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Antigens (Ags) are converted into immune complexes (antigen-antibody complexes, IC) as soon as they encounter their specific antibodies (Abs). In fluids containing complement, the process of IC formation and fixation of complement components occur simultaneously. Hence, the formation of Ag-Ab-complement complexes is the normal way of eliminating Ags from a host. C3b-C3b-IgG covalent complexes are immediately formed on interaction of serum C3 with IgG-IC. These C3b-C3b dimers constitute the core for the assembly of C3/C5-convertase on the IC, which are subsequently converted into iC3b-iC3b-IgG by the complement regulators. These complexes are detected on SDS-PAGE by two bands of molecular composition, C3alpha65-C3alpha43 (band A) and C3alpha65-heavy chain of the Ab (band B), which correspond to C3b-C3b and C3b-IgG covalent interaction respectively, and that identify opsonized IC (C3b-IC). C3b can attach to Fab and Fc regions of the Ab molecule with similar efficiency. The presence of multiple C3b binding regions on IgG is considered an advantageous characteristic that facilitates the elimination of Ags in the form of C3b(n)-IC. Ab molecules on the IC recognize the Ag, and also serve as a very good acceptor for C3b binding. In this way, Ags, even if they have no acceptor sites for C3b, can be efficiently processed and removed. When C3 is activated in serum by IC or other activators, secondary C3b-IgG covalent complexes are generated, with bystander monomeric circulating IgG, and thus constitute, physiological products of complement activation. These complexes gain importance when IgG concentration is extremely high as in cases of infusion of intravenous IgG (IVIG) in several pathologies. The covalent attachment of activated complement C3 (C3b, iC3b, C3 d,g) to Ags or IC links innate and adaptative immunity by targeting Ags to different cells of the immune system (follicular dendritic cells, phagocytes, B cells). Hence C3b marks Ags definitively, from the earliest cont, Ministerio de Educacion, Comunidad de Madrid, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub

Balochistan is a troubled province in the country since the inception of Pakistan in 1947. The political turmoil is deeply embedded in the process of princely states joining the newly established Pakistan. Political parties including the National Party tried to curb the situation and pave the way for a peaceful reconciliation between the marginalized people of Balochistan and the state of Pakistan. The National Party (NP) is one of the bigger mass political parties in the province. It is a social-democratic and center-to-the-left party whose legacy party is linked back to the Kalat State’s National Party. In 2003, the merger of two political parties, the Balochistan National Democratic Party (BNDP) of Mir Hasil Khan Bizenjo, and the Balochistan National Movement (BNM) of Abdul Hayee Baloch led to the foundation of this popular mass political party. The Baloch people have been denied their political, economic, and cultural rights. They also ignored their right to self-governance and the management of their region's natural resources, ever since Pakistan was founded. Balochistan was not represented at the state level and had little influence over how the government was run. The focus of this paper is to know about the role of the National Party in restoring peace after the insurgency and how the leadership of the National Party did an effort to bring back democracy in the province to keep the federation of Pakistan. The research is a qualitative study based on primary and secondary data collected by researchers. Primary data was collected from the key informants of political parties. The secondary data includes an analysis of the written literature of the parties. It is concluded that the role of such parties in the establishment of peace and reconciliation between the state and the people of the province is important for the prosperity of the people of Balochistan in particular, and Pakistan in general.

The low abundance of envelope spikes and the inability of IgG to aggregate virions render HIV-1 an inadequate target for antibody-mediated clearance by phagocytes. In an attempt to improve the ability of antibody to mediate the internalization of HIV-1 virions, we generated multimers of the broadly neutralizing HIV-1-specific monoclonal antibody (MAb) VRC01 using site-directed mutagenesis of the Fc segment. We then measured virion internalization using primary human monocytes and neutrophils. We found that, in the absence of complement, immune complexes consisting of HIV-1 virions and VRC01 multimers were slightly more efficiently internalized than were complexes formed with monomeric VRC01. The presence of complement, however, greatly augmented internalization of immune complexes formed with the multimeric MAb but had little impact on monomeric MAb-mediated internalization. Multimerization and the presence of complement overcome the limited ability of monomeric antibody to mediate internalization of HIV-1 virions and may thus provide a therapeutic approach to clearing virus. IMPORTANCE Antibody-mediated internalization of HIV-1 by phagocytes, a potential mechanism for clearing virus, is very inefficient. In an effort to improve viral clearance, we produced a multimeric form of the broadly neutralizing monoclonal antibody VRC01. We found that VRC01 antibody multimers (primarily hexamers) were only slightly more efficient in mediating HIV-1 internalization than was monomeric VRC01. However, the addition of complement resulted in substantially greater internalization of multimer-opsonized virus. In contrast, complement had little if any impact on internalization of monomer-opsonized virus. Therefore, antibody multimerization in combination with complement may overcome the limited ability of monomeric antibody to mediate internalization of HIV-1 virions. Our findings may provide a therapeutic approach to clearing virus.

BackgroundGlioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival.MethodsWe used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes.ResultsFifty-seven GBM patients (mean age, 57.8 ± 13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates.ConclusionsThese findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning.

Systems serology provides a broad view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. These studies contain structured biophysical profiling across disease-relevant antigen targets, alongside additional measurements made for single antigens or in an antigen-generic manner. Identifying patterns in these measurements helps guide vaccine and therapeutic antibody development, improve our understanding of diseases, and discover conserved regulatory mechanisms. Here, we report that coupled matrix-tensor factorization (CMTF) can reduce these data into consistent patterns by recognizing the intrinsic structure of these data. We use measurements from two previous studies of HIV- and SARS-CoV-2-infected subjects as examples. CMTF outperforms standard methods like principal components analysis in the extent of data reduction while maintaining equivalent prediction of immune functional responses and disease status. Under CMTF, model interpretation improves through effective data reduction, separation of the Fc and antigen-binding effects, and recognition of consistent patterns across individual measurements. Data reduction also helps make prediction models more replicable. Therefore, we propose that CMTF is an effective general strategy for data exploration in systems serology.

Systems serology provides a broad view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. These studies contain structured biophysical profiling across disease-relevant antigen targets, alongside additional measurements made for single antigens or in an antigen-generic manner. Identifying patterns in these measurements helps guide vaccine and therapeutic antibody development, improve our understanding of diseases, and discover conserved regulatory mechanisms. Here, we report that coupled matrix-tensor factorization (CMTF) can reduce these data into consistent patterns by recognizing the intrinsic structure of these data. We use measurements from two previous studies of HIV- and SARS-CoV-2-infected subjects as examples. CMTF outperforms standard methods like principal components analysis in the extent of data reduction while maintaining equivalent prediction of immune functional responses and disease status. Under CMTF, model interpretation improves through effective data reduction, separation of the Fc and antigen-binding effects, and recognition of consistent patterns across individual measurements. Data reduction also helps make prediction models more replicable. Therefore, we propose that CMTF is an effective general strategy for data exploration in systems serology.

BackgroundGlioblastoma (GBM; World Health Organization grade IV) assumes a variable appearance on MRI owing to heterogeneous proliferation and infiltration of its cells. As a result, the neurovascular units responsible for functional connectivity (FC) may exist within gross tumor boundaries, albeit with altered magnitude. Therefore, we hypothesize that the strength of FC within GBMs is predictive of overall survival.MethodsWe used predefined FC regions of interest (ROIs) in de novo GBM patients to characterize the presence of within-tumor FC observable via resting-state functional MRI and its relationship to survival outcomes.ResultsFifty-seven GBM patients (mean age, 57.8 ± 13.9 y) were analyzed. Functionally connected voxels, not identifiable on conventional structural images, can be routinely found within the tumor mass and was not significantly correlated to tumor size. In patients with known survival times (n = 31), higher intranetwork FC strength within GBM tumors was associated with better overall survival even after accounting for clinical and demographic covariates.ConclusionsThese findings suggest the possibility that functionally intact regions may persist within GBMs and that the extent to which FC is maintained may carry prognostic value and inform treatment planning.

Systems serology provides a broad view of humoral immunity by profiling both the antigen-binding and Fc properties of antibodies. These studies contain structured biophysical profiling across disease-relevant antigen targets, alongside additional measurements made for single antigens or in an antigen-generic manner. Identifying patterns in these measurements helps guide vaccine and therapeutic antibody development, improve our understanding of diseases, and discover conserved regulatory mechanisms. Here, we report that coupled matrix-tensor factorization (CMTF) can reduce these data into consistent patterns by recognizing the intrinsic structure of these data. We use measurements from two previous studies of HIV- and SARS-CoV-2-infected subjects as examples. CMTF outperforms standard methods like principal components analysis in the extent of data reduction while maintaining equivalent prediction of immune functional responses and disease status. Under CMTF, model interpretation improves through effective data reduction, separation of the Fc and antigen-binding effects, and recognition of consistent patterns across individual measurements. Data reduction also helps make prediction models more replicable. Therefore, we propose that CMTF is an effective general strategy for data exploration in systems serology.

Starting from the microscopic approach based on multiband Keldysh-Usadel kinetic theory we derive the minimal field-theoretical model equivalent to the time-dependent Ginzburg-Landau theory. We discuss the properties of resistive states determined by the ratio of electric field relaxation length to the superconducting coherence length. In contrast to the well-studied single-band systems we find that this ratio can vary in wide limits in multiband superconductors. As a result, the properties of resistive states in multiband superconductors can be tuned by the microscopic parameters such as the ratio of diffusion coefficients and pairing constants in different bands. As an example we consider moving Abrikosov vortices in two-band superconductor and show that the flux-flow magneto-resistance can strongly deviate from the single-component Bardeen-Stephen estimation in agreement with recent experimental results., QC 20200821

En el modelo flipped classroom (FC) los estudiantes trabajan de forma autónoma tareas previamente preparadas por el profesorado (Harrington et als, 2015 y Schwartz, 2014), metodología que permite mejorar su aprendizaje mediante el intercambio de roles profesor-alumno. Para las prácticas en laboratorio no hay estudios que muestren la satisfacción y beneficios de esta metodología respecto al método tradicional. Nuestro objetivo fue medir la satisfacción, motivación y aprendizaje del estudiante en las prácticas de laboratorio de farmacología utilizando FC. La muestra estuvo integrada por 58 individuos del Grado en Enfermería. Como herramientas utilizamos un esquema de preparación previa colgado en Moodle con enlace a Clinical Skills, con protocolos y materiales actualizados. El estudiante elaboró su propio video con las técnicas aprendidas. Un cuestionario (Canales & Hernández, 2019 y Landa & Ramirez, 2017), nos permitió medir su grado de satisfacción con la metodología. Los resultados concluyen la satisfacción del colectivo con FC como elemento de mejora de su conocimiento y por su contribución al fomento de la participación activa en el proceso de enseñanza-aprendizaje, así como de la interacción intragrupo, lo que contribuye al cambio de rol del estudiante hacia una actitud más proactiva. Como conclusión entendemos que en ciencias de la salud es prioritario adaptarse a las tecnologías virtuales y mejorar las habilidades del aprendizaje también en las prácticas de laboratorio.

En el modelo flipped classroom (FC) los estudiantes trabajan de forma autónoma tareas previamente preparadas por el profesorado (Harrington et als, 2015 y Schwartz, 2014), metodología que permite mejorar su aprendizaje mediante el intercambio de roles profesor-alumno. Para las prácticas en laboratorio no hay estudios que muestren la satisfacción y beneficios de esta metodología respecto al método tradicional. Nuestro objetivo fue medir la satisfacción, motivación y aprendizaje del estudiante en las prácticas de laboratorio de farmacología utilizando FC. La muestra estuvo integrada por 58 individuos del Grado en Enfermería. Como herramientas utilizamos un esquema de preparación previa colgado en Moodle con enlace a Clinical Skills, con protocolos y materiales actualizados. El estudiante elaboró su propio video con las técnicas aprendidas. Un cuestionario (Canales & Hernández, 2019 y Landa & Ramirez, 2017), nos permitió medir su grado de satisfacción con la metodología. Los resultados concluyen la satisfacción del colectivo con FC como elemento de mejora de su conocimiento y por su contribución al fomento de la participación activa en el proceso de enseñanza-aprendizaje, así como de la interacción intragrupo, lo que contribuye al cambio de rol del estudiante hacia una actitud más proactiva. Como conclusión entendemos que en ciencias de la salud es prioritario adaptarse a las tecnologías virtuales y mejorar las habilidades del aprendizaje también en las prácticas de laboratorio.

OBJECTIVE:To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment. METHODS:A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS:Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement. CONCLUSIONS:Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG. CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that efgartigimod is safe and well-tolerated

Банковский сектор в Российской Федерации находится на стадии перестройки и реформирования. Банк России каждую неделю отзывает лицензии у недобросовестных кредитных организаций. Летом 2017 года у крупнейшего частного банка в России понизили кредитный рейтинг, что вызвало волну волнений, а в конце августа и вовсе к введению временной администрации и санации «ФК Открытие ». В данном процессе много вопросов, хотя ответы на них есть в открытых источниках, но вызывают сомнения у многих. Что же произошло с «Открытием»? В чем причины такого краха?, The banking sector in the Russian Federation is in the process of restructuring and reform. Bank of Russia each week withdraws licenses from unscrupulous banking organizations. In the summer of 2017 the largest private bank in Russia lowered credit rating, which triggered a wave of unrest, but at the end of August and it is to the introduction of the Transitional Administration and sanation "FC". In this proc ess many questions, though answers to them have publicly, but many are doubtful. What happened to the "Discovery"? What are the reasons for such a collapse?

HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.

HIV-specific broadly neutralizing antibodies (bNAbs) confer protection after passive immunization, but the immunological mechanisms that drive their development are poorly understood. Structural features of bNAbs indicate that they originate from extensive germinal center (GC) selection, which relies on persistent GC activity. However, why a fraction of infected individuals are able to successfully drive more effective affinity maturation is unclear. Delivery of antigens in the form of antibody-immune complexes (ICs), which bind to complement receptors (CRs) or Fc receptors (FcRs) on follicular dendritic cells, represents an effective mechanism for antigen delivery to the GC. We sought to define whether IC-FcR or CR interactions differ among individuals who develop bNAb responses to HIV. Enhanced Fc effector functions and FcR/CR interactions, via altered Fc glycosylation profiles, were observed among individuals with neutralizing antibody responses to HIV compared with those without neutralizing antibody activity. Moreover, both polyclonal neutralizer ICs and monoclonal IC mimics of neutralizer antibodies induced higher antibody titers, higher-avidity antibodies, and expanded GC B cell reactions after immunization of mice via accelerated antigen deposition within B cell follicles in a complement-dependent manner. Thus, these data point to a direct role for altered Fc profile/complement interactions in shaping the maturation of the humoral immune response, providing insights into how GC activity may be enhanced to drive affinity maturation in next-generation vaccine approaches.

Macrophages protect the body from damage and disease by targeting antibody-opsonized cells for phagocytosis. Though antibodies can be raised against antigens with diverse structures, shapes, and sizes, it is unclear why some are more effective at triggering immune responses than others. Here, we define an antigen height threshold that regulates phagocytosis of both engineered and cancer-specific antigens by macrophages. Using a reconstituted model of antibody-opsonized target cells, we find that phagocytosis is dramatically impaired for antigens that position antibodies >10 nm from the target surface. Decreasing antigen height drives segregation of antibody-bound Fc receptors from the inhibitory phosphatase CD45 in an integrin-independent manner, triggering Fc receptor phosphorylation and promoting phagocytosis. Our work shows that close contact between macrophage and target is a requirement for efficient phagocytosis, suggesting that therapeutic antibodies should target short antigens in order to trigger Fc receptor activation through size-dependent physical segregation.

Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging-based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury.

Seasonal influenza virus epidemics represent a significant public health burden. Approximately 25% of all influenza virus infections are caused by type B viruses, and these infections can be severe, especially in children. Current influenza virus vaccines are an effective prophylaxis against infection but are impacted by rapid antigenic drift, which can lead to mismatches between vaccine strains and circulating strains. Here, we describe a broadly protective vaccine candidate based on chimeric hemagglutinins, consisting of globular head domains from exotic influenza A viruses and stalk domains from influenza B viruses. Sequential vaccination with these constructs in mice leads to the induction of broadly reactive antibodies that bind to the conserved stalk domain of influenza B virus hemagglutinin. Vaccinated mice are protected from lethal challenge with diverse influenza B viruses. Results from serum transfer experiments and antibody-dependent cell-mediated cytotoxicity (ADCC) assays indicate that this protection is antibody mediated and based on Fc effector functions. The present data suggest that chimeric hemagglutinin-based vaccination is a viable strategy to broadly protect against influenza B virus infection.IMPORTANCE While current influenza virus vaccines are effective, they are affected by mismatches between vaccine strains and circulating strains. Furthermore, the antiviral drug oseltamivir is less effective for treating influenza B virus infections than for treating influenza A virus infections. A vaccine that induces broad and long-lasting protection against influenza B viruses is therefore urgently needed.

Recent ICH quality guideline updates introduced the enhanced drug development which is based on Quality by Design approach. For this a Quality Risk Management has to be conducted based on scientific knowledge. Information gaps are closed through analysis of molecules with domain-specific modifications. The aim of this thesis was to evaluate methods to prepare a model IgG1 for such studies. The antibody fragments F(ab’)2, LHF, Fab and Fc and the Fc-glycosylation cleaved IgG with residual N-acetylglucosamine were selected. A representative IgG1 was digested with the recently discovered enzymes IdeS, Kgp, IgdE and EndoS2 and the digestion products were purified with common biotechnological down-stream methods. The F(ab’)2 was successfully isolated with a yield of 55% and a purity of 96%. After an initial digestion parameter optimization the LHF, Fab and Fc could be generated and an isolation method was established. A following scale-up was unsuccessful, due to reproducibility issues. A promising alternative was identified. The enzymatic glycan cleavage and product isolation was successful with a yield of 80% and a purity of 99%.

Blast mild traumatic brain injury (mTBI) is a leading cause of sustained impairment in military service members and veterans. However, the mechanism of persistent disability is not fully understood. The present study investigated disturbances in brain functioning in mTBI participants using a source-imaging-based approach to analyze functional connectivity (FC) from resting-state magnetoencephalography (rs-MEG). Study participants included 26 active-duty service members or veterans who had blast mTBI with persistent post-concussive symptoms, and 22 healthy control active-duty service members or veterans. The source time courses from regions of interest (ROIs) were used to compute ROI to whole-brain (ROI-global) FC for different frequency bands using two different measures: 1) time-lagged cross-correlation and 2) phase-lock synchrony. Compared with the controls, blast mTBI participants showed increased ROI-global FC in beta, gamma, and low-frequency bands, but not in the alpha band. Sources of abnormally increased FC included the: 1) prefrontal cortex (right ventromedial prefrontal cortex [vmPFC], right rostral anterior cingulate cortex [rACC]), and left ventrolateral and dorsolateral prefrontal cortex; 2) medial temporal lobe (bilateral parahippocampus, hippocampus, and amygdala); and 3) right putamen and cerebellum. In contrast, the blast mTBI group also showed decreased FC of the right frontal pole. Group differences were highly consistent across the two different FC measures. FC of the left ventrolateral prefrontal cortex correlated with executive functioning and processing speed in mTBI participants. Altogether, our findings of increased and decreased regionalpatterns of FC suggest that disturbances in intrinsic brain connectivity may be the result of multiple mechanisms, and are associated with cognitive sequelae of the injury.

Seasonal influenza virus epidemics represent a significant public health burden. Approximately 25% of all influenza virus infections are caused by type B viruses, and these infections can be severe, especially in children. Current influenza virus vaccines are an effective prophylaxis against infection but are impacted by rapid antigenic drift, which can lead to mismatches between vaccine strains and circulating strains. Here, we describe a broadly protective vaccine candidate based on chimeric hemagglutinins, consisting of globular head domains from exotic influenza A viruses and stalk domains from influenza B viruses. Sequential vaccination with these constructs in mice leads to the induction of broadly reactive antibodies that bind to the conserved stalk domain of influenza B virus hemagglutinin. Vaccinated mice are protected from lethal challenge with diverse influenza B viruses. Results from serum transfer experiments and antibody-dependent cell-mediated cytotoxicity (ADCC) assays indicate that this protection is antibody mediated and based on Fc effector functions. The present data suggest that chimeric hemagglutinin-based vaccination is a viable strategy to broadly protect against influenza B virus infection.IMPORTANCE While current influenza virus vaccines are effective, they are affected by mismatches between vaccine strains and circulating strains. Furthermore, the antiviral drug oseltamivir is less effective for treating influenza B virus infections than for treating influenza A virus infections. A vaccine that induces broad and long-lasting protection against influenza B viruses is therefore urgently needed.

Today, increasing relevance of the energy demand for energy generation and the need of energy management systems with the integration of energy storage are the key motivations for developing a smart community simulator, which is used to model, design, analyze, and investigate the deployment of smart grid. In this paper, a solar photovoltaic and a fuel cell energy system for the smart community simulator are discussed. Their energy system performances under human activities have been revealed by carrying out the simulation verification using the real experiment data that is obtained from iHouse., identifier:https://dspace.jaist.ac.jp/dspace/handle/10119/15496

5G stringent requirements entail numerous challenges to overcome. Optimizing Network Function Virtualization Infrastructure Point of Presence (NFVI-PoP) placement in a Fog Computing/5G environment is one of these challenges. To solve this problem, this paper proposes an approach for the NFVI-PoP placement problem solution considering 5G mobile network requirements in a Fog Computing (FC) and Software De¿ned Networks (SDN) ecosystem., Peer Reviewed, Postprint (published version)

Recent ICH quality guideline updates introduced the enhanced drug development which is based on Quality by Design approach. For this a Quality Risk Management has to be conducted based on scientific knowledge. Information gaps are closed through analysis of molecules with domain-specific modifications. The aim of this thesis was to evaluate methods to prepare a model IgG1 for such studies. The antibody fragments F(ab’)2, LHF, Fab and Fc and the Fc-glycosylation cleaved IgG with residual N-acetylglucosamine were selected. A representative IgG1 was digested with the recently discovered enzymes IdeS, Kgp, IgdE and EndoS2 and the digestion products were purified with common biotechnological down-stream methods. The F(ab’)2 was successfully isolated with a yield of 55% and a purity of 96%. After an initial digestion parameter optimization the LHF, Fab and Fc could be generated and an isolation method was established. A following scale-up was unsuccessful, due to reproducibility issues. A promising alternative was identified. The enzymatic glycan cleavage and product isolation was successful with a yield of 80% and a purity of 99%.

Today, increasing relevance of the energy demand for energy generation and the need of energy management systems with the integration of energy storage are the key motivations for developing a smart community simulator, which is used to model, design, analyze, and investigate the deployment of smart grid. In this paper, a solar photovoltaic and a fuel cell energy system for the smart community simulator are discussed. Their energy system performances under human activities have been revealed by carrying out the simulation verification using the real experiment data that is obtained from iHouse.

Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

Fuel cell systems are becoming more commonplace as a power generation method and are being researched, developed, and explored for commercial use, including portable fuel cells that appear in laptops, phones, and of course, chargers. This thesis examines a model constructed on inspiration from the myFC PowerTrekk, a portable fuel cell charger, using COMSOL Multiphysics, a finite element analysis software. As an educational tool and in the form of zero-dimensional, two-dimensional, and three-dimensional models, an investigation was completed into the geometric construction, air conditions and compositions, and product materials with a best case scenario completed that summarizes the results identified. On the basis of the results of this research, it can be concluded that polyoximetylen and high-density polyethylene were considered as possible materials for the majority of the product, though a more thorough investigation is needed. Air flow of above 10 m/s, air water vapour mass fraction below 50% and initial temperature between 308K and 298K was considered in this best scenario. Suggestions on future expansions to this project are also given in the conclusion.

BackgroundThe time to acquisition of simian immunodeficiency virus (SIV) infection following low-dose repeated rectal challenge correlated inversely with the number of transmitted/founder strains among macaques vaccinated with ALVAC-SIV/gp120 or gp120 alone. We determined if the ability of postvaccination, prechallenge sera to enhance SIVmac251 transcytosis across epithelial cells was associated with transmitted/founder strain number.MethodsTranscytosis was carried out by exposing sera and SIVmac251 to the apical surface of human endometrial carcinoma (HEC-1A) cells at pH 6.0 and 12 hours later quantifying virus in fluid bathing the basolateral cell surface (maintained at pH 7.4). These conditions allow Fc neonatal receptor (FcRn)-dependent shuttling of virus across cells.ResultsThere was a strong correlation between the amount of virus transcytosed and number of transmitted variants (R = 0.86, P < .0001). We also found that 4 animals who remained uninfected after repeated rectal challenges had lower serum transcytosis activity than did 19 animals who subsequently became infected (P = .003). Using immunohistochemistry, we demonstrated FcRn on columnar epithelial cells facing the lumen of the macaque rectum.ConclusionsVaccine-induced antibody capable of enhancing transcytosis in vitro via FcRn may play a role in determining transmitted/founder strain number and infection outcomes following in vivo challenge.

Immunoglobulin G (IgG)-based drugs are arguably the most successful class of protein therapeutics due in part to their remarkably long blood circulation. This arises from IgG interaction with the neonatal Fc receptor, FcRn. FcRn is the central regulator of IgG and albumin homeostasis throughout life and is increasingly being recognized as an important player in autoimmune disease, mucosal immunity, and tumor immune surveillance. Various engineering approaches that hijack or disrupt the FcRn-mediated transport pathway have been devised to develop long-lasting and non-invasive protein therapeutics, protein subunit vaccines, and therapeutics for treatment of autoimmune and infectious disease. In this review, we highlight the diverse biological functions of FcRn, emerging therapeutic opportunities, as well as the associated challenges of targeting FcRn for drug delivery and disease therapy.

Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression.

Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

Fuel cell systems are becoming more commonplace as a power generation method and are being researched, developed, and explored for commercial use, including portable fuel cells that appear in laptops, phones, and of course, chargers. This thesis examines a model constructed on inspiration from the myFC PowerTrekk, a portable fuel cell charger, using COMSOL Multiphysics, a finite element analysis software. As an educational tool and in the form of zero-dimensional, two-dimensional, and three-dimensional models, an investigation was completed into the geometric construction, air conditions and compositions, and product materials with a best case scenario completed that summarizes the results identified. On the basis of the results of this research, it can be concluded that polyoximetylen and high-density polyethylene were considered as possible materials for the majority of the product, though a more thorough investigation is needed. Air flow of above 10 m/s, air water vapour mass fraction below 50% and initial temperature between 308K and 298K was considered in this best scenario. Suggestions on future expansions to this project are also given in the conclusion.

PurposeIntact antibodies have a long serum persistence resulting in high background signal that inhibits their direct translation as imaging agents. Engineering of antibody fragments through the introduction of mutations in the fragment crystallizable (Fc) region can dramatically reduce serum persistence. We sought to develop a Fc-mutated, anti-CA19-9 antibody fragment (anti-CA 19-9 scFv-Fc H310A) to provide micro-positron emission tomography (microPET) imaging of pancreatic cancer xenografts.ProceduresThe anti-CA19-9 scFv-Fc H310A was successfully expressed and purified. Biochemical characterization included size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and flow cytometry. The antibody fragment was labeled with iodine-124 ((124)I) and injected into mice containing human pancreatic cancer xenografts. MicroPET/CT images were then obtained. Blood, organ, and tumor radioactivity was measured and expressed as the percent of injected dose per gram of tissue (%ID/g).ResultsBiochemical characterization was consistent with the creation of a 105 kD dimer containing a human Fc region. Flow cytometry demonstrated antigen-specific binding, and cell-based ELISA further established a dissociation constant (K D) of 10.7 nM. (124)I-labeled scFv-Fc H310A localized to the antigen-positive tumor xenografts as detected by microPET. Objective confirmation of targeting was demonstrated by higher %ID/g in the antigen-positive tumor compared to the blood, antigen-negative tumor, and liver.ConclusionsWe successfully engineered and produced an anti-CA19-9 scFv-Fc H310A antibody fragment that retains similar affinity when compared to the parental intact murine antibody. Additionally, our engineered and mutated fragment exhibited antigen-specific microPET imaging of both subcutaneous and orthotopic pancreatic cancer xenografts at early time points secondary to decreased serum half-life.

PurposeIntact antibodies have a long serum persistence resulting in high background signal that inhibits their direct translation as imaging agents. Engineering of antibody fragments through the introduction of mutations in the fragment crystallizable (Fc) region can dramatically reduce serum persistence. We sought to develop a Fc-mutated, anti-CA19-9 antibody fragment (anti-CA 19-9 scFv-Fc H310A) to provide micro-positron emission tomography (microPET) imaging of pancreatic cancer xenografts.ProceduresThe anti-CA19-9 scFv-Fc H310A was successfully expressed and purified. Biochemical characterization included size exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and flow cytometry. The antibody fragment was labeled with iodine-124 ((124)I) and injected into mice containing human pancreatic cancer xenografts. MicroPET/CT images were then obtained. Blood, organ, and tumor radioactivity was measured and expressed as the percent of injected dose per gram of tissue (%ID/g).ResultsBiochemical characterization was consistent with the creation of a 105 kD dimer containing a human Fc region. Flow cytometry demonstrated antigen-specific binding, and cell-based ELISA further established a dissociation constant (K D) of 10.7 nM. (124)I-labeled scFv-Fc H310A localized to the antigen-positive tumor xenografts as detected by microPET. Objective confirmation of targeting was demonstrated by higher %ID/g in the antigen-positive tumor compared to the blood, antigen-negative tumor, and liver.ConclusionsWe successfully engineered and produced an anti-CA19-9 scFv-Fc H310A antibody fragment that retains similar affinity when compared to the parental intact murine antibody. Additionally, our engineered and mutated fragment exhibited antigen-specific microPET imaging of both subcutaneous and orthotopic pancreatic cancer xenografts at early time points secondary to decreased serum half-life.

PurposeLenalidomide is an immunomodulatory agent with therapeutic activity in chronic lymphocytic leukemia (CLL). In preclinical models, lenalidomide acted synergistically with rituximab. The CLL Research Consortium initiated a phase II study to evaluate this combination in treatment-naive patients.Patients and methodsLenalidomide was initiated at 2.5 mg/day and was escalated based on treatment tolerability to a maximum of 10 mg/day, for 21 days/cycle, for a maximum of seven cycles. Rituximab was administered at the end of cycle 1 and was continued for seven cycles. Patients received allopurinol and aspirin for prophylaxis.ResultsSixty-nine patients enrolled onto one of two age-specific strata; patients' median age was 56 and 70 years for arms A and B, respectively. Patients in the older-patient stratum more frequently had elevated serum beta-2 microglobulin levels, high-risk Rai stage, and were less likely to complete the maximum planned therapy. Adverse events were similar in the two arms. Nonhematologic toxicity was predominantly at grade 1/2, and neutropenia was the most common hematologic adverse event. The response rate for arm A was 95%, with 20% complete responses (CRs) and 20% nodular partial responses. Of arm B patients, 78% achieved a response, of which 11% were CRs. Median progression-free survival (PFS) was 19 months for the younger cohort and 20 months for the older cohort.ConclusionIntrapatient dose-escalation was safe. The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined seven-cycle course of lenalidomide and rituximab therapy. Despite differences in baseline characteristics and the response rate between the two strata, the PFS did not differ.

Fuel cell (FC) is a device that gives us electrical and thermal energy from the chemical energy present in the fuels involved during the conversion process. The chemical conversion process occurs thanks to the different constitutive layers in the FC, i.e., active layer, anode/cathode support layer, catalyst layer, gas diffusion later and electrolyte. Most of them have the characteristic to allow the flow of the reactants. Understanding the behavior of the fluids in porous media help to improve the efficiency of fuel cells. Modeling different transport phenomena that occur inside fuel cells during the energy conversion process are important at microscale. Lattice Boltzmann method appears as a powerful tool for solving problems in complex geometries. In the first part of this work the solution of some physical problems at macroscale are presented. Finally, the solution of the momentum equation and the calculation of porosity and tortuosity in a simple and artificially generated porous domain are presented.

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.

El Plasma Rico en Plaquetas (PRP), como su nombre lo indica, posee una alta concentración de trombocitos; es un preparado autólogo, no tóxico y no alergénico, obtenido por centrifugación de la sangre a baja velocidad. Su función está directamente ligada a la liberación por parte de las plaquetas de Factores de Crecimiento (FC). Estos factores tienen propiedades de inducción de la regeneración de los tejidos. Para la elaboración del presente trabajo se realizó una búsqueda bibliográfica en diferentes fuentes documentales utilizando los descriptores: Plasma rico en plaquetas, PRP, Factores de crecimiento, FC, Odontología y Cirugía estética. En este artículo se realiza una descripción de algunos aspectos relevantes del PRP y su aplicación en las áreas de Odontología y Cirugía estética.

The importance of therapeutic recombinant proteins in medicine has led to a variety of tactics to increase their circulation time or to enable routes of administration other than injection. One clinically successful tactic to improve both protein circulation and delivery is to fuse the Fc domain of IgG to therapeutic proteins so that the resulting fusion proteins interact with the human neonatal Fc receptor (FcRn). As an alternative to grafting the high molecular weight Fc domain to therapeutic proteins, we have modified their N and/or C termini with a short peptide sequence that interacts with FcRn. Our strategy was motivated by results [Mezo AR, et al. (2008) Proc Natl Acad Sci USA 105:2337-2342] that identified peptides that compete with human IgG for FcRn. The small size and simple structure of the FcRn-binding peptide (FcBP) allows for expression of FcBP fusion proteins in Escherichia coli and results in their pH-dependent binding to FcRn with an affinity comparable to that of IgG. The FcBP fusion proteins are internalized, recycled, and transcytosed across cell monolayers that express FcRn. This strategy has the potential to improve protein transport across epithelial barriers, which could lead to noninvasive administration and also enable longer half-lives of therapeutic proteins.

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C'-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C'-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.

In this work ion conductivity and FC application were studied for the new type composite material based on SDC (samariurn doped ceria) and Li2SO4. Significant conductivity enhancement was achieved, e.g. 10(-2) - 0.4 Scm(-1) for the SDC-Li2SO4 compared to 10(-4) -10(-2) Scm(-1) for the SDC between 400 and 650degreesC. Some ion conductivity mechanisms were proposed correspondingly. Using the SDC-Li2SO4 composite materials as the electrolytes, we achieved high performances, 200-540 mWcm(-2). for intennediate temperature (450-650degreesC) solid oxide FC (ITSOFC) applications. Sulfates, typically Li2SO4, have an excellent chemical stability in sulfur containing atmosphere. The sulfate-ceria (SDC-Li2SO4) Composite materials can thus meet the demands to develop the sulfur tolerant and H2S FC technologies, which was also demonstrated successfully with significant importance for both fundamental and applied research., QC 20111013

DelftChemTech, Applied Sciences

DelftChemTech, Applied Sciences

På uppdrag av Naturvårdsverket har IVL Svenska Miljöinstitutet AB genomfört en kartläggning av förekomst, samt beräkning av potentiella och faktiska emissioner, av fluorerade växthusgaser i Sverige. Beräkningar har innefattat perioden 1990-1999, samt prognoser för åren 2005, 2010, 2015 och 2020. Kartläggningen och beräkningarna innefattar ofullständigt halogenerade fluorkolväten (HFC), fullständigt halogenerade fluorkolväten (FC) och svavelhexafluorid (SF6). I inventeringen har ingått en rad olika branscher, produktgrupper eller användningsområden, såsom kyl-, frys- och elektronikindustri, aluminiumtillverkning, magnesiumgjutning, elektrisk isolering, isolerglas samt joggingskor. Beräkningarna visar att de faktiska emissionerna ökat med 50% i Sverige mellan 1990 och 1999, från ca 0.52 till 0.78 miljoner ton CO2-ekvivalanter, På uppdrag av Naturvårdsverket har IVL Svenska Miljöinstitutet AB genomfört en kartläggning av förekomst, samt beräkning av potentiella och faktiska emissioner, av fluorerade växthusgaser i Sverige. Beräkningar har innefattat perioden 1990-1999, samt prognoser för åren 2005, 2010, 2015 och 2020. Kartläggningen och beräkningarna innefattar ofullständigt halogenerade fluorkolväten (HFC), fullständigt halogenerade fluorkolväten (FC) och svavelhexafluorid (SF6). I inventeringen har ingått en rad olika branscher, produktgrupper eller användningsområden, såsom kyl-, frys- och elektronikindustri, aluminiumtillverkning, magnesiumgjutning, elektrisk isolering, isolerglas samt joggingskor. Beräkningarna visar att de faktiska emissionerna ökat med 50% i Sverige mellan 1990 och 1999, från ca 0.52 till 0.78 miljoner ton CO2-ekvivalanter

På uppdrag av Naturvårdsverket har IVL Svenska Miljöinstitutet AB genomfört en kartläggning av förekomst, samt beräkning av potentiella och faktiska emissioner, av fluorerade växthusgaser i Sverige. Beräkningar har innefattat perioden 1990-1999, samt prognoser för åren 2005, 2010, 2015 och 2020. Kartläggningen och beräkningarna innefattar ofullständigt halogenerade fluorkolväten (HFC), fullständigt halogenerade fluorkolväten (FC) och svavelhexafluorid (SF6). I inventeringen har ingått en rad olika branscher, produktgrupper eller användningsområden, såsom kyl-, frys- och elektronikindustri, aluminiumtillverkning, magnesiumgjutning, elektrisk isolering, isolerglas samt joggingskor. Beräkningarna visar att de faktiska emissionerna ökat med 50% i Sverige mellan 1990 och 1999, från ca 0.52 till 0.78 miljoner ton CO2-ekvivalanter, På uppdrag av Naturvårdsverket har IVL Svenska Miljöinstitutet AB genomfört en kartläggning av förekomst, samt beräkning av potentiella och faktiska emissioner, av fluorerade växthusgaser i Sverige. Beräkningar har innefattat perioden 1990-1999, samt prognoser för åren 2005, 2010, 2015 och 2020. Kartläggningen och beräkningarna innefattar ofullständigt halogenerade fluorkolväten (HFC), fullständigt halogenerade fluorkolväten (FC) och svavelhexafluorid (SF6). I inventeringen har ingått en rad olika branscher, produktgrupper eller användningsområden, såsom kyl-, frys- och elektronikindustri, aluminiumtillverkning, magnesiumgjutning, elektrisk isolering, isolerglas samt joggingskor. Beräkningarna visar att de faktiska emissionerna ökat med 50% i Sverige mellan 1990 och 1999, från ca 0.52 till 0.78 miljoner ton CO2-ekvivalanter

Macrophage Fcgamma receptors (FcgammaRs) mediate the uptake and destruction of antibody-coated viruses, bacteria, and parasites. We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn. Many FcgammaR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases 1 and 2. Significant reduction of IgG-dependent phagocytosis was not seen in hck(-)(/)-fgr(-)(/)- or lyn(-)(/)- cells, although the single mutant lyn(-)(/)- macrophages did manifest signaling defects. Thus, Src family kinases clearly have roles in two events leading to FcgammaR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization. Since FcgammaR-mediated phagocytosis did occur at modest levels in a delayed fashion in triple mutant macrophages, these Src family kinases are not absolutely required for uptake of IgG-opsonized particles.

Macrophage Fcgamma receptors (FcgammaRs) mediate the uptake and destruction of antibody-coated viruses, bacteria, and parasites. We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn. Many FcgammaR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases 1 and 2. Significant reduction of IgG-dependent phagocytosis was not seen in hck(-)(/)-fgr(-)(/)- or lyn(-)(/)- cells, although the single mutant lyn(-)(/)- macrophages did manifest signaling defects. Thus, Src family kinases clearly have roles in two events leading to FcgammaR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization. Since FcgammaR-mediated phagocytosis did occur at modest levels in a delayed fashion in triple mutant macrophages, these Src family kinases are not absolutely required for uptake of IgG-opsonized particles.

The purpose of this investigation was to determine the role of Fc receptors for IgG (FcγRI, FcγRIIB, FcγRIII and FcRn) in immunoregulation. IgG is known to enhance the response to soluble antigens such as bovine serum albumin whereas the response to particulate antigens is suppressed. The ability of IgG to induce specific suppression of immune responses has been used clinically to prevent haemolytic disease of the newborn (Rhesus prophylaxis). The favoured mechanism behind IgG-mediated suppression has been specific inhibition of antibody production through an inhibitory Fc receptor for IgG, FcγRIIB. We here study the importance of Fc receptors for IgG using Fc receptor-deficient mice immunised with sheep red blood cells alone or together with IgG anti-sheep red blood cells. IgG was able to suppress the primary response in all Fc receptor-deficient mice measured as number of sheep red blood cell specific B cells. In addition, IgE and F(ab')2 fragments of IgG induced antigen-specific suppression, suggesting an Fc-independent mechanism involving masking of epitopes. FcγRIIB was required for suppression of secondary antibody responses in vitro but not in vivo. To study the enhancing effect by IgG, the Fc receptor-deficient mice were immunised with haptenated bovine serum albumin alone or together with hapten-specific IgG. The resulting enhancement was measured as specific bovine serum albumin antibody in serum. We found that in order for IgG to enhance the response to soluble antigen there is a requirement for the common-y chain which is a part of FcγRI and FcγRIII. Using mice specifically deficient for FcγRIII we find that IgG can enhance the response pointing towards FcγRI as the receptor responsible for the effect. An additional finding was that theenhancement was greatly elevated in mice lacking FcγRIIB. This suggests that FcγRIIB has a function in preventing antibody responses from exceeding a certain level rather than in causing complete suppression.

Attachment of the complement component C3 to antigen-antibody (Ag-Ab) complexes (immune complexes, IC) is the key molecular event responsible for the elimination of many Ag in the form of Ag-Ab-C3b. The CH1 domain and the Fc region of the Ab, which have previously been involved in the binding of C3b, are also the targets of several bacterial IgG-binding proteins, particularly proteins G and A. Here we describe the ability of a small recombinant protein G domain (B2; 6.5 kDa) to inhibit the covalent binding of C3b to the Fc portion of IgG without affecting the binding to the Fab part. Protein G (B2 domain) produced a remarkable inhibition of covalent binding of C3b to IC formed with rabbit IgG, but none with the F(ab')2 fragment, indicating that B2 interferes with the C3b binding to the Fc region. A weak inhibition was observed with IC formed with mouse IgG2b which preferentially binds B2 domain on the CH1 domain of the Fab. To confirm these data, recombinant single-chain Ab devoid of CH1 domains (scAb), and including the rabbit or human Fc portion (hinge-CH2-CH3), were produced and used to form IC. Protein G-B2 domain inhibited C3b binding to IC formed with scAb of either human or rabbit constant regions, supporting the view of a specific blockade of C3b binding to the Fc region. A similar inhibition of C3b binding was observed using protein A instead of protein G B2 domain and the same set of IC. On the CH1 domain, C3b and B2 bind on opposite faces, and therefore do not interfere with each other in their binding. However, B2 domain bound to the inter-CH2-CH3 region impedes the C3b binding to the Fc. This inhibition clarifies the specificity of C3b for the different regions of IgG and explains how bacterial IgG-binding proteins provide the bacteria with a mechanism of evasion from the opsonizing action of complement and contribute to the virulence. This could be a general mechanism of escape because protein G binds the majority of mammalian Ig., Ministerio de Educación (España), Comunidad de Madrid, Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Químicas, TRUE, pub