and education are well
placed to become influential positive role models (Lawrence, 2019).
The guidance is based on information obtained during a review of published
literature and interviews with thirty-four autistic people who work in professional
roles within health and education in Scotland. They were asked about their
experiences of training, recruitment, and employment, particularly factors that
offered them support, and factors which challenged them. They also provided
recommendations for improving training, recruitment, and employment for
neurodivergent people in the future. The guide was also reviewed by people
working in management and human resources roles across health and education.
This guide is intended to provide information which will support neurodivergent
people in employment. Often adjustments to language, mindsets and actions do
not cost money and can provide benefit to the whole diverse workforce.
Throughout this guide we have included direct quotations obtained during
interviews with autistic professionals. This guide and the research on which it
is based was conducted by a team which includes autistic and non-autistic
researchers.
Although our focus has been on autistic people, it is well known that most autistic
people experience co-occurring mental health and neurodevelopmental
differences. Similar experiences are shared by people with ADHD or who identify
as neurodivergent.pubpu
Effective description of general extensions of the Standard Model: the complete tree-level dictionary
We thank Nuria Rius and Arcadi Santamaria for an interesting discussion that motivated
this work. We also thank Paco del Ăguila and Toni Pich for useful comments.We compute all the tree-level contributions to the Wilson coefficients of
the dimension-six Standard-Model effective theory in ultraviolet completions with general
scalar, spinor and vector feld content and arbitrary interactions. No assumption about
the renormalizability of the high-energy theory is made. This provides a complete ultraviolet/
infrared dictionary at the classical level, which can be used to study the low-energy
implications of any model of interest, and also to look for explicit completions consistent
with low-energy dataThe work
of J.C.C., M.P.V. and J.S. has been supported by the Spanish MICINN project FPA2013-
47836-C3-2-P, the MINECO project FPA2016-78220-C3-1-P (Fondos FEDER) and the
Junta de AndalucĂa grant FQM101. The work of J.C.C. has also been supported by the
Spanish MECD grant FPU14. The work of M.P.V. and J.S. has also been supported by the European Commission through the contract PITN-GA-2012-316704 (HIGGSTOOLS).
J.C.C. is grateful for the hospitality of the Dipartimento di Fisica e Astronomia \Galileo
Galilei" of the University of Padova during part of this work. J.S. would like to thank
the Mainz Institute for Theoretical Physics (MITP) for its hospitality and partial support
during the completion of this work
Beyond Accommodations: Supporting Autistic Health Professionals. Practice based guide for employers and employees
This guide is intended to support neurodivergent people working in the healthcare
sector by providing information and practical suggestions based upon the views
and preferences of neurodivergent adults.
Autistic people can have poor employment outcomes, are under-represented in the
workforce, and often experience discrimination and poor mental health (Buckley
et al., 2021; Bury et al., 2021; Wood et al., 2022). Employment is often precarious (short term, part-time, low paid) and individuals are underemployed or overqualified for
their current roles. Although, as not all autistic people are diagnosed or choose to
share their autistic identity, the literature may not reflect the true picture.
It is therefore important that we increase our understanding of the challenges
facing autistic people not only in gaining employment but within the workforce.
This study draws on the experience of autistic professionals working in health and
education because professionals working within health and education are well
placed to become influential positive role models (Lawrence, 2019).
The guidance is based on information obtained during a review of published
literature and interviews with thirty-four autistic people who work in professional
roles within health and education in Scotland. They were asked about their
experiences of training, recruitment, and employment, particularly factors that
offered them support, and factors which challenged them. They also provided
recommendations for improving training, recruitment, and employment for
neurodivergent people in the future. The guide was also reviewed by people
working in management and human resources roles across health and education.
This guide is intended to provide information which will support neurodivergent
people in employment. Often adjustments to language, mindsets and actions do
not cost money and can provide benefit to the whole diverse workforce.
Throughout this guide we have included direct quotations obtained during
interviews with autistic professionals. This guide and the research on which
it is based was conducted by a team which includes autistic and non-autistic
researchers.
Although our focus has been on autistic people, it is well known that most
autistic people experience co-occurring mental health and neurodevelopmental
differences. Similar experiences are shared by people with ADHD or who identify
as neurodivergent.pubpu
Field redefinitions in effective theories at higher orders
The invariance of physical observables under redefinitions of the quantum fields
is a well-known and important property of quantum field theory. We study perturbative field redefinitions in effective theories, paying special attention to higher-order effects and
their impact on matching to an ultraviolet theory at the classical and quantum levels.Our
work has been supported by the Spanish MINECO project FPA2016-78220-C3-1-P (Fondos
FEDER) and the Junta de AndalucĂa grant FQM101. The work of J.C.C. has also been
supported by the Spanish MECD grant FPU14
'A good fit?' Bringing the Sociology of Footwear to the Clinical Encounter in Podiatry Services : A Narrative Review
Background: This narrative review explores the ways in which drawing on theories and methods used in sociological work on footwear and identity can contribute to healthcare research with podiatrists and their patients, highlighting recent research in this field, implications for practice and potential areas for future development. Traditionally, research within Podiatry Services has tended to adopt a quantitative, positivist focus, developing separately from a growing body of sociological work exploring the importance of shoes in constructing identity and self-image. Bringing qualitative research drawing on sociological theory and methods to the clinical encounter has real potential to increase our understanding of patient values, motivations and â crucially â any barriers to adopting âhealthierâ footwear that they may encounter. Such work can help practitioners to understand why patients may resist making changes to their footwear practices, and help us to devise new ways for practitioners to explore and ultimately break down individual barriers to change (including their own preconceptions as practitioners). This, in turn, may lead to long-term, sustainable changes to footwear practices and improvements in foot health for those with complex health conditions and the wider population. Conclusion: A recognition of the complex links between shoes and identity is opening up space for discussion of patient resistance to footwear changes, and paving the way for future research in this field beyond the temporary âmomentâ of the clinical encounter
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