Miracle-dz/UniFAR-FTUs huggingface dataset:
Fluorescence resonance energy transfer based quantitative analysis of feedforward and feedback loops in epidermal growth factor receptor signaling and the sensitivity to molecular targeting drugs

The Ras‐ERK and PI3K‐mTOR pathways are hyperactivated in various malignant tumors. Feedforward (FF) and feedback (FB) regulations between the Ras‐ERK and the PI3K‐mTOR pathways have been suggested to attenuate sensitivity to drugs targeting these pathways and confer tumor resistance to therapies. However, because analyses of such regulations require measurements and perturbations with high temporal resolution, the quantitative roles played by FF and FB regulations in the intrinsic resistance to molecular targeting drugs still remain unclear. To address this issue, we quantified FF and FB regulations of the epidermal growth factor receptor (EGFR) signaling pathway by Förster/fluorescence resonance energy transfer (FRET) imaging. EGF‐induced activation of EGFR, Ras, extracellular‐signal‐regulated kinase and S6K with or without inhibitors was measured by FRET imaging, and analyzed by semi‐automatic image processing. Based on the imaging data set and kinetic parameters determined by our previous studies, we identified the roles played by a coherent FF regulation and two negative FB regulations, one of which was not recognized previously. The systems analyses revealed how these FF and FB regulations shape the temporal dynamics of extracellular‐signal‐regulated kinase activity upon EGF stimulation. Furthermore, the simulation model predicts the response of molecular targeting drugs applied solely or in combination with each other to BRaf‐ or KRas‐mutated cancer cell lines, indicating the validity of a quantitative model integrating FF and FB regulations.
Involvement of calpain‐7 in epidermal growth factor receptor degradation via the endosomal sorting pathway

Calpain‐7 (CAPN7) is a unique intracellular cysteine protease that has a tandem repeat of microtubule interacting and trafficking (MIT) domains and lacks a penta‐EF‐hand domain. Although the MIT domains of CAPN7 were previously shown to interact with a subset of endosomal sorting complex required for transport (ESCRT)‐III and ESCRT‐III‐related proteins, including charged multivesicular body protein 1 and increased sodium tolerance (IST)1, knowledge of the involvement of the protease in membrane trafficking has been limited. In the present study, compared with control cells, we found that epidermal growth factor receptor (EGFR) degradation was mildly delayed in CAPN7‐knockdown HeLa cells and mouse embryonic fibroblast cells established from CAPN7 knockout (Capn7−/−) mice. Re‐expression of wild‐type CAPN7 but not a protease‐inactive mutant of CAPN7 (CAPN7C290S) resulted in a recovery of the rate of EGFR degradation. We found, by immunofluorescence microscopic analysis, that monomeric GFP fused with the protease‐inactive mutant of CAPN7 [monomeric green fluorescent protein (mGFP)‐CAPN7C290S] was mobilized to EGFR‐positive endosomes upon epidermal growth factor stimulation in HeLa cells. Although mGFP‐CAPN7C290S exhibited dominant‐negative effects on EGFR degradation, a deletion mutant of MIT domains in mGFP‐CAPN7C290S did not have such properties, suggesting that the interaction between the MIT domains and ESCRT proteins is important for the function of CAPN7. Moreover, we found that epidermal growth factor stimulation induces translocation of IST1 from the cytosol to endosomes positive in both EGFR and mGFP‐CAPN7C290S. When IST1 was knocked down, mGFP‐CAPN7C290S lost its co‐localization with EGFR. These results demonstrate for the first time that the proteolytic activity of CAPN7 is important for the acceleration of EGFR degradation via the endosomal sorting pathway utilizing a part of the ESCRT system.
Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema With Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial

Importance Prevalence of persistent central-involved diabetic macular edema (DME) through 24 weeks of anti–vascular endothelial growth factor therapy and its longer-term outcomes may be relevant to treatment. Objective To assess outcomes of DME persisting at least 24 weeks after randomization to treatment with 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab. Design, Setting, and Participants Post hoc analyses of a clinical trial, the DRCR.net Protocol T among 546 of 660 participants (82.7%) meeting inclusion criteria for this investigation. Interventions Six monthly intravitreous anti–vascular endothelial growth factor injections (unless success after 3 to 5 injections); subsequent injections or focal/grid laser as needed per protocol to achieve stability. Main Outcomes and Measures Persistent DME through 24 weeks, probability of chronic persistent DME through 2 years, and at least 10-letter (≥ 2-line) gain or loss of visual acuity. Results The mean age of participants was 60 years, 363 (66.5%) were white, and 251 (46.0%) were women. Persistent DME through 24 weeks was more frequent with bevacizumab (118 of 180 [65.6%]) than aflibercept (60 of 190 [31.6%]) or ranibizumab (73 of 176 [41.5%]) (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; and aflibercept vs ranibizumab, P = .05). Among eyes with persistent DME through 24 weeks (n = 251), rates of chronic persistent DME through 2 years were 44.2% with aflibercept, 68.2% with bevacizumab (aflibercept vs bevacizumab, P = .03), and 54.5% with ranibizumab (aflibercept vs ranibizumab, P = .41; bevacizumab vs ranibizumab, P = .16). Among eyes with persistent DME through 24 weeks, proportions with vs without chronic persistent DME through 2 years gaining at least 10 letters from baseline were 62% of 29 eyes vs 63% of 30 eyes (P = .88) with aflibercept, 51% of 70 vs 54% of 31 (P = .96) with bevacizumab, and 44% of 38 vs 65% of 29 (P = .10) with ranibizumab. Only 3 eyes with chronic persistent DME lost at least 10 letters. Conclusions and Relevance Persistent DME was more likely with bevacizumab than with aflibercept or ranibizumab. Among eyes with persistent DME, eyes assigned to bevacizumab were more likely to have chronic persistent DME than eyes assigned to aflibercept. These results suggest meaningful gains in vision with little risk of vision loss, regardless of anti–vascular endothelial growth factor agent given or persistence of DME through 2 years. Caution is warranted when considering switching therapies for persistent DME following 3 or more injections; improvements could be owing to continued treatment rather than switching therapies. Trial Registration clinicaltrials.gov Identifier: NCT01627249
Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages.

Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%-5.5%; P(corrected) < . 001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name "Asian lineage" be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.
One more step toward understanding the immune response to norovirus.

vivo small animal model for human NoV. Historical and recent challenge studies [5] using classic Norwalk virus demonstrated a low infectious dose and an average incubation period of 24–48 hours. Asymptomatic infection occurred and those with symptoms had diarrhea, nausea, vomiting (in >50% of cases), abdominal cramps, and malaise that usually resolved in 12–72 hours, with prolonged symptoms observed in young individuals, elderly individuals, and immunocompromised individuals. Infections were traditionally thought to result in only short-term immunity; this, coupled with the high genetic and antigenic diversity of NoV through mutations and recombination, would lead to frequent reexposure, repeat infections throughout life, and a large human reservoir [6]. Studies using recombinant virus-like particles (VLPs) or P-particles created by in vitro expression of NoV capsid proteins suggested that human histo-blood group antigens (HBGAs), a group of heterogeneous and complex carbohydrates on red blood cells, that are expressed on mucosal epithelia and intestines in 80% of the population (secretors) are important determining factors for host susceptibility to NoV infection [7]. Most human infections are caused by NoV genogroup I (GI; with 9 different genotypes) or GII (with 22 different genotypes). Since the 1990s, up to 85% of global epidemics of NoV infection have been dominated by various GII.4 (GII genotype 4) variants that emerge every 2–3 years. Study of epitope changes among the GII.4 variants supported the hypothesis that protective herd immunity drives the emergence of new GII.4 variants every 2– 4y ears [8–10]. A recent challenge study showed that, unlike other strains, GII.4 could infect secretors of all ABO blood groups, which represent a majority of the human population [11].
The interaction network of rhodopsin involving the heterotrimeric G‐protein transducin and the monomeric GTPase Rac1 is determined by distinct binding processes

The monomeric G‐protein Rac1, a member of the family of Rho/Rac/Cdc42 GTPases, is involved in light‐induced photoreceptor degeneration, but its specific role remains elusive. In particular, reports on Rac1 interacting with the visual pigment rhodopsin are puzzling and need a more quantitative examination. We probed the presence of Rac1 in rod outer segments by immunohistochemical staining of bovine retinae and western blot analysis of isolated rod outer segments. Rac1 was present throughout the whole retina except in the outer and inner nuclear layers, but was strongly expressed in photoreceptor cells. Rac1 was distributed in three different fractions of rod outer segments: one fraction was soluble in detergents, a second fraction cosegregated with lipid rafts, and a third fraction was associated with lipid bilayer free axonemal/cytoskeletal structures. We also investigated the interaction between rhodopsin and Rac1 by using surface plasmon resonance spectroscopy under dark and light conditions. Biophysical interaction studies revealed that Rac1 could interact with rhodopsin, but in a light‐independent manner, and kinetic analysis indicated that binding of Rac1 occurred with lower affinity and speed than the association of transducin and rhodopsin. Thus, in dark‐adapted rod cells, Rac1 cannot compete with transducin for binding to rhodopsin, and signalling can proceed normally. Instead, the concentration of transducin has to drop significantly so that Rac1 can bind to rhodopsin; in the outer segment, this occurs only under intense illumination, when transducin is translocated to the inner segment.
Evaluación y seguimiento de los pacientes sometidos a operación de Whipple o duodenopancreatectomía cefálica en un hospital de IV nivel de Medellín

Introduction: Objective: To evaluate the indications, results and survival of patients undergoing pancreatoduodenectomy at Hospital Pablo Tobon Uribe of Medellin. Materials and methods: We collected all patients that underwent pancreatoduodenectomy (Whipple operation), from April 2004 to April 2011. The information was obtained from a prospective database from the Hepato-Biliary and Pancreatic Unit of Hospital Pablo Tobon Uribe. Results: 68 patients were operated in total, with an average age of 59 years (16-82), 50% were men; the main indication for surgery was malignant disease (97%), with the following distribution: 25 patients with pancreatic adenocarcinoma ( 36.7%), 23 patients with ampullary carcinoma (33.8%), 8 with distal cholangiocarcinoma (11.7%), 4 patients with duodenal cancer (5.8%) and 11.7% with other indications. Average bleeding at surgery was 455 ml (200-2000ml), 5.8% of patients bled 1000 ml or more, 35.2% of cases required transfusion of red blood cells, with a range of 1-8 units, 5.8% of patients required 5 or more units of red cells. The range of ICU stay was 1-20 days, with an average of 2 days, 45.5% of these patients just stayed one day. Complications occurred in 33.8% of patients, the most common was gastric atony, distant infection and postoperative bleeding. Postoperative mortality at 30 days was 14.7% in the whole series, with an analysis of the last group of 25 patients, the number dropped to 8%, with an actuarial survival of the entire series of 54.4%. Conclusions: In our hospital, pancreatoduodenectomy mortality is still high compared to some reference centers in the world, but clearly has improved in recent years, morbidity results are consistent with those reported in centers of excellence around the world.
Combination treatment with meropenem plus levofloxacin is synergistic against Pseudomonas aeruginosa infection in a murine model of pneumonia.

BACKGROUND Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model. METHODS A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model. Meropenem and levofloxacin were administered to partially humanize their pharmacokinetic profiles in mouse serum. Total and resistant bacterial populations were estimated after 24 hours of therapy. Pharmacokinetic profiling of both drugs was performed in plasma and epithelial lining fluid, using a population model. RESULTS Meropenem and levofloxacin penetrations into epithelial lining fluid were 39.3% and 64.3%, respectively. Both monotherapies demonstrated good exposure responses. An innovative combination-therapy analytic approach demonstrated that the combination was statistically significantly synergistic (α = 2.475), as was shown in the hollow fiber infection model. Bacterial resistant to levofloxacin and meropenem was seen in the control arm. Levofloxacin monotherapy selected for resistance to itself. No resistant subpopulations were observed in any combination therapy arm. CONCLUSIONS The combination of meropenem plus levofloxacin was synergistic, producing good bacterial kill and resistance suppression. Given the track record of safety of each agent, this combination may be worthy of clinical trial.
Functional roles of transiently and intrinsically disordered regions within proteins

Proteins are structurally heterogeneous and comprise folded regions with variable conformational stabilities and intrinsically disordered protein regions that do not have well‐folded structures. Even small, well‐folded single‐domain proteins are structurally heterogeneous and contain multiple foldon units with different conformational stability. Although the ability of many intrinsically disordered protein regions to undergo at least partial folding at interaction with specific binding partners is a well‐established fact, recent studies have revealed that functions of some ordered proteins rely on the decrease in the amount of their ordered structure and require local or even global functional unfolding. This functional unfolding is induced by transient alterations in protein environment or by modification of protein structure and can be reversed as soon as the environment is restored or the modification is removed. Therefore, the important features of these conditionally disordered protein regions (or unfoldons) are the induced nature and the transient character of their disorder. In other words, structurally any protein can be described as a modular assembly of foldons, inducible foldons, semi‐foldons, nonfoldons and unfoldons. Obviously, differently ordered/disordered proteins and protein regions can possess very different functional repertoires. This review represents some of the key functions of transiently and intrinsically disordered protein regions.
SLOWING THE DETERIORATION OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE OBSERVED DURING BRONCHODILATOR THERAPY BY ADDING INHALED CORTICOSTEROIDS: A 4-YEAR PROSPECTIVE STUDY

Purpose of the Study. To determine if the deterioration in lung function, seen in adults with asthma or chronic obstructive pulmonary disease (COPD), could be reversed or slowed by the addition of inhaled beclomethasone. Many short-term studies have shown the benefits of inhaled steroids in asthma; in particular, their ability to improve pulmonary function, decrease bronchial hyperreactivity, and reduce symptoms. Few studies have evaluated the long-term effects of inhaled steroids on the clinical course of either asthma or COPD. Methods. This report is an extension of a 2-year study that followed 160 patients with asthma or COPD on bronchodilator therapy alone. From this group, 56 patients who displayed a rapid decline in pulmonary function (FEV1 ≥ 80 ml/year) and a high exacerbation rate (≥1/year) were selected to receive additional treatment with beclomethasone dipropionate 400 µg two times daily over 4 years. FEV1 and airways responsiveness to histamine were measured every 6 months and at 1 and 13 months upon completion of the study. Peak flows and symptom scores were recorded weekly, and compliance, inhaler technique, and adverse affects were monitored every 3 months. Findings. During the first 6 months of beclomethasone treatment, both groups showed a significant improvement in pre- and postbronchodilator FEV1 with the most significant change noted in the asthma group. Thereafter, the FEV1 began to decline again, as it had in the first 2 years of the study, but at a rate that was 33% slower. In addition to slowing the decline in FEV1, inhaled beclomethasone resulted in a substantial decrease in the degree of bronchial hyperreactivity, and peak flow rates improved.
Epidemiology and burden of colorectal cancer in Asia-Pacific region: what shall we do now?

The burden of colorectal cancer (CRC) is in a rising trend in Asia-Pacific. There is little health authority support for CRC screening and very low public awareness of this cancer in Asian countries. The surveillance system in countries with high burden needed to provide facilities for CRC screening and public awareness education program shall be considered in national and international planes to increases the selfparticipation of people. Financial limitation and lack of authorities are still the main obstacles in the way of CRC screening in most Asian countries with low income status.
Effect of Q211 and K222 PRNP Polymorphic Variants in the Susceptibility of Goats to Oral Infection With Goat Bovine Spongiform Encephalopathy.

BACKGROUND The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. METHODS Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrP(Sc)) and prion infectivity by mouse bioassay. RESULTS R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrP(Sc) were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrP(Sc) accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months). CONCLUSIONS These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE.
A literature review: the learning style preferences of multigenerational staff nurses and the theoretical consideration of learning style preferences by acute care educators

4 Introduction 5 Experiential Case Study 5 Methodology of the Literature Review 7 Applying Whittemore and Knafl (2005) 7 Problem identification. 8 Identification of generations in acute care. 9 Choosing key words. 10 Selection of databases 11 Search parameters. 11 Explanation of Terms 12 Post-graduate nurse 12 Multiple Generations 12 Criticism of generational diversity. 19 Learning Styles and Learning Theory 20 Criticism of learning styles. 25 Synthesis of Information 27 Synthesis and findings of data 28 Limitations of Literature Review 34 A LITERATURE REVIEW: THE LEARNING STYLE PREFERENCES 3 Considerations for Education of Staff Nurses 35 Considerations for further research 36 Conclusion 37 References 38 Appendix A 44 Appendix B 45 A LITERATURE REVIEW: THE LEARNING STYLE PREFERENCES 4 Abstract What do we know about learning styles related to the education of staff nurses? This paper explores information in the literature about the clinical nurse educator’s consideration of learning style preferences in the group education of multiple generations of registered staff nurses. Without research into the validation of learning style measurement tools and further large scale exploration of staff nurse learning styles, it is impossible to state that clinical educators shouldWhat do we know about learning styles related to the education of staff nurses? This paper explores information in the literature about the clinical nurse educator’s consideration of learning style preferences in the group education of multiple generations of registered staff nurses. Without research into the validation of learning style measurement tools and further large scale exploration of staff nurse learning styles, it is impossible to state that clinical educators should incorporate generational learning styles into their education. The current nursing workforce in hospitals spans four generations of nurses. I will explore expert opinion that suggests there are differences in attitudes toward work and learning between the generations. A search of current literature reveals ten articles that relate to my topic, only three of which contain empirical data. Theoretical articles suggest that it is important to pay attention to learning styles; however, the lack of research suggests otherwise. The authors of the empirical articles report there may be discrepancies in the findings regarding preferred learning styles. There are no research articles that provide a direct comparison of preferred learning styles within one generation. A LITERATURE REVIEW: THE LEARNING STYLE PREFERENCES 5 A Literature Review: The Learning Style Preferences of Multigenerational Staff Nurses and the Theoretical Consideration of Learning Style Preferences by Acute Care Educators