פרסומים

מטרה: לבחון את המוטיבציה של פקידים בכירים לשנות את סדר היום הציבורי, כפי שעלה בתקופת מחאת הצדק החברתי של קיץ 2011.// נבדקים: 64 פקידים בכירים בשבעה משרדי ממשלה.// שיטה וכלי מחקר: הנבדקים השתתפו במחקר מעורב – איכותני וכמותני כשלושה חודשים לאחר פרוץ המחאה החברתית של קיץ 2011, אשר כלל ראיונות ומילוי שאלונים סגורים. כלי המחקר בחנו הזדהות עם סדרי היום שהועלו במחאה ואת השפעתם על פעילותם הציבורית.// מן הממצאים: מרואיינים רבים העידו כי הם מזדהים עם הסיבות למחאה החברתית. חלק מהם זיהו עצמם כחלק מאותו המעמד של המפגינים. המרואיינים המבוגרים בני ה-50 וה-60 ראו במפגינים את ילדיהם והסכימו עם טענתם כי המצב החברתי-כלכלי בישראל אינו מאפשר איכות חיים נאותה לדור הצעיר. חלק מהמרואיינים השתייכו לקטגוריה של "בלתי מזדהים אך מלאי סימפתיה" למחאה ולאנשיה. נמצא קשר חיובי בין הזדהות עם סדר היום של המחאה החברתית ובין המוטיבציה של הנבדקים לחולל שינוי מדיניות. ממצא זה עלה בחתך כל התפקידים והמשרדים. בנוסף, נמצא כי גם פקידים שלא הזדהו עם המחאה החברתית, ראו בה הזדמנות לקדם מדיניות משופרת לטובת רווחת הציבור. הממצאים מאת

Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using the lipophilic prodrug charge masking approach (LPCM) can improve the bioavailability of hydrophilic peptides. To test this hypothesis, a cyclic N-methylated hexapeptide containing Arg-Gly-Asp (RGD) and its prodrug derivatives, masking the Arg and Asp charged side chains, were synthesized. The library was evaluated for intestinal permeability in vitro using the Caco-2 model. Further investigation of metabolic stability ex vivo models in rat plasma, brush border membrane vesicles (BBMVs), and isolated CYP3A4 microsomes and pharmacokinetic studies was performed on a selected peptide and its prodrug (peptide 12). The parent drug analogues were found to have a low permeability rate in vitro, corresponding to atenolol, a marker for paracellular permeability. Moreover, palmitoyl carnitine increased the P(app) of peptide 12 by 4-fold, indicating paracellular permeability. The P(app) of the prodrug derivatives was much higher than that of their parent peptides. For instance, the P(app) of the prodrug 12P was 20-fold higher than the P(app) of peptide 12 in the apical to basolateral (AB) direction. Whereas the permeability in the opposite direction (BA of the Caco-2 model) was significantly faster than the P(app) AB, indicating the involvement of an efflux system. These results were corroborated when verapamil, a P-gp inhibitor, was added to the Caco-2 model and increased the P(app) AB of prodrug 12P by 3-fold. The prodrug 12P was stable in the BBMVs environment, yet degraded quickly (less than 5 min) in the plasma into the parent peptide 12. Pharmacokinetic studies in rats showed an increase in the bioavailability of peptide 12 > 70-fold (from 0.58 ± 0.11% to 43.8 ± 14.9%) after applying the LPCM method to peptide 12 and converting it to the prodrug 12P. To conclude, the LPCM approach converted the absorption mechanism of the polar peptides from a paracellular to transcellular pathway that tremendously affects their oral bioavailability. The LPCM method provides a solution for the poor bioavailability of RGD cyclohexapeptides and paves the way for other active hydrophilic and charged peptides with poor oral bioavailability.

The brittle nature of the polymer beads used in SPPS dictates mild mixing techniques with low mass transfer. We demonstrate that vigorous overhead mechanical stirring with superior mass transfer properties kept the beads intact and significantly accelerates reaction kinetics and efficiency.

 

Although many nations advocate for the full inclusion of people with intellectual disabilities in all realms of life, these individuals are nevertheless still frequently excluded. One field of life that has rarely been considered central for inclusion of people with intellectual disabilities is military service. A unique programme was developed that provides an opportunity for people with intellectual disabilities to serve in the military in Israel. The centrality of the military within Israeli society, along with the aims and phases of the project are described, and brief evidence of the impact of the programme is provided.

The rupture fronts that mediate the onset of frictional sliding may propagate at speeds below the Rayleigh wave speed or may surpass the shear wave speed and approach the longitudinal wave speed. While the conditions for the transition from sub-Rayleigh to supershear propagation have been studied extensively, little is known about what dictates supershear rupture speeds and how the interplay between the stresses that drive propagation and interface properties that resist motion affects them. By combining laboratory experiments and numerical simulations that reflect natural earthquakes, we find that supershear rupture propagation speeds can be predicted and described by a fracture mechanics–based equation of motion. This equation of motion quantitatively predicts rupture speeds, with the velocity selection dictated by the interface properties and stress. Our results reveal a critical rupture length, analogous to Griffith’s length for sub-Rayleigh cracks, below which supershear propagation is impossible. Above this critical length, supershear ruptures can exist, once excited, even for extremely low preexisting stress levels. These results significantly improve our fundamental understanding of what governs the speed of supershear earthquakes, with direct and important implications for interpreting their unique supershear seismic radiation patterns.

Main Text: (Stem Cell Reports 5, 918–931; November 10, 2015) The karyotype pictures of iPSC clones iMCL#3 and iMCL#11 shown in Figure S1D in the original Supplemental Material were incorrect and have been replaced online. This graphical error does not affect the results and conclusions of the article. The authors apologize for this error. © 2018

Enteropathogenic (EPEC) belongs to a group of enteric human pathogens known as attaching-and-effacing (A/E) pathogens, which utilize a type III secretion system (T3SS) to translocate a battery of effector proteins from their own cytoplasm into host intestinal epithelial cells. Here we identified EspH to be an effector that prompts the recruitment of the tetraspanin CD81 to infection sites. EspH was also shown to be an effector that suppresses the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) signaling pathway at longer infection times. The inhibitory effect was abrogated upon deletion of the last 38 amino acids located at the C terminus of the protein. The efficacy of EspH-dependent Erk suppression was higher in CD81-deficient cells, suggesting that CD81 may act as a positive regulator of Erk, counteracting Erk suppression by EspH. EspH was found within CD81 microdomains soon after infection but was largely excluded from these domains at a later time. Based on our results, we propose a mechanism whereby CD81 is initially recruited to infection sites in response to EspH translocation. At a later stage, EspH moves out of the CD81 clusters to facilitate effective Erk inhibition. Moreover, EspH selectively inhibits the tumor necrosis factor alpha (TNF-α)-induced Erk signaling pathway. Since Erk and TNF-α have been implicated in innate immunity and cell survival, our studies suggest a novel mechanism by which EPEC suppresses these processes to promote its own colonization and survival in the infected gut.

This paper investigates issues that have arisen in recent efforts to revise long-standing knockdown factors for elastic shell buckling, which are widely regarded as being overly conservative for well-constructed shells. In particular, this paper focuses on cylindrical shells under axial compression with emphasis on the role of local geometric dimple imperfections and the use of lateral force probes as surrogate imperfections. Local and global buckling loads are identified and related for the two kinds of imperfections. Buckling loads are computed for four sets of relevant boundary conditions revealing a strong dependence of the global buckling load on overall end-rotation constraint when local buckling precedes global buckling. A reasonably complete picture emerges, which should be useful for informing decisions on establishing knockdown factors. Experiments are performed using a lateral probe to study the stability landscape for a cylindrical shell with overall end rotation constrained in the first set of tests and then unconstrained in the second set of tests. The nonlinear buckling behavior of spherical shells under external pressure is also examined for both types of imperfections. The buckling behavior of spherical shells is different in a number of important respects from that of the cylindrical shells, particularly regarding the interplay between local and global buckling and the post-buckling load-carrying capacity. These behavioral differences have bearing on efforts to revise buckling design rules. The present study raises questions about the perspicacity of using probe force imperfections as surrogates for geometric dimple imperfections.

Treatment of Mycobacterium abscessus infections is extremely challenging due to its intrinsic resistance to most antibiotics, and research of pathogenesis is limited due to a lack of a practical in vivo model of infection. The objective of this study was to establish a simple in vivo model for M. abscessus infection, virulence, and drug testing in Galleria mellonella larvae. We inoculated larvae with M. abscessus bacteria and assessed histopathology, CFU count, and mortality with and without antibiotic treatment. We also constructed a luminescent, recombinant M. abscessus mutant, mDB158, and imaged infected larvae using the IVIS in vivo imaging system. M. abscessus proliferated and induced granuloma-like responses in infected larvae, leading to larval mortality. The G. mellonella model was further validated successfully by demonstration of the expected favorable antimicrobial effect of treatment with meropenem and the superiority of combination treatment (meropenem and tigecycline) over that with single agents. We then used IVIS imaging of larvae infected with luminescent M. abscessus, allowing live real-time assessment of bacterial load. We used this method to compare the antimicrobial effects of various antibiotics (meropenem, amikacin, linezolid, levofloxacin, etc.) on bacterial proliferation and larval survival. Meropenem and amikacin had the most favorable effects, correlating well with common clinical practice guidelines. These findings suggest G. mellonella to be an excellent in vivo model for research of M. abscessus infection, pathogenesis, and treatment. Luminescent M. abscessus and IVIS imaging further facilitates this model. Results obtained in this model clearly substantiated common clinical practice, thus validating the model as a predictor of treatment efficacy and outcome.

ABSTRACTThe economic and socio-political interactions between countries can have major impacts on transboundary conservation decisions and outcomes. Here, we examined for 14 Western Indian Ocean (WIO) continental and island nations the extent of their marine coral reef species, fisheries and marine protected areas (MPAs), in the context of their geopolitical and socio-economic connections. We also examined the role of external countries and organisations in collaboration within the region. We found large variation between the different countries in their protected area size, and management, which result from different interests in establishing the MPAs, ranging from fisheries management, biodiversity conservation to asserting sovereignty claims. Seventy-four per cent of the 154 MPAs in the region belong to island nations; however, the largest MPAs in the WIO were established by European powers, and include Mayotte and Glorioso Islands (France) and Chagos (UK). While the majority of MPAs are managed by individual countries, between-country collaboration within and outside the region is key if the aim is to achieve effective conservation of ecosystems and species across the island and mainland nations in the region. This may be advanced by creating transboundary MPAs and by regional conservation investment by external powers that benefit from the region’s resources.