The hetZ Gene Regulates Heterocyst Formation in Anabaena sp. strain PCC 7120

To form a complex multicellular organism, stem cells must differentiate into each cell/tissue type along proper spatiotemporal scales. The study of differentiation and organismal development has historically been conducted in prokaryotes due to their genetic and morphological simplicity. Anabaena sp. strain PCC 7120 is a multicellular filamentous cyanobacterium that differentiates a morphologically distinct secondary cell type, the heterocyst, in response to a lack of combined environmental nitrogen. Heterocysts are regularly spaced along filaments and fix atmospheric dinitrogen to maintain organismal viability in its absence. Previous work suggested that the hetZ gene is involved in heterocyst differentiation, but the insertional mutants created produced inconsistent phenotypes, so a specific role was not assigned. In this work, a clean hetZ mutant incapable of heterocyst differentiation was generated and the mutation was complemented with the reintroduction of hetZ alone. Overexpression of hetZ bypassed a mutation of hetR, the master regulator of heterocyst differentiation that controls biological pattern formation, but not a mutation of hetP, a regulator of commitment to a differentiated cell fate, which places hetZ roughly between these processes. A protein-protein interaction study showed that HetZ interacts with both HetR and itself. Assessment of transcriptional fusions between the hetZ, hetR, hetP, and patS (an inhibitor of HetR) promoter regions and GFP, and overexpression of HetR in a hetZ mutant resulted in the differentiation of heterocyst-like cells, together indicated that HetZ may act in concert with HetR as an early regulator of development. Taken together, these data describe a non-linear pathway of regulation leading to heterocyst development governed by both HetR and HetZ

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

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EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma

SummaryThe aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation

The ‘vicious cycle’ of personalised asthma action plan implementation in primary care: a qualitative study of patients and health professionals’ views

Background: Personal asthma action plans (PAAPs) have been guideline recommended for years, but consistentlyunder-issued by health professionals and under-utilised by patients. Previous studies have investigated sub-optimalPAAP implementation but more insight is needed into barriers to their use from the perspective of professionals,patients and primary care teams.Methods: A maximum variation sample of professional and patient participants were recruited from five demographicallydiverse general practices and another group of primary care professionals in one Scottish region. Interviews were digitallyrecorded and data thematically analysed using NVivo.Results: Twenty-nine semi-structured interviews were conducted (11 adults with asthma, seven general practitioners, tenpractice nurses, one hospital respiratory nurse). Three over-arching themes emerged: 1) patients generally do not valuePAAPs, 2) professionals do not fully value PAAPs and, 3) multiple barriers reduce the value of PAAPs in primary care. Sixpatients had a PAAP but these were outdated, not reflecting their needs and not used. Patients reported not wanting orneeding PAAPs, yet identified circumstances when these could be useful. Fifteen professionals had selectively issuedPAAPs with eight having reviewed one. Many professionals did not value PAAPs as they did not see patients using theseand lacked awareness of times when patients could have benefited from one. Multi-level compounding barriers emerged.Individual barriers included poor patient awareness and professionals not reinforcing PAAP use. Organisational barriersincluded professionals having difficulty accessing PAAP templates and fragmented processes including patients not beingasked to bring PAAPs to their asthma appointments.Conclusions: Primary care PAAP implementation is in a vicious cycle. Professionals infrequently review/update PAAPswith patients; patients with out-dated PAAPs do not value or use these; professionals observing patients’ lack of interestin PAAPs do not discuss these. Patients observing this do not refer to their plans and perceive them to be of little valuein asthma self-management. Twenty-five years after PAAPs were first recommended, primary care practices are still notready to support their implementation. Breaking this vicious cycle to create a healthcare context more conducive to PAAPimplementation requires a whole systems approach with multi-faceted interventions addressing patient, professional andorganisational barriers

Assessment of the efficacy of vehicle side airbags: A matched cohort study of vehicle-vehicle side collisions using the GIDAS database

Current literature, whilst limited, highlights inconsistencies in the efficacy of vehicle torso side airbags (tSAB). The objective of this study is to further investigate this using data from the German In‐depth Accident Study (GIDAS). Collisions involving vehicle-vehicle/light‐truck interaction, whereby an injured occupant is seated nearside and in the front row, was used. From this, a matched cohort study is undertaken, in which collisions with a torso side airbag (exposure) deployed are paired with similar collisions without a tSAB (non‐exposure) on the basis of; occupant, vehicle and collision characteristics. This pairing process is automated by a Genetic Matching algorithm that calculates a matrix of optimal weighting values for the selected matching criteria and is capable of returning multiple non‐exposure collisions per exposure collision. A conditional logistic regression then outputs the Odds Ratios for a given injury severity. Results show that for collisions with a deployed tSAB, the risk of overall thoracic injury was not reduced (MAIS1+, OR=1.08, 95%CI[0.65‐1.82]), however a non‐significant reduced risk for rib fracture occurred (MAIS1+, RR=0.67, 95%CI[0.29‐1.54]). When stratified by change of velocity, a strong protective effect for the thoracic region occurred for dV range similar to EuroN‐CAP testing (MAIS1+, RR=0.48, 95%CI[0.18‐1.27]), however an increased risk of injury occurred for greater speeds (MAIS1+, RR=1.63, 95%CI[0.59‐4.4]). Additionally the occupant may be more susceptible to light thoracic injury at mid‐low impact speeds (MAIS1+, RR=2.48, 95%CI[0.93‐6.16]