Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1

Complex conformational dynamics are essential for function of the dimeric molecular cha- perone heat shock protein 90 (Hsp90), including transient, ATP-biased N-domain dimer- ization that is necessary to attain ATPase competence. The intrinsic, but weak, ATP hydrolyzing activity of human Hsp90 is markedly enhanced by the co-chaperone Aha1. However, the cellular concentration of Aha1 is substoichiometric relative to Hsp90. Here we report that initial recruitment of this cochaperone to Hsp90 is markedly enhanced by phosphorylation of a highly conserved tyrosine (Y313 in Hsp90α) in the Hsp90 middle domain. Importantly, phosphomimetic mutation of Y313 promotes formation of a transient complex in which both N- and C-domains of Aha1 bind to distinct surfaces of the middle domains of opposing Hsp90 protomers prior to ATP-directed N-domain dimerization. Thus, Y313 represents a phosphorylation-sensitive conformational switch, engaged early after client loading, that affects both local and long-range conformational dynamics to facilitate initial recruitment of Aha1 to Hsp90

Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Background: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4+IL17+, CD11b+Ly6G+ and CD11b+Ly6C+ cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.This work was sponsored by grants from Acción Estratégica en Salud (PI13/00297 and PI11/00581), the Neurosciences and Aging Foundation, the Francisco Soria Melguizo Foundation, Octopharma, and Parkinson Madrid (PI2012/0032).S

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear

Iron deposition and inflammation in multiple sclerosis. Which one comes first?

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor

A Model for Solving the Optimal Water Allocation Problem in River Basins with Network Flow Programming When Introducing Non-Linearities

[EN] The allocation of water resources between different users is a traditional problem in many river basins. The objective is to obtain the optimal resource distribution and the associated circulating flows through the system. Network flow programming is a common technique for solving this problem. This optimisation procedure has been used many times for developing applications for concrete water systems, as well as for developing complete decision support systems. As long as many aspects of a river basin are not purely linear, the study of non-linearities will also be of great importance in water resources systems optimisation. This paper presents a generalised model for solving the optimal allocation of water resources in schemes where the objectives are minimising the demand deficits, complying with the required flows in the river and storing water in reservoirs. Evaporation from reservoirs and returns from demands are considered, and an iterative methodology is followed to solve these two non-network constraints. The model was applied to the Duero River basin (Spain). Three different network flow algorithms (Out-of-Kilter, RELAX-IVand NETFLO) were used to solve the allocation problem. Certain convergence issues were detected during the iterative process. There is a need to relate the data from the studied systems with the convergence criterion to be able to find the convergence criterion which yields the best results possible without requiring a long calculation time.We thank the Spanish Ministry of Economy and Competitivity (Comision Interministerial de Ciencia y Tecnologia, CICYT) for funding the projects INTEGRAME (contract CGL2009-11798) and SCARCE (program Consolider-Ingenio 2010, project CSD2009-00065). We also thank the European Commission (Directorate-General for Research & Innovation) for funding the project DROUGHT-R&SPI (program FP7-ENV-2011, project 282769). And last, but not least, to the Fundacion Instituto Euromediterraneo del Agua with the project "Estudio de Adaptaciones varias del modelo de optimizacion de gestiones de recursos hidricos Optiges".Haro Monteagudo, D.; Paredes Arquiola, J.; Solera Solera, A.; Andreu Álvarez, J. (2012). A Model for Solving the Optimal Water Allocation Problem in River Basins with Network Flow Programming When Introducing Non-Linearities. Water Resources Management. 26(14):4059-4071. https://doi.org/10.1007/s11269-012-0129-7S405940712614Ahuja R, Magnanti T, Orlin J (1993) Network flows: theory, algorithms and applications. Prentice Hall, New YorkAndreu J, Capilla J, Sanchís E (1996) AQUATOOL, a generalized decision-support system for water resources planning and operational management. J Hydrol 177:269–291Bersetkas D (1985) A unified framework for primal-dual methods in minimum cost network flows problems. Math Program 32:125–145Bersetkas D, Tseng P (1988) The relax codes for linear minimum cost network flow problems. Ann Oper Res 13:125–190Bersetkas D, Tseng P (1994) RELAX-IV: A faster version of the RELAX code for solving minimum cost flow problems. Completion Report under NSFGrant CCR-9103804. Dept. of Electrical Engineering and Computer Science, MIT, BostonChou F, Wu C, Lin C (2006) Simulating multi-reservoir operation rules by network flow model. ASCE Conf Proc 212:33Chung F, Archer M, DeVries J (1989) Network flow algorithm applied to California aqueduct simulation. J Water Resour Plan Manag 115:131–147Ford L, Fulkerson D (1962) Flows in networks. Princeton University Press, PrincetonFredericks J, Labadie J, Altenhofen J (1998) Decision support system for conjunctive stream-aquifer management. J Water Resour Plan Manag 124:69–78Harou JJ, Medellín-Azuara J, Zhu T et al (2010) Economic consequences of optimized water management for a prolonged, severe drought in California. Water Resour Res 46:W05522Hsu N, Cheng K (2002) Network Flow Optimization Model for Basin-Scale Water Supply Planning. J Water Resour Plan Manag 128:102–112Ilich N (1993) Improvement of the return flow allocation in the Water Resources Management Model of Alberta Environment. Can J Civ Eng 20:613–621Ilich N (2009) Limitations of network flow algorithms in river basin modeling. J Water Resour Plan Manag 135:48–55Kennington JL, Helgason RV (1980) Algorithms for network programming. John Wiley and Sons, New YorkKhaliquzzaman, Chander S (1997) Network flow programming model for multireservoir sizing. J Water Resour Plan Manag 123:15–21Kuczera G (1989) Fast Multireservoir Mulltiperiod Linear Programming Models. Water Resour Res 25:169–176Kuczera G (1993) Network linear programming codes for water-supply headworks modeling. J Water Resour Plan Manag 119:412–417Labadie J (2004) Optimal operation of multireservoir systems: state-of-the-art review. J Water Resour Plan Manag 130:93–111Labadie J (2006) MODSIM: river basin management decision support system. In: Singh W, Frevert D (eds) Watershed models. CRC, Boca Raton, pp 569–592Labadie J, Baldo M, Larson R (2000) MODSIM: decision support system for river basin management. Documentation and user manual. Dept. Of Civil Engineering, CSU, Fort CollinsManca A, Sechi G, Zuddas P (2010) Water supply network optimisation using equal flow algorithms. Water Resour Manag 24:3665–3678MMA (2000) Libro blanco del agua en España. Ministerio de Medio Ambiente, Secretaría general Técnica, Centro de PublicacionesMMA (2008) Confederación Hidrográfica del Duero. Memoria 2008. http://www.chduero.es/Inicio/Publicaciones/tabid/159/Default.aspx . Last accessed 25 June 2012Perera B, James B, Kularathna M (2005) computer software tool REALM for sustainable water allocation and management. J Environ Manag 77:291–300Rani D, Moreira M (2010) Simulation-optimization modeling: a survey and potential application in reservoir systems operation. Water Resour Manag 24:1107–1138Reca J, Roldán J, Alcaide M, López R, Camacho E (2001a) Optimisation model for water allocation in deficit irrigation systems I. Description of the model. Agric Water Manag 48:103–116Reca J, Roldán J, Alcaide M, López R, Camacho E (2001b) Optimisation model for water allocation in deficit irrigation systems II. Application to the Bembézar irrigation system. Agric Water Manag 48:117–132Sechi G, Zuddas P (2008) Multiperiod hypergraph models for water systems optimization. Water Resour Manag 22:307–320Sun H, Yeh W, Hsu N, Louie P (1995) Generalized network algorithm for water-supply-system optimization. J Water Resour Plan Manag 121:392–398Wurbs R (1993) Reservoir-system simulation and optimization models. J Water Resour Plan Manag 119:455–472Wurbs R (2005) Modeling river/reservoir system management, water allocation, and supply reliability. J Hydrol 300:100–113Yamout G, El-Fadel M (2005) An optimization approach for multi-sectoral water supply management in the greater Beirut area. Water Resour Manag 19:791–812Yates D, Sieber J, Purkey D, Hubert-Lee A (2005) WEAP21 – a demand-, priority-, and preference-driven water planning model. Part 1: model characteristics. Water Int 30:487–500Zoltay V, Vogel R, Kirshen P, Westphal K (2010) Integrated watershed management modeling: generic optimization model applied to the Ipswich river basin. J Water Resour Plan Manag 136:566–57

External validation of a clinical prediction model in multiple sclerosis

Background: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). Objective: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. Methods: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. Results: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%–96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%–91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. Conclusion: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions. © The Author(s), 2022

Disability accrual in primary and secondary progressive multiple sclerosis

BackgroundSome studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. MethodsWe compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age &gt;= 18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. ResultsIncluded patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p&lt;0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p&lt;0.001) and similar age at wheelchair dependence. ConclusionsWe demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials

Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells

Introduction: Stem cell-based therapies are currently widely explored as a tool to treat neuroimmune diseases. MAPC (Multipotent Adult Progenitor Cells) have been suggested to have strong immunomodulatory and neuroprotective properties in several experimental models. In this study, we investigate whether MAPC are of therapeutic interest for neuroinflammatory disorders such as multiple sclerosis (MS), by evaluating their capacities to modulate crucial pathological features and gain insights in the molecular pathways involved. Methods: Rat MAPC (rMAPC) were treated with combinations of pro-inflammatory cytokines that are closely associated with neuroinflammatory conditions, a process called licensing. mRNA expression of immunomodulatory molecules, chemokines and chemokine receptors was investigated. The migratory potential of licensed rMAPC towards a broad spectrum of chemokines was tested in a Transwell assay. Furthermore, the effect of licensing on the ability of rMAPC to attract and suppress the proliferation of encephalitogenic T cells was assessed. Finally, neuroprotective properties of rMAPC were determined in the context of protection from oxidative stress of oligodendrocytes. Therefore, rMAPC were incubated with conditioned medium of OLN93 cells subjected to sub-lethal doses of hydrogen peroxide (H2O2) and the gene expression of neurotrophic factors was assessed. Results: After licensing, a wide variety of immunomodulatory molecules and chemokines, including Nitric Oxide synthase (iNOS) and fractalkine, was up-regulated by rMAPC. The migratory properties of rMAPC towards various chemokines were also altered. In addition, rMAPC were found to inhibit antigen specific T cell proliferation and this suppressive effect was further enhanced after pro-inflammatory treatment. This phenomenon was partially mediated through iNOS or cyclooxygenase-2 (COX-2). Activated rMAPC secreted factors that led to attraction of myelin specific T cells. Finally, exposure of rMAPC to in vitro simulated neurodegenerative environment induced the up-regulation of mRNA levels of vascular endothelial growth factor (VEGF) and ciliary neurotrophic factor (CNTF). Factors secreted by rMAPC in response to this environment partially protected OLN93 cells from H2O2 induced cell death. Conclusions: rMAPC possess immune modulatory and neuroprotective properties which are enhanced in response to neuroinflammatory signals. These findings thereby warrant further research to evaluate MAPC transplantation as a therapeutic approach in diseases with an immunological and neurodegenerative component such as MS.The authors would like to thank Ms. Katrien Wauterickx, Ms. Christel Bocken and Mr. Jo Janssen (Hasselt University, Biomedical Research institute) for overall technical assistance. Additionally, we gratefully thank Ms. Ellen Van Houtven (ReGenesys) for her assistance in designing the migration assays. This research was supported by the Belgian Charcot Foundation

Keys to success of a community of clinical practice in primary care : a qualitative evaluation of the ECOPIH project

The current reality of primary care (PC) makes it essential to have telemedicine systems available to facilitate communication between care levels. Communities of practice have great potential in terms of care and education, and that is why the Online Communication Tool between Primary and Hospital Care was created. This tool enables PC and non-GP specialist care (SC) professionals to raise clinical cases for consultation and to share information. The objective of this article is to explore healthcare professionals' views on communities of clinical practice (CoCPs) and the changes that need to be made in an uncontrolled real-life setting after more than two years of use. A descriptive-interpretative qualitative study was conducted on a total of 29 healthcare professionals who were users and non-users of a CoCP using 2 focus groups, 3 triangular groups and 5 individual interviews. There were 18 women, 21 physicians and 8 nurses. Of the interviewees, 21 were PC professionals, 24 were users of a CoCP and 7 held managerial positions. For a system of communication between PC and SC to become a tool that is habitually used and very useful, the interviewees considered that it would have to be able to find quick, effective solutions to the queries raised, based on up-to-date information that is directly applicable to daily clinical practice. Contact should be virtual - and probably collaborative - via a platform integrated into their habitual workstations and led by PC professionals. Organisational changes should be implemented to enable users to have more time in their working day to spend on the tool, and professionals should have a proactive attitude in order to make the most if its potential. It is also important to make certain technological changes, basically aimed at improving the tool's accessibility, by integrating it into habitual clinical workstations. The collaborative tool that provides reliable, up-to-date information that is highly transferrable to clinical practice is valued for its effectiveness, efficiency and educational capacity. In order to make the most of its potential in terms of care and education, organisational changes and techniques are required to foster greater use. The online version of this article (10.1186/s12875-018-0739-0) contains supplementary material, which is available to authorized users