Structural Parameters of Seven SMC Intermediate-Age and Old Star Clusters

We present structural parameters for the seven intermediate-age and old star clusters NGC121, Lindsay 1, Kron 3, NGC339, NGC416, Lindsay 38, and NGC419 in the Small Magellanic Cloud. We fit King profiles and Elson, Fall, and Freeman profiles to both surface-brightness and star count data taken with the Advanced Camera for Surveys aboard the Hubble Space Telescope. Clusters older than 1 Gyr show a spread in cluster core radii that increases with age, while the youngest clusters have relatively compact cores. No evidence for post core collapse clusters was found. We find no correlation between core radius and distance from the SMC center, although consistent with other studies of dwarf galaxies, some relatively old and massive clusters have low densities. The oldest SMC star cluster, the only globular NGC121, is the most elliptical object of the studied clusters. No correlation is seen between ellipticity and distance from the SMC center. The structures of these massive intermediate-age (1-8 Gyr) SMC star clusters thus appear to primarily result from internal evolutionary processes.Comment: 16 pages, 13 figure

Age Determination of Six Intermediate-age SMC Star Clusters with HST/ACS

We present a photometric analysis of the star clusters Lindsay 1, Kron 3, NGC339, NGC416, Lindsay 38, and NGC419 in the Small Magellanic Cloud (SMC), observed with the Hubble Space Telescope Advanced Camera for Surveys (ACS) in the F555W and F814W filters. Our color magnitude diagrams (CMDs) extend ~3.5 mag deeper than the main-sequence turnoff points, deeper than any previous data. Cluster ages were derived using three different isochrone models: Padova, Teramo, and Dartmouth, which are all available in the ACS photometric system. Fitting observed ridgelines for each cluster, we provide a homogeneous and unique set of low-metallicity, single-age fiducial isochrones. The cluster CMDs are best approximated by the Dartmouth isochrones for all clusters, except for NGC419 where the Padova isochrones provided the best fit. The CMD of NGC419 shows several main-sequence turn-offs, which belong to the cluster and to the SMC field. We thus derive an age range of 1.2-1.6 Gyr for NGC419. Interestingly, our intermediate-age star clusters have a metallicity spread of ~0.6 dex, which demonstrates that the SMC does not have a smooth, monotonic age-metallicity relation. We find an indication for centrally concentrated blue straggler star candidates in NGC416, while for the other clusters these are not present. Using the red clump magnitudes, we find that the closest cluster, NGC419 (~50kpc), and the farthest cluster, Lindsay 38 (~67kpc), have a relative distance of ~17kpc, which confirms the large depth of the SMC.Comment: 25 pages, 45 Figure

Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year's different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches

The zebrafish as a new model for the in vivo study of Shigella flexneri interaction with phagocytes and bacterial autophagy.

Autophagy, an ancient and highly conserved intracellular degradation process, is viewed as a critical component of innate immunity because of its ability to deliver cytosolic bacteria to the lysosome. However, the role of bacterial autophagy in vivo remains poorly understood. The zebrafish (Danio rerio) has emerged as a vertebrate model for the study of infections because it is optically accessible at the larval stages when the innate immune system is already functional. Here, we have characterized the susceptibility of zebrafish larvae to Shigella flexneri, a paradigm for bacterial autophagy, and have used this model to study Shigella-phagocyte interactions in vivo. Depending on the dose, S. flexneri injected in zebrafish larvae were either cleared in a few days or resulted in a progressive and ultimately fatal infection. Using high resolution live imaging, we found that S. flexneri were rapidly engulfed by macrophages and neutrophils; moreover we discovered a scavenger role for neutrophils in eliminating infected dead macrophages and non-immune cell types that failed to control Shigella infection. We observed that intracellular S. flexneri could escape to the cytosol, induce septin caging and be targeted to autophagy in vivo. Depletion of p62 (sequestosome 1 or SQSTM1), an adaptor protein critical for bacterial autophagy in vitro, significantly increased bacterial burden and host susceptibility to infection. These results show the zebrafish larva as a new model for the study of S. flexneri interaction with phagocytes, and the manipulation of autophagy for anti-bacterial therapy in vivo

Mechanical force induces mitochondrial fission.

Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria - via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces - results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm

Mitochondria mediate septin cage assembly to promote autophagy of Shigella.

Septins, cytoskeletal proteins with well-characterised roles in cytokinesis, form cage-like structures around cytosolic Shigella flexneri and promote their targeting to autophagosomes. However, the processes underlying septin cage assembly, and whether they influence S. flexneri proliferation, remain to be established. Using single-cell analysis, we show that the septin cages inhibit S. flexneri proliferation. To study mechanisms of septin cage assembly, we used proteomics and found mitochondrial proteins associate with septins in S. flexneri-infected cells. Strikingly, mitochondria associated with S. flexneri promote septin assembly into cages that entrap bacteria for autophagy. We demonstrate that the cytosolic GTPase dynamin-related protein 1 (Drp1) interacts with septins to enhance mitochondrial fission. To avoid autophagy, actin-polymerising Shigella fragment mitochondria to escape from septin caging. Our results demonstrate a role for mitochondria in anti-Shigella autophagy and uncover a fundamental link between septin assembly and mitochondria

Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.

Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The septin cage: a novel mechanism of host defence to restrict bacterial replication

Autophagy is a highly conserved intracellular degradation process crucial for cell-autonomous immunity against bacterial infection. However, some bacteria may subvert the host cytoskeleton to escape recognition from autophagy. In the cytosol, Shigella flexneri and Listeria monocytogenes use actin-based motility to avoid cell-autonomous immunity and spread from cell-to-cell. The host cytoskeleton plays a key role in autophagy and its ability to restrict or promote bacterial replication. Septins, a cytoskeletal component that interacts with cellular membranes and actin filaments, are GTP-binding proteins that polymerize into non-polar filaments and rings. Our lab has discovered that septin cage-like structures entrap actin-polymerising Shigella targeted to autophagy. The septin cage is recognized as a mechanism of host defence mechanism, however the precise fate of septin cage entrapped Shigella remains unknown. Evidence has suggested that mitochondria provide membrane for the biogenesis of autophagosomes during starvation. The role of the mitochondria during the autophagy of Shigella is unknown. Mitochondria are highly dynamic organelles characterised by events of membrane fission and fusion. Work has previously established a role for the host cell division machinery, i.e. actin and myosin, in the regulation of mitochondrial dynamics (a process called ‘mitokinesis’). Whether septins are also involved in mitochondrial dynamics has not yet been tested. For my thesis, the entrapment of Shigella by septin cages was used as a paradigm to better understand host defence against bacterial infection and to discover new septin biology. Results have shown that mitochondria mediate the assembly of septins into cage that target Shigella to degradation by autophagy. We have also discovered that septins regulate mitochondrial fission. Finally, we have revealed a new link between septins, autophagy, and host cell metabolism. Together these results suggest that a more complete understanding of septin biology during bacterial infection can enable its manipulation for therapeutic purposes.Open Acces