Ectopic A-lattice seams destabilize microtubules

Natural microtubules typically include one A-lattice seam within an otherwise helically symmetric B-lattice tube. It is currently unclear how A-lattice seams influence microtubule dynamic instability. Here we find that including extra A-lattice seams in GMPCPP microtubules, structural analogues of the GTP caps of dynamic microtubules, destabilizes them, enhancing their median shrinkage rate by >20-fold. Dynamic microtubules nucleated by seeds containing extra A-lattice seams have growth rates similar to microtubules nucleated by B-lattice seeds, yet have increased catastrophe frequencies at both ends. Furthermore, binding B-lattice GDP microtubules to a rigor kinesin surface stabilizes them against shrinkage, whereas microtubules with extra A-lattice seams are stabilized only slightly. Our data suggest that introducing extra A-lattice seams into dynamic microtubules destabilizes them by destabilizing their GTP caps. On this basis, we propose that the single A-lattice seam of natural B-lattice MTs may act as a trigger point, and potentially a regulation point, for catastrophe

Bone mass and microarchitecture of irradiated and bone marrow-transplanted mice: influences of the donor strain

Summary Total body irradiation and bone marrow transplantation induced dramatic trabecular bone loss and cortical thickening in mice. Transplanted cells were engrafted in bone marrow, along trabeculae, and in periosteal and endosteal envelopes. None of the osteocytes were of donor origin. Bone microarchitecture of transplanted mice changed to tend toward the donor phenotype. Introduction Osteopenia and osteoporosis are complications of bone marrow transplants (BMT) attributed to related chemotherapy. However, the specific influence of total body irradiation (TBI) is unknown. Methods We investigated the effects of TBI and BMT on bone mass and microarchitecture by micro-CT. Eighteen C57Bl/6 (B6) mice receiving lethal TBI had a BMT with marrow cells from green fluorescent protein--transgenic-C57Bl/6 (GFP) mice. Transplanted (TGFPB6), B6, and GFP mice were euthanized 1, 3, and 6 months after BMT or at a related age. Results TGFPB6 presented a dramatic bone loss compared with B6 and did not restore their trabecular bone mass over time, despite a cortical thickening 6 months after BMT. Serum testosterone levels were not significantly reduced after BMT. During aging, GFP mice have less trabeculae, thicker cortices, but a narrower femoral shaft than B6 mice. From 3 months after BMT, cortical characteristics of TGFPB6 mice differed statistically from B6 mice and were identical to those of GFP mice. GFP+ cells were located along trabecular surfaces and in periosteal and endosteal envelopes, but none of the osteocytes expressed GFP. Conclusion Our findings suggest that engrafted cells did not restore the irradiation-induced trabecular bone loss, but reconstituted a marrow microenvironment and bone remodeling similar to those of the donor. The effects of irradiation and graft on bone remodeling differed between cortical and trabecular bone

Social media policies at US medical schools

Background/Purpose: Today's medical students are learning in a social media era in which patient confidentiality is at risk yet schools’ social media policies have not been elucidated. The purpose of this study is to describe the presence of medical schools on top social media sites and to identify whether student policies for these schools explicitly address social media use. Method: Websites of all 132 accredited US medical schools were independently assessed by two investigators for their presence (as of March 31, 2010) on the most common social networking and microblogging sites (Facebook and Twitter) and their publicly available policies addressing online social networking. Key features from these policies are described. Results: 100% (n=132) of US medical schools had websites and 95.45% (126/132) had any Facebook presence. 25.76% (34/132) had official medical school pages, 71.21% (94/132) had student groups, and 54.55% (72/132) had alumni groups on Facebook. 10.6% of medical schools (14/132) had Twitter accounts. 128 of 132 medical schools (96.97%) had student guidelines or policies publicly available online. 13 of these 128 schools (10.16%) had guidelines/policies explicitly mentioning social media. 38.46% (5/13) of these guidelines included statements that defined what is forbidden, inappropriate, or impermissible under any circumstances, or mentioned strongly discouraged online behaviors. 53.85% (7/13) encouraged thoughtful and responsible social media use. Conclusions: Medical schools and their students are using social media. Almost all US medical schools have a Facebook presence, yet most do not have policies addressing student online social networking behavior. While social media use rises, policy informing appropriate conduct in medical schools lags behind. Established policies at some medical schools can provide a blueprint for others to adopt and adapt

Elastic properties of grafted microtubules

We use single-particle tracking to study the elastic properties of single microtubules grafted to a substrate. Thermal fluctuations of the free microtubule's end are recorded, in order to measure position distribution functions from which we calculate the persistence length of microtubules with contour lengths between 2.6 and 48 micrometers. We find the persistence length to vary by more than a factor of 20 over the total range of contour lengths. Our results support the hypothesis that shearing between protofilaments contributes significantly to the mechanics of microtubules.Comment: 9 pages, 3 figure

Pathological Narcissism in Adolescents: Relationships with Childhood Maltreatment and Internalizing and Externalizing Difficulties

Background: There are significant gaps in our understanding of vulnerable and grandiose narcissism in adolescents and whether it is associated with psychosocial difficulties as well as risk factors such as child maltreatment. Objective: The aim of this study was to examine vulnerable and grandiose narcissism in adolescents and young adults. Method: 570 participants (ages 14-21) from the community completed an online survey. Vulnerable and grandiose narcissism were assessed with the Pathological Narcissism Inventory, while psycho-social difficulties were assessed with the Child Behaviour Checklist and maltreatment with the Childhood Experiences of Care and Abuse Questionnaire. Results: Gender-specific age trends were identified, with narcissism appearing to decrease with age for females, while increasing for males into early adulthood. For females, vulnerable and grandiose narcissism was associated with maltreatment and partially mediated the relationship between abuse and neglect and internalizing and externalizing difficulties. Conclusion: These findings underscore the importance of considering the relationship between childhood maltreatment experiences and suggest that the relationship between such experiences and adolescent psychosocial difficulties may be partially accounted for by the negative impact that maltreatment has on narcissism

Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity

Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers

Factors that contribute to social media influence within an Internal Medicine Twitter learning community

Medical societies, faculty, and trainees use Twitter to learn from and educate other social media users. These social media communities bring together individuals with various levels of experience. It is not known if experienced individuals are also the most influential members. We hypothesize that participants with the greatest experience would be the most influential members of a Twitter community. We analyzed the 2013 Association of Program Directors in Internal Medicine Twitter community. We measured the number of tweets authored by each participant and the number of amplified tweets (re-tweets). We developed a multivariate linear regression model to identify any relationship to social media influence, measured by the PageRank. Faculty (from academic institutions) comprised 19% of the 132 participants in the learning community (p < 0.0001). Faculty authored 49% of all 867 tweets (p < 0.0001). Their tweets were the most likely to be amplified (52%, p < 0.01). Faculty had the greatest influence amongst all participants (mean 1.99, p < 0.0001). Being a faculty member had no predictive effect on influence (β = 0.068, p = 0.6). The only factors that predicted influence (higher PageRank) were the number of tweets authored (p < 0.0001) and number of tweets amplified (p < 0.0001) The status of “faculty member� did not confer a greater influence. Any participant who was able to author the greatest number of tweets or have more of his/her tweets amplified could wield a greater influence on the participants, regardless of his/her authority

Global Disease Outbreaks Associated with the 2015–2016 El Niño Event

Interannual climate variability patterns associated with the El Niño-Southern Oscillation phenomenon result in climate and environmental anomaly conditions in specific regions worldwide that directly favor outbreaks and/or amplification of variety of diseases of public health concern including chikungunya, hantavirus, Rift Valley fever, cholera, plague, and Zika. We analyzed patterns of some disease outbreaks during the strong 2015–2016 El Niño event in relation to climate anomalies derived from satellite measurements. Disease outbreaks in multiple El Niño-connected regions worldwide (including Southeast Asia, Tanzania, western US, and Brazil) followed shifts in rainfall, temperature, and vegetation in which both drought and flooding occurred in excess (14–81% precipitation departures from normal). These shifts favored ecological conditions appropriate for pathogens and their vectors to emerge and propagate clusters of diseases activity in these regions. Our analysis indicates that intensity of disease activity in some ENSO-teleconnected regions were approximately 2.5–28% higher during years with El Niño events than those without. Plague in Colorado and New Mexico as well as cholera in Tanzania were significantly associated with above normal rainfall (p \u3c 0.05); while dengue in Brazil and southeast Asia were significantly associated with above normal land surface temperature (p \u3c 0.05). Routine and ongoing global satellite monitoring of key climate variable anomalies calibrated to specific regions could identify regions at risk for emergence and propagation of disease vectors. Such information can provide sufficient lead-time for outbreak prevention and potentially reduce the burden and spread of ecologically coupled diseases

Structure–property relation and relevance of beam theories for microtubules: a coupled molecular and continuum mechanics study

Quasi-one-dimensional microtubules (MTs) in cells enjoy high axial rigidity but large transverse flexibility due to the inter-protofilament (PF) sliding. This study aims to explore the structure–property relation for MTs and examine the relevance of the beam theories to their unique features. A molecular structural mechanics (MSM) model was used to identify the origin of the inter-PF sliding and its role in bending and vibration of MTs. The beam models were then fitted to the MSM to reveal how they cope with the distinct mechanical responses induced by the inter-PF sliding. Clear evidence showed that the inter-PF sliding is due to the soft inter-PF bonds and leads to the length-dependent bending stiffness. The Euler beam theory is found to adequately describe MT deformation when the inter-PF sliding is largely prohibited. Nevertheless, neither shear deformation nor the nonlocal effect considered in the ‘more accurate’ beam theories can fully capture the effect of the inter-PF sliding. This reflects the distinct deformation mechanisms between an MT and its equivalent continuous body

Detailed spectral and morphological analysis of the shell type SNR RCW 86

Aims: We aim for an understanding of the morphological and spectral properties of the supernova remnant RCW~86 and for insights into the production mechanism leading to the RCW~86 very high-energy gamma-ray emission. Methods: We analyzed High Energy Spectroscopic System data that had increased sensitivity compared to the observations presented in the RCW~86 H.E.S.S. discovery publication. Studies of the morphological correlation between the 0.5-1~keV X-ray band, the 2-5~keV X-ray band, radio, and gamma-ray emissions have been performed as well as broadband modeling of the spectral energy distribution with two different emission models. Results:We present the first conclusive evidence that the TeV gamma-ray emission region is shell-like based on our morphological studies. The comparison with 2-5~keV X-ray data reveals a correlation with the 0.4-50~TeV gamma-ray emission.The spectrum of RCW~86 is best described by a power law with an exponential cutoff at $E_{cut}=(3.5\pm 1.2_{stat})$ TeV and a spectral index of $\Gamma$~$1.6\pm 0.2$. A static leptonic one-zone model adequately describes the measured spectral energy distribution of RCW~86, with the resultant total kinetic energy of the electrons above 1 GeV being equivalent to $\sim$0.1\% of the initial kinetic energy of a Type I a supernova explosion. When using a hadronic model, a magnetic field of $B$~100$\mu$G is needed to represent the measured data. Although this is comparable to formerly published estimates, a standard E$^{-2}$ spectrum for the proton distribution cannot describe the gamma-ray data. Instead, a spectral index of $\Gamma_p$~1.7 would be required, which implies that ~$7\times 10^{49}/n_{cm^{-3}}$erg has been transferred into high-energy protons with the effective density $n_{cm^{-3}}=n/ 1$ cm^-3. This is about 10\% of the kinetic energy of a typical Type Ia supernova under the assumption of a density of 1~cm^-3.Comment: accepted for publication by A&