The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape

Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood. Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor FcyRIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes. This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.Comment: Accepted for publication in BMC Systems Biology. 17 pages, 6 Figures, + supplementary informatio

The Role of RFamide-Related Peptide-3 in Age-Related Reproductive Decline in Female Rats.

Reproductive senescence, the point in time when females cease to show estrous cyclicity, is associated with endocrine changes in the hypothalamus, pituitary, and gonads. However, the mechanisms triggering this transition are not well understood. To gain a better understanding of the top-down control of the transition from reproductive competence to a state of reproductive senescence, we investigated middle-aged female rats exhibiting varying degrees of reproductive decline, including individuals with normal cycles, irregular cycles, and complete cessation of cycles. We identified hormonal changes in the brain that manifest before ovarian cycles exhibit any deterioration. We found that females exhibit an increase in RFamide-related peptide-3 (RFRP3) mRNA expression in the hypothalamus in middle age prior to changes in estrous cycle length. This increase is transient and followed by subsequent decreases in kisspeptin (KiSS1) and gonadotropin-releasing hormone (GnRH) mRNA expression. Expression of RFRP3 and its receptor also increased locally in the ovaries with advancing age. While it is well known that aging is associated with decreased GnRH release and downstream disruption of the hypothalamic-pituitary-gonadal (HPG) axis, herein, we provide evidence that reproductive senescence is likely triggered by alterations in a network of regulatory neuropeptides upstream of the GnRH system

Spitzer Mid-Infrared Spectroscopy of Infrared Luminous Galaxies at z~2 II: Diagnostics

We present mid-IR spectral decomposition of a sample of 48 Spitzer-selected ULIRGs spanning z~1-3 and likely L_IR~10^12-10^13Lsun. Our study aims at quantifying the star-formation and AGN processes in these sources which recent results suggest have evolved strongly between the observed epoch and today. To do this, we study the mid-IR contribution of PAH emission, continuum, and extinction. About 3/4 of our sample are continuum- (i.e. AGN) dominated sources, but ~60% of these show PAH emission, suggesting the presence of star-formation activity. These sources have redder mid-IR colors than typical optically-selected quasars. About 25% of our sample have strong PAH emission, but none are likely to be pure starbursts as reflected in their relatively high 5um hot dust continua. However, their steep 30um-to-14um slopes suggest that star-formation might dominate the total infrared luminosity. Six of our z~2 sources have EW6.2>~0.3um and L_14um>~10^12Lsun (implying L_IR>~10^13Lsun). At these luminosities, such high EW6.2 ULIRGs do not exist in the local Universe. We find a median optical depth at 9.7um of =1.4. This is consistent with local IRAS-selected ULIRGs, but differs from early results on SCUBA-selected z~2 ULIRGs. Similar to local ULIRGs about 25% of our sample show extreme obscuration (tau_9.7>~3) suggesting buried nuclei. In general, we find that our sources are similar to local ULIRGs, but are an order of magnitude more luminous. It is not clear whether our z~2 ULIRGs are simply scaled-up versions of local ULIRGs, or subject to fundamentally different physical processes.Comment: 60 pages, 15 figures, accepted for publication in Ap

The Wireless Readiness Innovation Index: Enhancing the Effectiveness of the Public Sector in New Service Introduction

National and regional public authorities need to align their planned introduction of mobile/wireless innovation with the maturity levels of both their workforce (who will manage and maintain the new applications) and their citizens (who will use them). We draw on the experience of working with local authorities in three Mediterranean countries (Greece, Italy and Spain) to develop a method towards the effective introduction and adoption of innovative mobile services by public organizations. Specifically, we discuss the development and pilot implementation of a) the Wireless Readiness Innovation Index , a tool that aims at measuring the local authority’s and end users’ readiness towards providing and using innovative wireless services and b) the Wireless Innovation Operational Toolkit , a tool that aims at matching users’ and local authority’s readiness levels with candidate services so as to maximize the likelihood of successful introduction and sustained use

Testing metallicity indicators at z~1.4 with the gravitationally lensed galaxy CASSOWARY 20

We present X-shooter observations of CASSOWARY 20 (CSWA 20), a star-forming (SFR ~6 Msol/yr) galaxy at z=1.433, magnified by a factor of 11.5 by the gravitational lensing produced by a massive foreground galaxy at z=0.741. We analysed the integrated physical properties of the HII regions of CSWA 20 using temperature- and density-sensitive emission lines. We find the abundance of oxygen to be ~1/7 of solar, while carbon is ~50 times less abundant than in the Sun. The unusually low C/O ratio may be an indication of a particularly rapid timescale of chemical enrichment. The wide wavelength coverage of X-shooter gives us access to five different methods for determining the metallicity of CSWA 20, three based on emission lines from HII regions and two on absorption features formed in the atmospheres of massive stars. All five estimates are in agreement, within the factor of ~2 uncertainty of each method. The interstellar medium of CSWA 20 only partially covers the star-forming region as viewed from our direction; in particular, absorption lines from neutrals and first ions are exceptionally weak. We find evidence for large-scale outflows of the interstellar medium (ISM) with speeds of up 750 km/s, similar to the values measured in other high-z galaxies sustaining much higher rates of star formation.Comment: 18 pages, 11 figures, accepted for publication in MNRA

Adhesion to Vitronectin and Collagen I Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells

The mechanisms controlling human mesenchymal stem cells (hMSC) differentiation are not entirely understood. We hypothesized that the contact with extracellular matrix (ECM) proteins normally found in bone marrow would promote osteogenic differentiation of hMSC in vitro. To test this hypothesis, we cultured hMSC on purified ECM proteins in the presence or absence of soluble osteogenic supplements, and assayed for the presence of well-established differentiation markers (production of mineralized matrix, osteopontin, osteocalcin, collagen I, and alkaline phosphatase expression) over a 16-day time course. We found that hMSC adhere to ECM proteins with varying affinity ([Formula: see text]) and through distinct integrin receptors. Importantly, the greatest osteogenic differentiation occurred in cells plated on vitronectin and collagen I and almost no differentiation took place on fibronectin or uncoated plates. We conclude that the contact with vitronectin and collagen I promotes the osteogenic differentiation of hMSC, and that ECM contact alone may be sufficient to induce differentiation in these cells

Food Storage in Permafrost and Seasonally Frozen Ground in Chukotka and Alaska Communities

Food cellars, otherwise referred to as ice or meat cellars, (lednik in Russian, k’aetyran in Chukchi, siġļuaq in Iñupiaq, and siqlugaq in Yupik) are a natural form of refrigeration in permafrost or seasonally frozen ground used to preserve, age, and ferment foods harvested for subsistence, including marine mammals, birds, fish, and plants. Indigenous peoples throughout the Arctic have constructed cellars in frozen ground for millennia. This paper focuses on cellars in Russian and American coastal and island communities of the Bering Strait, the region otherwise known as Beringia. This area has a unique, culturally rich, and politically dynamic history. Many traditions associated with cellars are threatened in Chukchi communities in Russia because of the impacts of climate change, relocation, dietary changes, and industrial development. However, even with warmer temperatures, cellars still provide a means to age and ferment food stuffs following traditional methods. In cooperation with local stakeholders, we measured internal temperatures of 18 cellars in 13 communities throughout the Bering Strait region and northern Alaska. Though cellars are widely used in permafrost regions, their structure, usage, and maintenance methods differ and exhibit influences of local climates, traditions, and economic activities. Monitoring internal temperatures and recording structural descriptions of cellars is important in the face of climate change to better understand the variety and resilience of living adaptations in different cold regions.Les caves à denrées, aussi connues sous le nom de caves à glace ou de caves à viande (lednik en russe, k’aetyran en tchouktche, siġļuaq en iñupiaq, et siqlugaq en yupik) constituent une forme de réfrigération naturelle dans le pergélisol ou dans le gélisol saisonnier permettant de conserver, de maturer et de fermenter les denrées récoltées à des fins de subsistance, dont les mammifères marins, les oiseaux, les poissons et les plantes. Cela fait des millénaires que les peuples autochtones de l’Arctique construisent des caves dans le gélisol. Cet article porte sur les caves se trouvant dans les localités côtières et insulaires russes et américaines du détroit de Béring, région qui porte également le nom de Béringie. L’histoire de cette région est unique, culturellement riche et politiquement dynamique. De nombreuses traditions liées aux caves des localités tchouktches de la Russie sont menacées en raison des incidences du changement climatique, de la délocalisation, du changement des régimes alimentaires et de l’expansion industrielle. Cependant, malgré les températures plus élevées, les caves constituent toujours un moyen de maturer et de fermenter les denrées alimentaires selon les méthodes traditionnelles. En collaboration avec les parties prenantes de la région, nous avons mesuré les températures internes de 18 caves situées dans 13 localités de la région du détroit de Béring et du nord de l’Alaska. Bien que les caves soient courantes dans les régions de pergélisol, leur structure, leur usage et les méthodes d’entretien diffèrent, et elles sont à l’image des influences des traditions, des activités économiques et des climats locaux. La surveillance des températures internes et l’enregistrement des descriptions structurales des caves revêtent de l’importance à la lumière du changement climatique, car elles permettent de mieux comprendre la variété et la résilience des adaptations de vie dans différentes régions froides.называемые иногда мясными ямами (лéдник по-русски, к’этыран по-чукотски, Siġļuaq или Siqlugaq по-эскимосски), обустроены как в вечномёрзлых породах, так и в сезонноталом слое и являются естественной формой заморозки для сохранения, выдержки и ферментации пищевых продуктов, добытых для пропитания: мясо морских млекопитающих, дичь, рыба, растения и др. Коренные жители Арктики обустраивали хранилища в мерзлоте на протяжении тысячелетий. Данная статья посвящена подземным хранилищам в российских и американских поселениях на берегах Берингова пролива – региона, также называемого Берингией. Эта территория имеет уникальную, богатую культурой и политически динамичную историю. Многие традиции, связанные с хранилищами в поселениях Чукотки, находятся под угрозой исчезновения из-за климатических изменений, миграции жителей, изменений в рационе и промышленного освоения территории. Однако даже при повышении температуры воздуха в хранилищах по-прежнему можно выдерживать и ферментировать пищу традиционными способами. При сотрудничестве с местным населением мы измерили температуры внутреннего воздуха в 18 лéдниках в 13 поселениях в регионе Берингова пролива и на севере Аляски. Несмотря на широкое использование таких хранилищ в криолитозоне, их структура, использование и методы обслуживания различаются под влиянием климатических условий, традиций и особенностей промысла. Мониторинг внутренней температуры воздуха в лéдниках и описание их конструкций важны в контексте изменения климата для лучшего понимания разнообразия и эффективности различных способов адаптации к жизни в холодных регионах

The Impact of Free Health Screenings at Community Pharmacies on Diabetes

Diabetes is a prevalent issue in the United States, with an estimated 8.1 million people un-diagnosed as of 2012. Health screenings have been proven to identify diseases earlier, thereby resulting in earlier and more satisfactory treatment. Community pharmacies can offer many of the same screenings as those in doctor offices. The objective of this study was to assess the impact of free health screenings in community pharmacies on patient follow-up, perceptions, and knowledge of diabetes through blood glucose screenings and patient education. The study design was a pre-post observational study using surveys, blood sugar screenings, and patient education on diabetes. Participants were voluntary patients from four REM Corporation pharmacies in Ohio who were 18 or older, not recently tested for diabetes, non-diabetic, not pregnant, and without disorders that could hinder survey responses and education. Pre- and post-surveys assessed both patient perceptions on free health screenings in community pharmacies and on diabetes knowledge. Results among the 26 participants showed there was no statistically significant difference between patient perception pre- and post-surveys (all p-values ≥ 0.05), however there was a statistically significant difference between pre and post diabetes knowledge surveys (p \u3c 0.001). Limitations of this study were the small sample size due to the relatively small pharmacies utilized and short length of study time. Future directions should focus on using more demographically diverse pharmacies and a longer study time. Due to patients already having highly positive perceptions of health screenings in community pharmacies, future research should assess patient knowledge of diseases and the impact of patient education on overall health outcomes. Results of the study showed patients had positive opinions on free health screenings in community pharmacies and these screenings can help patients understand disease states and be more aware of their health