3113 Professional Dr Suite 3
Auburn CA 95603
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Mapping of Ebolavirus Neutralization by Monoclonal Antibodies in the ZMapp Cocktail Using Cryo-Electron Tomography and Studies of Cellular Entry. - Journal of virology
ZMapp, a cocktail of three monoclonal antibodies (mAbs; c2G4, c4G7 and c13C6) against the ebolavirus (EBOV) glycoprotein (GP), shows promise for combatting outbreaks of EBOV, as occurred in West Africa in 2014. Prior studies showed that Fabs from these mAbs bind a soluble EBOV GP ectodomain, and that mAbs c2G4 and c4G7, but not c13C6, neutralize infections in cell cultures. Using cryo-electron tomography, we extended these findings by characterizing the structures of c2G4, c4G7 and c13C6 IgGs bound to native, full-length GP from the West African 2014 isolate embedded in filamentous viral-like particles (VLPs). As with the isolated ectodomain, c13C6 bound to the glycan cap, while c2G4 and c4G7 bound to the base region of membrane-bound GP. The tomographic data suggest that all three mAbs bind with high occupancy, and that the base-binding antibodies can potentially bridge neighboring GP spikes. Functional studies indicated that c2G4 and c4G7, but not c13C6, competitively inhibit entry of VLPs bearing EBOV GP into the host cell cytoplasm, without blocking trafficking of VLPs to NPC1(+) endolysosomes, where EBOV fuses. Moreover, c2G4 and c4G7 bind to and can block entry mediated by the primed (19 kDa) form of GP without impeding binding of the C-loop of NPC1, the endolysosomal receptor for EBOV. The most likely mode of action of c2G4 and c4G7 is, therefore, by inhibiting conformational changes in primed, NPC1-bound GP that initiate fusion between the viral and target membranes, similar to the action of certain broadly neutralizing antibodies against influenza HA and HIV Env.The recent West African outbreak of ebolavirus caused the deaths of over 11,000 individuals. Hence there is an urgent need to be prepared with vaccines and therapeutics for similar future disasters. ZMapp, a cocktail of three mAbs directed against the ebolavirus glycoprotein, is a promising anti-ebolavirus therapeutic. Using cryo-electron tomography we provide structural information on how each of the mAbs in this cocktail binds to the ebolavirus glycoprotein as it is displayed-embedded in the membrane and present at high density-on filamentous viral-like particles that recapitulate the surface structure and entry functions of ebolavirus. Moreover, after confirming that two of the mAbs bind to the same region in the base of the glycoprotein, we show that they competitively block the entry function of the glycoprotein and that they can do so after the glycoprotein is proteolytically-primed and bound to its intracellular receptor, Niemann-Pick C1. These findings should inform future developments of ebolavirus therapeutics.Copyright Â© 2016, American Society for Microbiology. All Rights Reserved.
Meaningful Learning Moments on a Family Medicine Clerkship: When Students Are Patient Centered. - Family medicine
Reflection after patient encounters is an important aspect of clinical learning. After our medical school instituted a reflection paper assignment for all clerkships, we wanted to learn about the types of encounters that students found meaningful on a family medicine clerkship and how they impacted students' learning.Family and Community Medicine Clerkship students completed a reflection paper after the clerkship, based on guidelines that were used for all clerkship reflection papers at our medical school. Two reviewers independently organized student responses into themes and then jointly prioritized common themes and negotiated any initial differences into other themes.A total of 272 reflection papers describing an actual learning moment in patient care were submitted during the study period of January 2011--December 2012. In describing actions performed, students most frequently wrote about aspects of patient-centered care such as listening to the patient, carefully assessing the patient's condition, or giving a detailed explanation to the patient. In describing effects of those actions, students wrote about what they learned about the patient-physician interaction, the trust that patients demonstrated in them, the approval they gained from their preceptors, and the benefits they saw from their actions.An important contribution of a family medicine clerkship is the opportunity for students to further their skills in patient-centered care and realize the outcomes of providing that type of care.
The Roles of Histidines and Charged Residues as Potential Triggers of a Conformational Change in the Fusion Loop of Ebola Virus Glycoprotein. - PloS one
Ebola virus (EBOV) enters cells from late endosomes/lysosomes under mildly acidic conditions. Entry by fusion with the endosomal membrane requires the fusion loop (FL, residues 507-560) of the EBOV surface glycoprotein to undergo a pH-dependent conformational change. To find the pH trigger for this reaction we mutated multiple conserved histidines and charged and uncharged hydrophilic residues in the FL and measured their activity by liposome fusion and cell entry of virus-like particles. The FL location in the membrane was assessed by NMR using soluble and lipid-bound paramagnetic relaxation agents. While we could not identify a single residue to be alone responsible for pH triggering, we propose that a distributed pH effect over multiple residues induces the conformational change that enhances membrane insertion and triggers the fusion activity of the EBOV FL.
Using the common sense model of illness to examine interrelationships between symptom severity and health outcomes in end-stage osteoarthritis patients. - Rheumatology (Oxford, England)
The aim was to evaluate the utility of the common sense model (CSM) in characterizing contributors to psychological well-being and quality of life (QoL) in patients with end-stage OA.One hundred and twenty patients [34 males, 86 females; mean (s.d.) age 65.52 (9.14) years] with end-stage OA (57.5% hip, 42.5% knee) were recruited. OA symptom severity was evaluated according to the WOMAC; coping styles were assessed with the Carver Brief COPE scale; illness perceptions were explored with the Brief Illness Perceptions Questionnaire; self-efficacy was assessed with the Arthritis Self-efficacy scale; anxiety, depression and overall distress were measured using the Hospital Anxiety and Depression Scale; and QoL was assessed using the WHO Quality of Life-short version. The CSM was used to explore the interrelationships between OA symptom severity, illness perceptions and coping strategies in patients.Two structural equation models were developed, with both found to have good fit. Consistent with the CSM, the standard model indicated that self-reported OA symptom severity directly influenced illness perceptions, which in turn had direct impacts upon maladaptive coping, distress and QoL. The addition of self-efficacy to the CSM resulted in a complex interaction, with OA severity directly influencing self-efficacy and self-efficacy influencing maladaptive coping, distress and QoL.We found interrelationships amongst OA activity, illness perceptions, coping strategies, self-efficacy, psychological distress and QoL broadly consistent with the CSM. The CSM may help inform the approach to the psychological support that patients with end-stage OA often require.Â© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Lactoferrin Expression in Human and Murine Ocular Tissue. - Current eye research
Lactoferrin (LF) is a multifunctional protein known to provide innate defense due to its antimicrobial and anti-inflammatory properties. In the eye, LF has been identified in the tears and vitreous humor. Its presence in other ocular tissues has not been determined. Our aim is to assess the presence of LF in the cornea, iris, retina and retinal pigment epithelium (RPE) of humans and mice.To test for the endogenous production of LF, reverse transcription polymerase chain reaction was performed in cultured human cells from the cornea and RPE and in murine tissues. To confirm LF localization in specific ocular tissue, immunohistochemistry was performed on flat mounts of cornea, retina and RPE in human donor eyes. The presence of LF was assessed by western blotting in human and mouse ocular tissue and human culture cells (cornea and RPE). To verify antibody specificity, purified human LF and transferrin (TF) were used on 1D and 2D western blots.LF gene expression was confirmed in the cornea and RPE cell cultures from humans, suggesting that LF is an endogenously produced protein. PCR results from mouse ocular tissue showed LF expression in cornea, iris, RPE, but not in retina. These results were also consistent with immunohistochemical localization of LF in human donor tissue. Antibody reaction for human LF was specific and western blotting showed its presence in the cornea, iris and RPE tissues. A faint reaction for the retina was observed but was likely due to contamination from other ocular tissues. Multiple commercially available antibodies for murine LF cross-reacted with TF, so no reliable results were obtained for murine western blot.LF is expressed in multiple eye tissues of humans and mice. This widespread expression and multifunctional activity of LF suggests that it may play an important role in protecting eye tissues from inflammation-associated diseases.
A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. - Science translational medicine
Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.Copyright Â© 2015, American Association for the Advancement of Science.
Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step. - Journal of virology
Ebola virus (EBOV) causes hemorrhagic fevers with high mortality rates. During cellular entry, the virus is internalized by macropinocytosis and trafficked through endosomes until fusion between the viral and an endosomal membrane is triggered, releasing the RNA genome into the cytoplasm. We found that while macropinocytotic uptake of filamentous EBOV viruslike particles (VLPs) expressing the EBOV glycoprotein (GP) occurs relatively quickly, VLPs only begin to enter the cytoplasm after a 30-min lag, considerably later than particles bearing the influenza hemagglutinin or GP from lymphocytic choriomeningitis virus, which enter through late endosomes (LE). For EBOV, the long lag is not due to the large size or unusual shape of EBOV filaments, the need to prime EBOV GP to the 19-kDa receptor-binding species, or a need for unusually low endosomal pH. In contrast, since we observed that EBOV entry occurs upon arrival in Niemann-Pick C1 (NPC1)-positive endolysosomes (LE/Lys), we propose that trafficking to LE/Lys is a key rate-defining step. Additional experiments revealed, unexpectedly, that severe acute respiratory syndrome (SARS) S-mediated entry also begins only after a 30-min lag. Furthermore, although SARS does not require NPC1 for entry, SARS entry also begins after colocalization with NPC1. Since the only endosomal requirement for SARS entry is cathepsin L activity, we tested and provide evidence that NPC1(+) LE/Lys have higher cathepsin L activity than LE, with no detectable activity in earlier endosomes. Our findings suggest that both EBOV and SARS traffic deep into the endocytic pathway for entry and that they do so to access higher cathepsin activity.Ebola virus is a hemorrhagic fever virus that causes high fatality rates when it spreads from zoonotic vectors into the human population. Infection by severe acute respiratory syndrome coronavirus (SARS-CoV) causes severe respiratory distress in infected patients. A devastating outbreak of EBOV occurred in West Africa in 2014, and there was a significant outbreak of SARS in 2003. No effective vaccine or treatment has yet been approved for either virus. We present evidence that both viruses traffic late into the endocytic pathway, to NPC1(+) LE/Lys, in order to enter host cells, and that they do so to access high levels of cathepsin activity, which both viruses use in their fusion-triggering mechanisms. This unexpected similarity suggests an unexplored vulnerability, trafficking to NPC1(+) LE/Lys, as a therapeutic target for SARS and EBOV.Copyright Â© 2015, American Society for Microbiology. All Rights Reserved.
Modulations of eye movement patterns by spatial filtering during the learning and testing phases of an old/new face recognition task. - Attention, perception & psychophysics
In two experiments, we examined the effects of varying the spatial frequency (SF) content of face images on eye movements during the learning and testing phases of an old/new recognition task. At both learning and testing, participants were presented with face stimuli band-pass filtered to 11 different SF bands, as well as an unfiltered baseline condition. We found that eye movements varied significantly as a function of SF. Specifically, the frequency of transitions between facial features showed a band-pass pattern, with more transitions for middle-band faces (â‰ˆ5-20 cycles/face) than for low-band (â‰ˆ<5Â cpf) or high-band (â‰ˆ>20Â cpf) ones. These findings were similar for the learning and testing phases. The distributions of transitions across facial features were similar for the middle-band, high-band, and unfiltered faces, showing a concentration on the eyes and mouth; conversely, low-band faces elicited mostly transitions involving the nose and nasion. The eye movement patterns elicited by low, middle, and high bands are similar to those previous researchers have suggested reflect holistic, configural, and featural processing, respectively. More generally, our results are compatible with the hypotheses that eye movements are functional, and that the visual system makes flexible use of visuospatial information in face processing. Finally, our finding that only middle spatial frequencies yielded the same number and distribution of fixations as unfiltered faces adds more evidence to the idea that these frequencies are especially important for face recognition, and reveals a possible mediator for the superior performance that they elicit.
Spatial localization of the Ebola virus glycoprotein mucin-like domain determined by cryo-electron tomography. - Journal of virology
The Ebola virus glycoprotein mucin-like domain (MLD) is implicated in Ebola virus cell entry and immune evasion. Using cryo-electron tomography of Ebola virus-like particles, we determined a three-dimensional structure for the full-length glycoprotein in a near-native state and compared it to that of a glycoprotein lacking the MLD. Our results, which show that the MLD is located at the apex and the sides of each glycoprotein monomer, provide a structural template for analysis of MLD function.Copyright Â© 2014, American Society for Microbiology. All Rights Reserved.
Responding to moderate breaches in professionalism: an intervention for medical students. - Medical teacher
Much has been written about how we understand, teach and evaluate professionalism in medical training. Less often described are explicit responses to mild or moderate professionalism concerns in medical students. To address this need, Baylor College of Medicine created a mechanism to assess professionalism competency for medical students and policies to address breaches in professional behavior. This article describes the development of an intervention using a guided reflection model, student responses to the intervention, and how the program evolved into a credible resource for deans and other educational leaders.
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3113 Professional Dr Suite 3 Auburn, CA 95603