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- BookDaria Mochly-Rosen, Kevin Grimes, editors.Summary: Written by the founders of the SPARK program at Stanford University, this book is a practical guide designed for professors, students and clinicians at academic research institutions who are interested in learning more about the drug development process and how to help their discoveries become the novel drugs of the future. Often many potentially transformative basic science discoveries are not pursued because they are deemed "too early" to attract industry interest. There are simple, relatively cost-effective things that academic researchers can do to advance their findings to the point that they can be tested in the clinic or attract more industry interest.
Contents:
Getting started
Discovery and preclinical work
Preparing for the clinic
Transferring technology
Commercialization and entrepreneurship
Concluding thoughts.Digital Access Springer 2014 - ArticleKam JH, Jeffery G.Oncotarget. 2015 Sep 29;6(29):26690-701.Mitochondrial function declines with age and is associated with age-related disorders and cell death. In the retina this is critical as photoreceptor energy demands are the greatest in the body and aged cell loss large (~30%). But mitochondria can fuse or divide to accommodate changing demands. We explore ageing mitochondrial dynamics in young (1 month) and old (12 months) mouse retina, investigating changes in mitochondrial fission (Fis1) and fusion (Opa1) proteins, cytochrome C oxidase (COX III), which reflects mitochondrial metabolic status, and heat shock protein 60 (Hsp60) that is a mitochondrial chaperon for protein folding.Western blots showed each protein declined with age. However, within this, immunostaining revealed increases of around 50% in Fis1 and Opa1 in photoreceptor inner segments (IS). Electron microscope analysis revealed mitochondrial fragmentation with age and marked changes in morphology in IS, consistent with elevated dynamics. COX III declined by approximately 30% in IS, but Hsp60 reductions were around 80% in the outer plexiform layer.Our results are consistent with declining mitochondrial metabolism. But also with increased photoreceptor mitochondrial dynamics that differ from other retinal regions, perhaps reflecting attempts to maintain function. These changes are the platform for age related photoreceptor loss initiated after 12 months.
- ArticleKaur A, Kandari S, Saini S, Dhoot DK, Kandari A.Cureus. 2022 Jul;14(7):e26690.Chyluria is the presence of chyle in the urine and is associated with some degree of proteinuria. We report two patients with chyluria who presented with milky urine, weight loss, and edema and were found to have nephrotic-range proteinuria. Although filarial antigen was detected in only one of the patients, flexible cystoscopy could demonstrate chyle efflux from the left ureter in first patient and from both the ureters in the second patient. Both patients received endoscopic sclerotherapy with 0.2% povidone-iodine, which resulted in the clearance of milky urine in three to five days and complete resolution of nephrotic-range proteinuria on follow-up. They remained symptom-free until the six-month follow-up. We deferred renal biopsy in both patients, as proteinuria was confirmed to be non-glomerular in origin.
- ArticleHermans RI, Dueck B, Ndieyira JW, McKendry RA, Aeppli G.Sci Rep. 2016 06 03;6:26690.We explore and exploit diffraction effects that have been previously neglected when modelling optical measurement techniques for the bending of micro-mechanical transducers such as cantilevers for atomic force microscopy. The illumination of a cantilever edge causes an asymmetric diffraction pattern at the photo-detector affecting the calibration of the measured signal in the popular optical beam deflection technique (OBDT). The conditions that avoid such detection artefacts conflict with the use of smaller cantilevers. Embracing diffraction patterns as data yields a potent detection technique that decouples tilt and curvature and simultaneously relaxes the requirements on the illumination alignment and detector position through a measurable which is invariant to translation and rotation. We show analytical results, numerical simulations and physiologically relevant experimental data demonstrating the utility of the diffraction patterns. We offer experimental design guidelines and quantify possible sources of systematic error in OBDT. We demonstrate a new nanometre resolution detection method that can replace OBDT, where diffraction effects from finite sized or patterned cantilevers are exploited. Such effects are readily generalized to cantilever arrays, and allow transmission detection of mechanical curvature, enabling instrumentation with simpler geometry. We highlight the comparative advantages over OBDT by detecting molecular activity of antibiotic Vancomycin.
- ArticleButa JG, Dame B, Ayala T.Heliyon. 2024 Mar 15;10(5):e26690.One of the most promising solutions to the current energy crisis is an efficient catalytic transformation of abundant low-cost renewable raw biomass into high-quality biofuel. Herein, a highly effective catalyst was constructed systematically for the selective synthesis of 2,5-dimethylfuran (DMF) biofuel from biomass-derived 5-hydroxymethylfurfural (HMF) via green catalytic transfer hydrogenolysis (CTH) using a nitrogen-doped ordered mesoporous carbon (N-CMK-1) decorated ruthenium (Ru)-based catalyst in i-propanol as hydrogen source. The structures and properties of different catalysts were characterized by different characterization techniques such as FTIR, XRD, N2-sorption, CO2-sorption, TGA, TEM, ICP-AES, CHNO analysis, and acid-base back titration. A complete HMF conversion with a high DMF yield of 88% was achieved under optimized reaction conditions. Regarding substrate conversion and product yield, the influence of reaction temperature, time, and hydrogen donors was thoroughly investigated. The nitrogen-promoted carbon support enhanced the dispersion of Ru due to the formation of appropriate basic site density which could efficiently promote the activation of alcohol hydroxyl in i-propanol and subsequent release of active hydrogen species. In the meantime, highly dispersed surface Ru nanoparticles (NPs) were beneficial for hydrogen transfer and activation of both carbonyl and hydroxyl groups in HMF. Moreover, Arrhenius kinetic analysis was studied by identifying 5-methyl furfural (5-MF) and 2,5-bishydroxymethylfuran (BHMF) as two key intermediates that dominate a distinct reaction pathway during hydrogenolysis of HMF to DMF via CTH. Furthermore, high stability without obvious loss of activity after three consecutive cycles was observed in a fabricated N-CMK-1 decorated Ru-based catalyst as a result of superior metal-support interaction and the mesoporous framework nature of the catalyst. These findings would not only offer a robust catalyst synthetic approach but also open a new avenue for the exploitation of biomass to specialty chemicals and advanced biofuels.
- ArticleBogler C, Zangrossi A, Miller C, Sartori G, Haynes JD.Hum Brain Mapp. 2024 May;45(7):e26690.One potential application of forensic "brain reading" is to test whether a suspect has previously experienced a crime scene. Here, we investigated whether it is possible to decode real life autobiographic exposure to spatial locations using fMRI. In the first session, participants visited four out of eight possible rooms on a university campus. During a subsequent scanning session, subjects passively viewed pictures and videos from these eight possible rooms (four old, four novel) without giving any responses. A multivariate searchlight analysis was employed that trained a classifier to distinguish between "seen" versus "unseen" stimuli from a subset of six rooms. We found that bilateral precuneus encoded information that can be used to distinguish between previously seen and unseen rooms and that also generalized to the two stimuli left out from training. We conclude that activity in bilateral precuneus is associated with the memory of previously visited rooms, irrespective of the identity of the room, thus supporting a parietal contribution to episodic memory for spatial locations. Importantly, we could decode whether a room was visited in real life without the need of explicit judgments about the rooms. This suggests that recognition is an automatic response that can be decoded from fMRI data, thus potentially supporting forensic applications of concealed information tests for crime scene recognition.
- ArticleXia S, Shao M, Zhou X, Pan G, Ni Z.Phys Chem Chem Phys. 2015 Oct 28;17(40):26690-702.A series of novel organic-inorganic nanoscale layered materials were synthesized by intercalating the Ti-containing Schiff base complex into the interlayer of the ZnM layered double hydroxides (LDHs, M = Al, Cr, Fe, Ce). The hybrid material was further calcined to make metal oxide composites with highly dispersed Ti elements (Ti/ZnO-MxOy). The structural characterization and photocatalytic results showed that, after intercalation and calcination, the metal oxide composites with a unique flower-like crystal morphology not only had high specific surface area, uniform pore size distribution and narrow band gap, but also showed extremely high photocatalytic performance for hexachlorobenzene (HCB) degradation. The Ti/ZnO-Cr2O3 composite with the narrowest band gap (2.40 eV) and the highest surface area (227 m(2)) showed the highest photocatalytic performance for HCB (95.5% within 240 min) among the four metal oxide composites. Particularly, it was found that composites derived from layered materials with different supramolecular structure of the host and guest showed different photocatalytic properties. In addition, based on the results from ESR, GC-MS and HPLC-MS, the type and amount of hydroxyl radicals, the decomposition intermediates and the pathway of HCB degradation photocatalyzed by Ti/ZnO-MxOy composites are also discussed in detail.
- ArticleAmundsen S, Øvrebø TG, Amble NMS, Poole AC, Nordeng H.BMJ Open. 2019 02 27;9(2):e026690.OBJECTIVES: To examine risk perception, beliefs about migraine medications and medical adherence among pregnant and breastfeeding women with migraine.
DESIGN AND SETTING: Cross-sectional study conducted in Norway from October 2013 to February 2014. Data were collected via an anonymous, electronic questionnaire.
PARTICIPANTS: Women with migraine, either pregnant or having delivered within the previous 18 months.
MAIN OUTCOMES: Women's perception of teratogenic risk (numeric rating scale 0-10) was obtained for 14 different drugs/substances, including medications commonly used in the acute treatment of migraine. Women's perspectives on migraine drug therapy were assessed by 10 statements from the Beliefs about Medicines Questionnaire (BMQ-Specific) and six pregnancy/breastfeeding-specific statements. Adherence to migraine treatment during pregnancy and breastfeeding period was assessed by maternal self-report.
RESULTS: The study population included 401 women with migraine, of which 140 were pregnant and 261 were new mothers. More than 70% of the women reported use of migraine medications during pregnancy. Still, the majority severely overestimated the risk associated with migraine medications and were concerned about using medications to manage their migraine during pregnancy and breastfeeding. Almost 9 out of 10 women had at some point deliberately avoided using migraine medications during their pregnancy. Women reporting use of migraine medications, however, were more positive and overestimated to a lesser extent the risks of using such medications in pregnancy compared with their counterparts.
CONCLUSIONS: Women with migraine severely overestimated the risk associated with migraine pharmacotherapy in pregnancy. The majority of women were concerned about use of migraine medications during pregnancy and breastfeeding and reported non-adherence to needed treatment. More attention should be focused on women's beliefs and concerns regarding migraine pharmacotherapy during pregnancy and breastfeeding in order to improve management of disease, reduce unfounded concerns and enhance adherence to needed treatment. - ArticleBoudes PF.Rare Dis. 2013;1:e26690.Lysosomal storage disorders (LSDs) consist of over 40 diseases, some of which are amenable to treatment. In this review, we consider the regulatory context in which LSDs studies are performed, highlight design specificities and explore operational challenges. Orphan drug legislations, both in Europe and US, were effective to stimulate LSDs drug development. However, regulators flexibilities toward approval vary leading to global discrepancies in access to treatments. Study designs are constrained because few patients can be studied. This implies LSDs treatments need to demonstrate large levels of clinical efficacy. If not, an appropriate level of evidence is difficult to achieve. While biomarkers could address this issue, none have been truly accepted as primary outcome. Enrichment of study population can increase the chance of success, especially with clinical outcomes. Adaptive designs are operationally challenging. Innovative methods of analysis can be used, notably using a patient as his/her own control and responder analysis. The use of extension phases and patient registries as a source of historical comparison can facilitate data interpretation. Operationally, few patients are available per centers and multiple centers need to be initiated in multiple countries. This impacts time-lines and budget. In the future, regulators flexibility will be essential to provide patients access to innovative treatments.
- ArticleFed Regist. 1998 May 13;63(92):26690-3.The Food and Drug Administration (FDA) is publishing this companion proposed rule to the direct final rule, published elsewhere in this issue of the Federal Register, which is intended to repeal FDA's regulations governing certification of drugs containing insulin and make conforming amendments to other sections of the agency's regulations. The agency is taking this action in accordance with provisions of the Food and Drug Administration Modernization Act of 1997 (FDAMA). FDAMA repealed the statutory provision in the Federal Food, Drug, and Cosmetic Act (the act) under which the agency certified drugs containing insulin. FDAMA also made conforming amendments to the act.
- ArticleZhang KP, Fang X, Zhang Y, Chao M.Medicine (Baltimore). 2021 Aug 27;100(34):e26690.BACKGROUND: It is well known that liposome-based delivery of cytotoxic chemotherapeutics has been proposed as a putative strategy to enhance drug tolerability and efficacy compared to the conventional chemotherapy. However, its potential effect on improving prognosis remains largely unknown. The current meta-analysis is to explore the prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy.
METHODS: A detailed review of English and Chinese literature was conducted up to March 21, 2020. We evaluate its possible correlations using hazard ratios (HRs) with 95% confidence intervals (CIs). The pooled data were calculated by STATA software and Review Manager 5.3 software.
RESULTS: Consequently, 26 studies including 7943 patients were satisfied in current analysis. There were no significant differences between liposomal and conventional chemotherapy in OS (HR = 0.98, 95%CI: 0.93-1.04, P = .544) and PFS (HR = 1.00, 95%CI: 0.92-1.10, P = .945). Likewise, subgroup-analysis regarding country, cancer type, and sample sizes also showed the similar results of the 2 paired groups.
CONCLUSION: Taken together, our finding has demonstrated that there was no association of undergoing liposomal doxorubicin-based chemotherapy with cancer prognosis. However, detailed and further studies are needed to confirm our conclusion. - ArticleRouzer CA, Marnett LJ.J Biol Chem. 2005 Jul 22;280(29):26690-700.Cyclooxygenase (COX)-2 oxygenates arachidonic acid (AA) and 2-arachidonylglycerol (2-AG) to endoperoxides, which are subsequently transformed to prostaglandins (PGs) and glycerylprostaglandins (PG-Gs). PG-G formation has not been demonstrated in intact cells treated with a physiological agonist. Resident peritoneal macrophages, which express COX-1, were pretreated with lipopolysaccharide to induce COX-2. Addition of zymosan caused release of 2-AG and production of the glyceryl esters of PGE2 and PGI2 over 60 min. The total quantity of PG-Gs (16 +/- 6 pmol/10(7) cells) was much lower than that of the corresponding PGs produced from AA (21,000 +/- 7,000 pmol/10(7) cells). The differences in PG-G and PG production were partially explained by differences in the amounts of 2-AG and AA released in response to zymosan. The selective COX-2 inhibitor, SC236, reduced PG-G and PG production by 49 and 17%, respectively, indicating a significant role for COX-1 in PG-G and especially PG synthesis. Time course studies indicated that COX-2-dependent oxygenation rapidly declined 20 min after zymosan addition. When exogenous 2-AG was added to macrophages, a substantial portion was hydrolyzed to AA and converted to PGs; 1 microm 2-AG yielded 820 +/- 200 pmol of PGs/10(7) cells and 78 +/- 41 pmol of PG-Gs/10(7) cells. SC236 reduced PG-G and PG production from exogenous 2-AG by 88 and 76%, respectively, indicating a more significant role for COX-2 in the utilization of exogenous substrate. In conclusion, lipopolysaccharide-pretreated macrophages produce PG-Gs from endogenous 2-AG during zymosan phagocytosis, but PG-G formation is limited by substrate hydrolysis and inactivation of COX-2.
- ArticleZhao YC, Ahmad Z, Long WM, Khan Z, Ledentsov N, Sanayeh MB, Pan TL, Chen CC, Chang CJ, Lu TC, Ledentsov NN, Shi JW.Opt Express. 2022 Jul 18;30(15):26690-26700.In this work, a novel design for the electrodes in a near quasi-single-mode (QSM) vertical-cavity surface-emitting laser (VCSEL) array with Zn-diffusion apertures inside is demonstrated to produce an effective improvement in the high-speed data transmission performance. By separating the electrodes in a compact 2×2 coupled VCSEL array into two parts, one for pure dc current injection and the other for large ac signal modulation, a significant enhancement in the high-speed data transmission performance can be observed. Compared with the single electrode reference, which parallels 4 VCSEL units in the array, the demonstrated array with its separated electrode design exhibits greater dampening of electrical-optical (E-O) frequency response and a larger 3-dB E-O bandwidth (19 vs. 15 GHz) under the same amount of total bias current (20 mA). Moreover, this significant improvement in dynamic performance does not come at the cost of any degradation in the static performance in terms of the maximum near QSM optical output power (17 mW @ 20 mA) and the Gaussian-like optical far-field pattern which has a narrow divergence angle (full-width half maximum (FWHM): 10° at 20 mA). The advantages of the separated electrode design lead to a much better quality of 32 Gbit/sec eye-opening as compared to that of the reference device (jitter: 1.5 vs. 2.8 ps) and error-free 32 Gbit/sec transmissions over a 500 m multi-mode fiber has been achieved under a moderate total bias current of 20 mA.
- ArticleChristensen SL, Johansen MM, Michieletto M, Triches M, Maack MD, Lægsgaard J.Opt Express. 2020 Aug 31;28(18):26690-26705.In this work we investigate transverse mode instability (TMI) in the presence of pump intensity noise and a controlled perturbation of the input coupling for a rod-type fiber amplifier using spatially and temporally resolved imaging (ST). We show that inherent pump intensity noise from the power supply can define significant peaks in the resulting TMI spectrum. ST measurements show that the TMI in the transition region consists of different orientations of LP11. This finding indicates that the simple picture of TMI being seeded by the combination of a static initial fraction of LP11 and pump or signal intensity noise is not valid for our measurements. Furthermore we present seeding of TMI by perturbing the input coupling dynamically. ST measurements of the resulting TMI as a function of perturbation frequency provides quantitative information regarding the frequency response of the non-linear coupling coefficient. Finally, ST measurements of the resulting TMI as a function of signal power shows that the TMI experiences an exponential gain long before visible beam fluctuations appear.
- ArticleFerrer J, Prats C, López D, Vidal-Mas J, Gargallo-Viola D, Guglietta A, Giró A.PLoS One. 2011;6(10):e26690.Variability is a hallmark of microbial systems. On the one hand, microbes are subject to environmental heterogeneity and undergo changeable conditions in their immediate surroundings. On the other hand, microbial populations exhibit high cellular diversity. The relation between microbial diversity and variability of population dynamics is difficult to assess. This connection can be quantitatively studied from a perspective that combines in silico models and thermodynamic methods and interpretations. The infection process of Plasmodium falciparum parasitizing human red blood cells under laboratory cultivation conditions is used to illustrate the potential of Individual-based models in the context of predictive microbiology and parasitology. Experimental data from several in vitro cultures are compared to the outcome of an individual-based model and analysed from a thermodynamic perspective. This approach allows distinguishing between intrinsic and external constraints that give rise to the diversity in the infection forms, and it provides a criterion to quantitatively define transient and stationary regimes in the culture. Increasing the ability of models to discriminate between different states of microbial populations enhances their predictive capability which finally leads to a better the control over culture systems. The strategy here presented is of general application and it can substantially improve modelling of other types of microbial communities.
- ArticleLi Z, Fang Y, Yang J, Chen H, Yang B, Wang Y.RSC Adv. 2023 Sep 04;13(38):26690-26699.A novel two-step enzymatic esterification-hydrolysis method that generates high-purity conjugated linoleic acid (CLA) isomers was developed. CLA was first partially purified by enzymatic esterification and then further purified by efficient, selective enzymatic hydrolysis in a three-liquid-phase system (TLPS). Compared with traditional two-step selective enzymatic esterification, this novel method produced highly pure cis-9, trans-11 (c9,t11)-CLA (96%) with high conversion (approx. 36%) and avoided complicated rehydrolysis and reesterification steps. The catalytic efficiency and selectivity of CLA ester enzymatic hydrolysis was greatly improved with TLPSs, as high-speed stirring provided a larger interface area for the reaction and product inhibition was effectively reduced by extraction of the product into other phases. Furthermore, the enzyme-enriched phase (liquid immobilization support) was effectively and economically reused more than 8 times because it contained more than 90% of the concentrated enzyme. Therefore, this novel enzymatic esterification-hydrolysis method can be considered ideal to produce high-purity fatty acid monomers.
- ArticleFuh G, Garcia KC, de Vos AM.J Biol Chem. 2000 Sep 01;275(35):26690-5.Neuropilin-1 (NP-1) was first identified as a semaphorin receptor involved in neuron guidance. Subsequent studies demonstrated that NP-1 also binds an isoform of vascular endothelial growth factor (VEGF) as well as several VEGF homologs, suggesting that NP-1 may also function in angiogenesis. Here we report in vitro binding experiments that shed light on the interaction between VEGF165 and NP-1, as well as a previously unknown interaction between NP-1 and one of the VEGF receptor tyrosine kinases, VEGFR1 or Flt-1. BIAcore analysis demonstrated that, with the extracellular domain (ECD) of NP-1 immobilized at low density, VEGF165 bound with low affinity (K(d) = 2 microm) and fast kinetics. The interaction was dependent on the heparin-binding domain of VEGF165 and increased the affinity of VEGF165 for its signaling receptor VEGFR2 or kinase insert domain-containing receptor. The affinity of VEGF165 for the NP-1 ECD was greatly enhanced either by increasing the density of immobilized NP-1 (K(d) = 113 nm) or by the addition of heparin (K(d) = 25 nm). We attribute these affinity enhancements to avidity effects mediated by the bivalent VEGF165 homodimer or multivalent heparin. We also show that the NP-1 ECD binds with high affinity (K(d) = 1.8 nm) to domains 3 and 4 of Flt-1 and that this interaction inhibits the binding of NP-1 to VEGF165. Based on these results, we propose that NP-1 acts as a coreceptor for various ligands and that these functions are dependent on the density of NP-1 on the cell membrane. Furthermore, Flt-1 may function as a negative regulator of angiogenesis by competing for NP-1.
- ArticleMclaughlin M, Duff J, McKenzie T, Campbell E, Sutherland R, Wiggers J, Wolfenden L.JMIR Pediatr Parent. 2021 Jul 26;4(3):e26690.BACKGROUND: Effectively scaled-up physical activity interventions are urgently needed to address the high prevalence of physical inactivity. To facilitate scale-up of an efficacious school-based physical activity program (Physical Activity 4 Everyone [PA4E1]), provision of implementation support to physical education (PE) teachers was adapted from face-to-face and paper-based delivery modes to partial delivery via a website. A lack of engagement (usage and subjective experience) with digital delivery modes, including websites, may in part explain the typical reduction in effectiveness of scaled-up interventions that use digital delivery modes. A process evaluation focused on the PA4E1 website was undertaken.
OBJECTIVE: The 2 objectives were to (1) describe the usage of the PA4E1 program website by in-school champions (PE teachers leading the program within their schools) and PE teachers using quantitative methods; (2) examine the usage, subjective experience, and usability of the PA4E1 program website from the perspective of in-school champions using mixed methods.
METHODS: The first objective used website usage data collected across all users (n=273) throughout the 9 school terms of the PA4E1 implementation support. The 4 usage measures were sessions, page views, average session duration, and downloads. Descriptive statistics were calculated and explored across the duration of the 26-month program. The second objective used mixed methods, triangulating data from the first objective with data from a think-aloud survey and usability test completed by in-school champions (n=13) at 12 months. Qualitative data were analyzed thematically alongside descriptive statistics from the quantitative data in a triangulation matrix, generating cross-cutting themes using the "following a thread" approach.
RESULTS: For the first objective, in-school champions averaged 48.0 sessions per user, PE teachers 5.8 sessions. PE teacher sessions were of longer duration (10.5 vs 7.6 minutes) and included more page views (5.4 vs 3.4). The results from the mixed methods analysis for the second objective found 9 themes and 2 meta-themes. The first meta-theme indicated that the website was an acceptable and appropriate delivery mode, and usability of the website was high. The second meta-theme found that the website content was acceptable and appropriate, and identified specific suggestions for improvement.
CONCLUSIONS: Digital health interventions targeting physical activity often experience issues of lack of user engagement. By contrast, the findings from both the quantitative and mixed methods analyses indicate high usage and overall acceptability and appropriateness of the PA4E1 website to school teachers. The findings support the value of the website within a multidelivery mode implementation intervention to support schools to implement physical activity promoting practices. The analysis identified suggested intervention refinements, which may be adopted for future iterations and further scale-up of the PA4E1 program.
TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000681358; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372870. - ArticleSolomon V, Goldberg AL.J Biol Chem. 1996 Oct 25;271(43):26690-7.Recent studies have suggested that activation of the ubiquitin-proteasome pathway is primarily responsible for the rapid loss of muscle proteins in various types of atrophy. The present studies were undertaken to test if different classes of muscle proteins are degraded by this pathway. In extracts of rabbit psoas muscle, the complete degradation of soluble proteins to amino acids was stimulated up to 6-fold by ATP. Peptide aldehyde inhibitors of the proteasome or the removal of proteasomes markedly inhibited only the ATP-dependent process. Addition of purified myosin, actin, troponin, or tropomyosin to these extracts showed that these proteins served as substrates for the ubiquitin-proteasome pathway. By contrast, degradation of myoglobin did not require ATP, proteasomes, or any known proteases in muscles. When myosin, actin, and troponin were added as actomyosin complexes or as intact myofibrils to these extracts, they were not hydrolyzed at a significant rate, probably because in these multicomponent complexes, these proteins are protected from degradation. Accordingly, actin (but not albumin or troponin) inhibited the degradation of 125I-myosin, and actin was found to selectively inhibit ubiquitin conjugation to 125I-myosin. Also, the presence of tropomyosin inhibited the degradation of 125I-troponin. However, neither actin nor tropomyosin inhibited the degradation of 125I-lysozyme or soluble muscle proteins. Thus, specific interactions between the myofibrillar proteins appear to protect them from ubiquitin-dependent degradation, and the rate-limiting step in their degradation is probably their dissociation from the myofibril.
- ArticleTeo M, Manser E, Lim L.J Biol Chem. 1995 Nov 03;270(44):26690-7.The brain-enriched p21cdc42/rac1-activated serine/threonine kinase, p65PAK, was identified and purified on the basis of overlays with [gamma-32P]GTP-Cdc42 onto SDS-fractionated proteins (Manser, E., Leung, T., Salihuddin, H., Zhao, Z.-S., and Lim, L. (1994) Nature 367, 40-46). In this study, the ubiquitously expressed p21cdc42/rac1 binding protein with relative molecular weight of 62,000 was purified from rat testes and shown to contain peptides related to PAK. It has thus been designated as the gamma-PAK isoform (alpha- and beta-isoforms being brain enriched). Isolation of gamma-PAK cDNAs show that the kinase is highly conserved with alpha-PAK in both the p2 binding and kinase domains. The purified protein exhibited kinase activity that was activated by GTP-Cdc42 or GTP-Rac1 in vitro. In platelets, a p62 in situ renaturable kinase was recognized by antibodies raised against gamma-PAK. This thrombin-activated protein kinase appears to coprecipitate with another kinase of M(r) 86,000, suggesting that PAK may be part of a thrombin-responsive signaling complex.