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Valence electronic structure is crucial for understanding and predicting reactivity. Valence non-resonant X-ray photoelectron spectroscopy (NRXPS) provides a direct method for probing the overall valence electronic structure. However, it is often difficult to separate the varying contributions to NRXPS; for example, contributions of solutes in solvents or functional groups in complex molecules. In this work we show that valence resonant X-ray photoelectron spectroscopy (RXPS) is a vital tool for obtaining atomic contributions to valence states. We combine RXPS with NRXPS and density functional theory calculations to demonstrate the validity of using RXPS to identify atomic contributions for a range of solutes (both neutral and ionic) and solvents (both molecular solvents and ionic liquids). Furthermore, the one-electron picture of RXPS holds for all of the closed shell molecules/ions studied, although the situation for an open-shell metal complex is more complicated. The factors needed to obtain a strong RXPS signal are investigated in order to predict the types of systems RXPS will work best for; a balance of element electronegativity and bonding type is found to be important. Additionally, the dependence of RXPS spectra on both varying solvation environment and varying local-covalent bonding is probed. We find that RXPS is a promising fingerprint method for identifying species in solution, due to the spectral shape having a strong dependence on local-covalency but a weak dependence on the solvation environment.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available COVID-19 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors which block formation of the so-called HR1HR2 six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. Here we performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based fusion, VSV-SARS-CoV-2 chimera, and authentic SARS-CoV-2 infection assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ~100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a pre-hairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the pre-hairpin intermediate of the S protein.Significance StatementSARS-CoV-2 infection requires fusion of viral and host membranes, mediated by the viral spike glycoprotein (S). Due to the importance of viral membrane fusion, S has been a popular target for developing vaccines and therapeutics. We discovered a simple peptide that inhibits infection by all major variants of SARS-CoV-2 with nanomolar efficacies. In marked contrast, widely used shorter peptides that lack a key N-terminal extension are about 100 x less potent than this peptide. Our results suggest that a simple peptide with a suitable sequence can be a potent and cost-effective therapeutic against COVID-19 and they provide new insights at the virus entry mechanism.

Presynaptic Ca(v)2 channels are essential for Ca2+-triggered exocytosis. In addition, there are two competing models for their roles in synapse structure. First, Ca2+ channels or Ca2+ entry may control synapse assembly. Second, active zone proteins may scaffold Ca(v)2s to presynaptic release sites, and synapse structure is Ca(v)2 independent. Here, we ablated all three Ca(v)2s using conditional knockout in cultured hippocampal neurons or at the calyx of Held, which abolished evoked exocytosis. Compellingly, synapse and active zone structure, vesicle docking, and transsynaptic nano-organization were unimpaired. Similarly, long-term blockade of action potentials and Ca2+ entry did not disrupt active zone assembly. Although Ca(v)2 knockout impaired the localization of beta subunits, alpha 2 delta-1 localized normally. Rescue with Ca(v)2 restored exocytosis, and Ca(v)2 active zone targeting depended on the intracellular C-terminus. We conclude that synapse assembly is independent of Ca(v)2s or Ca2+ entry through them. Instead, active zone proteins recruit and anchor Ca(v)2s via Ca(v)2 C-termini.

Presynaptic Ca

In vivo imaging of tissue/vasculature oxygen saturation levels is of prime interest in many clinical applications. To this end, the feasibility of combining two distinct and complementary imaging modalities is investigated: optoacoustics (OA) and near‐infrared optical tomography (NIROT), both operating noninvasively in reflection mode. Experiments were conducted on two optically heterogeneous phantoms mimicking tissue before and after the occurrence of a perturbation. OA imaging was used to resolve submillimetric vessel‐like optical absorbers at depths up to 25 mm, but with a spectral distortion in the OA signals. NIROT measurements were utilized to image perturbations in the background and to estimate the light fluence inside the phantoms at the wavelength pair (760 nm, 830 nm). This enabled the spectral correction of the vessel‐like absorbers' OA signals: the error in the ratio of the absorption coefficient at 830 nm to that at 760 nm was reduced from 60%‐150% to 10%‐20%. The results suggest that oxygen saturation (SO 2) levels in arteries can be determined with, Optoacoustics (OA) is combined with near‐infrared optical tomography (NIROT) in reflection mode to quantitatively image vasculature oxygen saturation (SO 2) levels in phantoms containing vessels at depths up to 25 mm. Using NIROT to estimate the light fluence, the OA signals' spectral distortion was reduced from 60%‐150% to 10%‐20%. Results suggest that SO 2 levels can be determined with

Synaptic vesicle exocytosis relies on the tethering of release ready vesicles close to voltage-gated Ca 2+ channels and specific lipids at the future site of fusion. This enables rapid and efficient neurotransmitter secretion during presynaptic depolarization by an action potential. Extensive research has revealed that this tethering is mediated by an active zone, a protein dense structure that is attached to the presynaptic plasma membrane and opposed to postsynaptic receptors. Although roles of individual active zone proteins in exocytosis are in part understood, the molecular mechanisms that hold the protein scaffold at the active zone together and link it to the presynaptic plasma membrane have remained unknown. This is largely due to redundancy within and across scaffolding protein families at the active zone. Recent studies, however, have uncovered that ELKS proteins, also called ERC, Rab6IP2 or CAST, act as active zone scaffolds redundant with RIMs. This redundancy has led to diverse synaptic phenotypes in studies of ELKS knockout mice, perhaps because different synapses rely to a variable extent on scaffolding redundancy. In this review, we first evaluate the need for presynaptic scaffolding, and we then discuss how the diverse synaptic and non-synaptic functional roles of ELKS support the hypothesis that ELKS provides molecular scaffolding for organizing vesicle traffic at the presynaptic active zone and in other cellular compartments.

Die aggressiven Non-Hodgkin-Lymphome stellen eine biologisch und prognostisch heterogene Gruppe an Erkrankungen dar. Dem Konzept der Ursprungszelle entsprechend entstehen B-Zell-Lymphome aus Zellen des Keimzentrums oder aus aktivierten B-Zellen plasmoblastischer Differenzierung unmittelbar vor Verlassen des Keimzentrums. Es werden die gegenwartigen therapeutischen Konzepte in der Therapie aggressiver Lymphome einschlieslich ihrer Begrundungen zusammengefasst. Gegenwartig ergeben sich aus dem Konzept der Ursprungszelle noch keine differenzialtherapeutischen Konsequenzen. Die valideste Einschatzung der Prognose gewahrleistet trotz Fortschritten im Verstandnis der Biologie und Genese weiterhin der International Prognostic Index (IPI). Die Behandlung beruht mit Ausnahme der nasalen NK/T-Zell-Lymphome auf der systemischen Chemotherapie mit CHOP-basierten Protokollen, die Rituximab bei B-Zell-Lymphomen obligat inkludieren. Der einheitlichen Behandlung mit R-CHOP-21 steht das Konzept einer anhand des IPI stratifizierten risikoadaptierten Therapie gegenuber, welches auf Ergebnissen von in distinkten Risikogruppen durchgefuhrten randomisierten Studien basiert. Bei den peripheren T-Zell-Lymphomen wurde insbesondere bei jungeren Patienten durch Hinzunahme von Etoposid als CHOEP eine konsolidierende Hochdosistherapie das ereignisfreie Uberleben verbessert.. Im Rezidiv ist die Prognose der aggressiven Lymphome auch unter Einschluss von Hochdosiskonzepten sehr schlecht, sodass fur die meisten Patienten die Erstlinientherapie die einzige Option einer Heilung darstellt.

To assess rate of late presentation with HIV in Southwestern Germany and to identify patient characteristics correlated with CD4 nadir.Patients with primary diagnosis who presented to one of ten participating clinics rated on knowledge and behavior towards HIV testing on a self-developed questionnaire, whereas clinical data was assessed by the physician.161 patients were included. Risk factors were homosexual (59.5 %) or heterosexual contacts (26.8 %), drug use (2.0 %), migration (3.9 %), or others (7.8 %). 63.5 % had a CD4 T cell count350/µl. 52.5, 17.4, and 31.1 % were diagnosed in CDC stadium A, B or C, respectively. 209 disease episodes were reported, from whom 83.7 % had led to the diagnosis of HIV. 75.2 and 68.3 % said to have been well-informed about ways of transmission and testing offerings, respectively, and 20.4 % admitted to have psychologically repressed the possibility of being infected. 48 patients rated their personal behavioral risk as "high" or "very high". Of these, however, only ten had performed at test in the precedent year. Performing a regression analysis, younger age and previous testing were correlated with a higher CD4 T cell nadir (p = 0.005, and 0.018, resp.).The rate of late presentation in this region was even higher compared to national or European surveys. Most infected patients perceived to have had only a low risk. Several disease episodes did not lead to the initiation of HIV testing by the physician.

Psychische Erkrankungen sind seit Jahren in der Gesellschaft in aller Munde: Eine steigende Zahl von Betroffenen, lange Arbeitsunfahigkeitszeiten und ein hoher Anteil an Erwerbsminderungsrenten haben das Tabuthema in ein anderes Licht geruckt. Fur Betroffene stellen die Erkrankungen mit allen Unsicherheiten jedoch weiterhin eine grose Belastung dar, die Ruckkehr in den Betrieb nach einer langeren Abwesenheit ist mit grosen Unsicherheiten und Angsten verbunden. Hier sind insbesondere auch die Unternehmen gefordert, den Betroffenen fruhzeitig Wege der Ruckkehr in den Betrieb aufzuzeigen. Eingliederungsmasnahmen wie die stufenweise Eingliederung mussen von einer guten Kooperation mit internen und externen Akteuren, einem gesundheitsgerechten und -forderlichen Arbeitsplatz sowie einer positiven und wertschatzenden Atmosphare im Team begleitet werden.

In a presynaptic nerve terminal, synaptic vesicle exocytosis is restricted to specialized sites called active zones. At these sites, neurotransmitter release is determined by the number of releasable vesicles and their probability of release. Proteins at the active zone set these parameters by controlling the presynaptic Ca2+signal, and through docking and priming of synaptic vesicles. Vertebrate ELKS proteins are enriched at presynaptic active zones, but their functions are not well understood. ELKS proteins are produced by two genes in vertebrates, and each gene contributes ∼50% to total brain ELKS. We generated knock-out mice for ELKS1 and found that its constitutive removal causes lethality. To bypass lethality, and to circumvent redundancy between ELKS1 and ELKS2 in synaptic transmission, we used a conditional genetic approach to remove both genes in cultured hippocampal neurons after synapses are established. Simultaneous removal of ELKS1 and ELKS2 resulted in a 50% decrease of neurotransmitter release at inhibitory synapses, paralleled by a reduction in release probability. Removal of ELKS did not affect synapse numbers or their electron microscopic appearance. Using Ca2+imaging, we found that loss of ELKS caused a 30% reduction in single action potential-triggered Ca2+influx in inhibitory nerve terminals, consistent with the deficits in synaptic transmission and release probability. Unlike deletion of the active zone proteins RIM, RIM-BP, or bruchpilot, ELKS removal did not lead to a measurable reduction in presynaptic Ca2+channel levels. Our results reveal that ELKS is required for normal Ca2+influx at nerve terminals of inhibitory hippocampal neurons.

Optoacoustic imaging is a promising non-ionizing hybrid imaging modality combining high optical contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound and speed of sound imaging thus allowing multimodal quantitative aberration free imaging.

In a nerve terminal, synaptic vesicle docking and release are restricted to an active zone. The active zone is a protein scaffold that is attached to the presynaptic plasma membrane and opposed to postsynaptic receptors. Here, we generated conditional knockout mice removing the active zone proteins RIM and ELKS, which additionally led to loss of Munc13, Bassoon, Piccolo, and RIM-BP, indicating disassembly of the active zone. We observed a near-complete lack of synaptic vesicle docking and a strong reduction in vesicular release probability and the speed of exocytosis, but total vesicle numbers, SNARE protein levels, and postsynaptic densities remained unaffected. Despite loss of the priming proteins Munc13 and RIM and of docked vesicles, a pool of releasable vesicles remained. Thus, the active zone is necessary for synaptic vesicle docking and to enhance release probability, but releasable vesicles can be localized distant from the presynaptic plasma membrane.

In a presynaptic nerve terminal, synaptic strength is determined by the pool of readily releasable vesicles (RRP) and the probability of release (P) of each RRP vesicle. These parameters are controlled at the active zone and vary across synapses, but how such synapse specific control is achieved is not understood. ELKS proteins are enriched at vertebrate active zones and enhance P at inhibitory hippocampal synapses, but ELKS functions at excitatory synapses are not known. Studying conditional knockout mice for ELKS, we find that ELKS enhances the RRP at excitatory synapses without affecting P. Surprisingly, ELKS C-terminal sequences, which interact with RIM, are dispensable for RRP enhancement. Instead, the N-terminal ELKS coiled-coil domains that bind to Liprin-α and Bassoon are necessary to control RRP. Thus, ELKS removal has differential, synapse-specific effects on RRP and P, and our findings establish important roles for ELKS N-terminal domains in synaptic vesicle priming. DOI: http://dx.doi.org/10.7554/eLife.14862.001, eLife digest Nerve cells in the brain communicate with one another at connections known as synapses: one nerve cell releases signaling molecules called neurotransmitters into the synapse, which are then sensed by the second cell. For the brain to work correctly, it is important that the nerve cells control when and how much neurotransmitter they release. Nerve cells package neurotransmitters into small packets called vesicles. These vesicles can be released at the so-called active zones of each synapse, though only a small subset of vesicles at a synapse are releasable. Many proteins at the active zone control the release of vesicles to influence how nerve cells communicate with each another. ELKS is one of the proteins found at the active zones of nerve cells that release either of the two most common neurotransmitters in the brain: glutamate and GABA. Held et al. have now found that the ELKS protein affects the release of these two neurotransmitters in different ways in the two types of nerve cells. The experiments showed that the number of releasable neurotransmitter-filled vesicles was lower in mouse nerve cells that release glutamate when the genes for the ELKS proteins were deleted in these cells. When the ELKS genes were deleted in the nerve cells that release GABA, the number of releasable vesicles remained the same, though the vesicles were less likely to be released. The fact that removing ELKS has different effects at these two types of synapses suggests that the active zone is not the same at all synapses. Furthermore, these results imply that ELKS is capable of fine-tuning the communication between nerve cells. Future experiments will address how glutamate- and GABA-releasing active zones differ at the molecular and structural levels. Ultimately, this will lead to a better understanding of how information is processed in the brain. DOI: http://dx.doi.org/10.7554/eLife.14862.002

Optoacoustic imaging is a promising non-ionizing hybrid imaging modality combining high optical contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound and speed of sound imaging.

The chemical composition, as well as the sources contributing to rainwater chemistry have been determined at Skukuza, in the Kruger National Park, South Africa. Major inorganic and organic ions were determined in 93 rainwater samples collected using an automated wet-only sampler from July 1999 to June 2002. The results indicate that the rain is acidic and the averaged precipitation pH was 4.72. This acidity results from a mixture of mineral acids (82%, of which 50% is H2SO4) and organic acids (18%). Most of the H2SO4 component can be attributed to the emissions of sulphur dioxide from the industrial region on the Highveld. The wet deposition of S and N is 5.9 kgS⋅ha−1⋅yr−1 and 2.8 kgN⋅ha−1⋅yr−1, respectively. The N deposition was mainly in the form of NH4 +. Terrigenous, sea salt component, nitrogenous and anthropogenic pollutants have been identified as potential sources of chemical components in rainwater. The results are compared to observations from other African regions.

In November 2013, an acute Zika virus (ZIKV) infection was diagnosed in a German traveller returning from Thailand. The patient reported a clinical picture resembling dengue fever. Serological investigations revealed anti-ZIKV-IgM and -IgG, as well as ZIKV-specific neutralising antibodies in the patient's blood. In Europe, viraemic travellers may become a source of local transmission of ZIKV, because Aedes albopictus (Skuse) and Ae. aegypti (Linnaeus) are invasive mosquitoes and competent vectors for ZIKV. .

Wireless LAN technology is a swiftly moving target. Knowing the basics can help you deploy it safely in your organization. WLAN is actually a series of standards and not just one. The initial IEEE 802.11 standard supported three transmission methods-infrared, direct sequence spread spectrum, and frequency hopping spread spectrum-although a single product would use only one method. All three transmission methods can operate at 1 and 2 Mbps.

Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability (ID) and autism spectrum disorders (ASD). Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). De novo genetic mutations of the synaptic GTPase-activating protein (SynGAP) are associated with ID and ASD. SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength. However, exactly how SynGAP acts to maintain synaptic AMPAR content is unclear. We show here that SynGAP limits excitatory synaptic strength, in part, by suppressing protein synthesis in cortical neurons. The data presented here from in vitro, rat and mouse cortical networks, demonstrate that regulation of translation by SynGAP involves ERK, mTOR, and the small GTP-binding protein Rheb. Furthermore, these data show that GluN2B-containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation-dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks.

Low-level jets (LLJ) over various regions of southern Africa are shown to occur mostly as a result of a thermal gradient established over gently sloping terrain and have been observed to overlie the nocturnal temperature inversions. Strong low-level winds associated with plain-mountain and mountain-plain circulations have also been observed over the central Namib desert and Natal interior. With the exception of the Namib and Natal, where no temperature profiles accompanied wind profile observations, the LLJ is seen to increase in strength as the nocturnal surface temperature inversion intensifies through the night. The height of the LLJ above the surface also increases as the inversion deepens. Wind speeds in all regions exceed 10 m s−1 in the jet core, which typically is located between 200 and 300 m above ground level (agl). Over the central Namib, the summertime plain-mountain wind reaches similar wind speeds in a jetlike core located about 200 to 600 m agl. The Natal mountain-plain winds may exceed 10 m s−1 in a layer of up to 1000 m deep. It is suggested that all these regional-scale wind systems transport pyrogenic products in excess of 400 km during a single night. Subsequent daytime convective lifting of these ozone precursors, coupled with synoptic-scale anticyclonic circulation, provides a transport mechanism for pyrogenic products over southern Africa toward the Atlantic and Indian Oceans.

The experimental phase of SAFARI-92 in the Kruger National Park took place from September 7 to 26, 1992. Eskom's Environmental Sciences was committed to provide meteorological support during the experimental burns in the Pretoriuskop area of the KNP and to characterize the boundary layer during the field campaign. Surface temperature inversions were found during most nights when vertical soundings were available. The inversion strength was generally ≤3.5° with a depth of ≤270 m above ground level (agl). Low-level elevated inversions with a base height of 350 to 500 m agl and a strength of ≤3.6°C were found on four occasions. The base height of the subsidence inversion, when observed, varied between 1500 and 2500 m agl. Significant superadiabatic temperature gradients, impacting directly on the vertical dispersion of pyrogenic products, have been observed to reach as high as several hundred meters above ground level. Vertical profiles of wind speed and direction varied greatly from day to day in response to the changes in the synoptic pattern. However, weak low-level wind maxima just above the surface inversion were observed during most nights, generally with speeds of

Made available in DSpace on 2013-08-28T14:11:56Z (GMT). No. of bitstreams: 1 WOS000292183400004.pdf: 4179321 bytes, checksum: 4244a6184542ca360e9f7148b60e061e (MD5) Made available in DSpace on 2013-09-30T19:23:07Z (GMT). No. of bitstreams: 2 WOS000292183400004.pdf: 4179321 bytes, checksum: 4244a6184542ca360e9f7148b60e061e (MD5) WOS000292183400004.pdf.txt: 99323 bytes, checksum: 83dfb242aa73c3c29d166c8d826e9aca (MD5) Previous issue date: 2011-01-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:34:05Z No. of bitstreams: 2 WOS000292183400004.pdf: 4179321 bytes, checksum: 4244a6184542ca360e9f7148b60e061e (MD5) WOS000292183400004.pdf.txt: 99323 bytes, checksum: 83dfb242aa73c3c29d166c8d826e9aca (MD5) Made available in DSpace on 2014-05-20T15:34:05Z (GMT). No. of bitstreams: 2 WOS000292183400004.pdf: 4179321 bytes, checksum: 4244a6184542ca360e9f7148b60e061e (MD5) WOS000292183400004.pdf.txt: 99323 bytes, checksum: 83dfb242aa73c3c29d166c8d826e9aca (MD5) Previous issue date: 2011-01-01 ESA Multi-Taste EC GEOmon Belgian PRODEX SECPEA projects Accurate long-term monitoring of total ozone is one of the most important requirements for identifying possible natural or anthropogenic changes in the composition of the stratosphere. For this purpose, the NDACC (Network for the Detection of Atmospheric Composition Change) UV-visible Working Group has made recommendations for improving and homogenizing the retrieval of total ozone columns from twilight zenith-sky visible spectrometers. These instruments, deployed all over the world in about 35 stations, allow measuring total ozone twice daily with limited sensitivity to stratospheric temperature and cloud cover. The NDACC recommendations address both the DOAS spectral parameters and the calculation of air mass factors (AMF) needed for the conversion of O-3 slant column densities into vertical column amounts. The most important improvement is the use of O-3 AMF look-up tables calculated using the TOMS V8 (TV8) O-3 profile climatology, that allows accounting for the dependence of the O-3 AMF on the seasonal and latitudinal variations of the O-3 vertical distribution. To investigate their impact on the retrieved ozone columns, the recommendations have been applied to measurements from the NDACC/SAOZ (Systeme d'Analyse par Observation Zenithale) network. The revised SAOZ ozone data from eight stations deployed at all latitudes have been compared to TOMS, GOMEGDP4, SCIAMACHY-TOSOMI, SCIAMACHY-OL3, OMI-TOMS, and OMI-DOAS satellite overpass observations, as well as to those of collocated Dobson and Brewer instruments at Observatoire de Haute Provence (44 degrees N, 5.5 degrees E) and Sodankyla (67 degrees N, 27 degrees E), respectively. A significantly better agreement is obtained between SAOZ and correlative reference ground-based measurements after applying the new O-3 AMFs. However, systematic seasonal differences between SAOZ and satellite instruments remain. These are shown to mainly originate from (i) a possible problem in the satellite retrieval algorithms in dealing with the temperature dependence of the ozone cross-sections in the UV and the solar zenith angle (SZA) dependence, (ii) zonal modulations and seasonal variations of tropospheric ozone columns not accounted for in the TV8 profile climatology, and (iii) uncertainty on the stratospheric ozone profiles at high latitude in the winter in the TV8 climatology. For those measurements mostly sensitive to stratospheric temperature like TOMS, OMI-TOMS, Dobson and Brewer, or to SZA like SCIAMACHY-TOSOMI, the application of temperature and SZA corrections results in the almost complete removal of the seasonal difference with SAOZ, improving significantly the consistency between all ground-based and satellite total ozone observations. Belgian Inst Space Aeron BIRA IASB, Brussels, Belgium CNRS, LATMOS, Guyancourt, France Univ Versailles St Quentin, Guyancourt, France Natl Ocean & Atmospher Adm NOAA, Global Monitoring Div, Earth Syst Res Lab, Boulder, CO USA St Petersburg State Univ, Inst Phys Res, Dept Atmospher Phys, St Petersburg, Russia Finnish Meteorol Inst FMI, Arctic Res Ctr, Sodankyla, Finland Univ Estadual Paulista, Meteorol Res Inst, Bauru, SP, Brazil Danish Meteorol Inst, Copenhagen, Denmark Cent Aerol Observ, Moscow, Russia Inst Tecn Aerospacial INTA, Torrejon de Ardoz, Spain Univ Estadual Paulista, Meteorol Res Inst, Bauru, SP, Brazil

Optical fiber promises higher data rates, but first it must get around a few hurdles presented by physics. Optical networking's capacity is increasing in response to Web surfing, images attached to e-mail, and the development of remote-collaboration applications. All these applications consume significant amounts of bandwidth. Optical networking uses two basic methods to increase an optical fiber's transmission capacity. First, you can increase data transmission rates. Second, you can couple multiple wavelengths onto a single fiber. An obvious outgrowth of these two basic methods is to combine them by transmitting more quickly on individual wavelengths and packing more wavelengths onto a common optical fiber. In November 2000, Global Crossing teamed up with Lucent Technologies to upgrade a 70km fiber network in Belgium to a 40Gbps operating rate for an approximately one-week OC-768 field trial. Although the field trial produced promising results, an actual upgrade of the existing optical infrastructure might not occur for several years. This pessimism comes from several factors, most of which relate to physics The most significant problem arises from a simple fact of physics: As the data rate increases, pulses become narrower. Although the field trial indicated OC-768 can operate over modern optical fiber, the jury is still out on the effect of multiple wavelengths, each operating at 40 Gbps.

Accurate long-term monitoring of total ozone is one of the most important requirements for identifying possible natural or anthropogenic changes in the composition of the stratosphere. For this purpose, the NDACC (Network for the Detection of Atmospheric Composition Change) UV-visible Working Group has made recommendations for improving and homogenizing the retrieval of total ozone columns from twilight zenith-sky visible spectrometers. These instruments, deployed all over the world in about 35 stations, allow measurements of total ozone twice daily with little sensitivity to stratospheric temperature and cloud cover. The NDACC recommendations address both the DOAS retrieval parameters and the calculation of air mass factors (AMF) needed for the conversion of O3 slant column densities into vertical column amounts. The most important improvement is the use of O3 AMF look-up tables calculated using the TOMS V8 O3 profile climatology, that allows accounting for the dependence of the O3 AMF on the seasonal and latitudinal variations of the O3 vertical distribution. To investigate their impact on the retrieved ozone columns, the recommendations have been applied to measurements from the NDACC/SAOZ (Système d'Analyse par Observation Zénithale) network. The revised SAOZ ozone data from eight stations covering all latitude regions have been compared to TOMS, GOME-GDP4, SCIAMACHY-TOSOMI, OMI-TOMS, and OMI-DOAS satellite overpass observations, as well as to those of collocated Dobson and Brewer instruments. A significant improvement is obtained after applying the new O3 AMFs, although systematic seasonal differences between SAOZ and all other instruments remain. These are shown to mainly originate from i) the temperature dependence of the ozone absorption cross sections in the UV being not or improperly corrected by some retrieval algorithms, and ii) the longitudinal differences in tropospheric ozone column being ignored by zonal climatologies. For those measurements sensitive to stratospheric temperature like TOMS, OMI-TOMS, Dobson and Brewer, the application of a temperature correction results in the almost complete removal of the seasonal difference with SAOZ, improving significantly the consistency between all ground-based and satellite total ozone observations.

SummaryIncreased amounts of anti-neutrophil cytoplasm antibody (ANCA) directed against proteinase 3 (PR3) are a diagnostic and pathogenic hallmark of full-blown Wegener's granulomatosis (WG). Aggregates of B lymphocytes proximal to PR3+ cells as well as plasma cells have been described as substantial components of Wegener's granuloma and could participate in forming tertiary lymphoid structures, which might promote autoantibody formation. Our aim was a molecular analysis of single B cells in order to develop a methodological approach that allows examination of potential ANCA formation in the tissue. Single B cells from cryo-conserved endonasal biopsies of three WG patients were isolated, using laser-assisted microdissection. Subsequently, their immunoglobulin variable heavy (VH) and light (Vκ, Vλ) chain genes were analysed by single cell polymerase chain reaction and direct sequencing. Sixteen immunoglobulin VH-Vκ or VH-Vλ chain gene couples were characterized. Twelve of these immunoglobulin gene couples resembled memory B cells. Two offsprings of one B cell were detected, indicating clonal expansion. VH genes representing 39 single B cells of WG tissues displayed significantly more mutations when compared with VH genes from peripheral blood of a healthy donor. The findings confirm and extend our previous results, arguing for an initial selection and affinity maturation of B cells within Wegener's granuloma. Further, the methodology provides the initial basis for the recombinant generation of antibodies derived from tissue cells.

Wegener's granulomatosis (WG) is characterized by granulomatous inflammation of the respiratory tract and Anti Neutrophil Cytoplasmic Antibody (ANCA)-associated systemic vasculitis. The pathognomonic ANCA in WG is typically directed against proteinase 3 (PR3). Germinal centre-like clusters of lymphocytes were seen in granulomata of WG patients suggesting an antigen-driven maturation of B lymphocytes potentially leading to ANCA formation. The goal of this study was to develop a system to determine the specificity of B cells found in WG granulomata via the generation of fab fragments as antibody analogues. These fab fragments have the identical antigen binding site like the B-cell receptor from which the DNA was derived.Single B cells were isolated from B cell clusters within the granuloma of a WG patient by laser-assisted microdissection. Their immunoglobulin genes (VH/Vkappa, VH/Vlambda) were characterized by seminested single cell PCR and cloned into a phagemid vector in order to produce fab fragments. The fabs were characterized by protein gel electrophoresis and western blot.The immunoglobulin genes from lymphocyte infiltrates of WG granulomata reveal antigen-driven selection. On the basis of two individual couples of mutated VH/Vlambda PCR products functional fabs were generated that represent the B cell receptors of WG tissue-derived single B cells.This is the first in vitro model to test for specificity of B cell receptors from WG granulomata. With respect to ANCA origin in WG this system provides a tool to elucidate the structure-function relationship of apparently antigen-driven maturation of B cells within Wegener's granuloma.

The success of rituximab, the first monoclonal antibody ever licensed for the treatment of a human malignancy, has not only increased survival and cure rates in many non-Hodgkin lymphomas of the B-cell type, but has prompted an explosion in the development of novel antibodies and biologically active substances with specific cellular targets ("targeted therapy") both in the field of hematological malignancies and solid tumors. The chimeric anti-CD20 monoclonal antibody rituximab is the first drug that was shown to increase overall survival in follicular lymphomas and to cut lymphoma-associated deaths in patients with CD20+ aggressive lymphomas into half. In this review the current role of monoclonal antibodies in the treatment of different hematological neoplasms will be discussed and perspectives for their future use in leukemia and lymphomas will be shown.

Plague, or the Black Death, is a zoonotic disease that is spread from mammal to mammal by fleas. This mode of transmission demands that the causative agent of this disease, Yersinia pestis, is able to survive and multiply in both mammals and insects. In recent years the complete genome sequence of a number of Y. pestis strains have been determined. This sequence information indicates that Y. pestis contains a cluster of genes with homology to insecticidal toxin encoding genes of the insect pathogen Photorhabdus luminescens. Here we demonstrate that Y. pestis KIM strains produced the encoded proteins. Production of the locus-encoded proteins was dependent on a gene (yitR) encoding a member of the LysR family of transcriptional activators. Evidence suggests the proteins are type III secretion substrates. N terminal amino acids (100 to 367) of each protein fused to an epitope tag were secreted by the virulence plasmid type III secretion type. A fusion protein comprised of the N-terminus of YipB and the enzymatic active component of Bordetella pertussis adenylate cyclase (Cya) was translocated into both mammalian and insect cells. In conclusion, a new class of Y. pestis type III secreted and translocated proteins has been identified. We hypothesize that these proteins function to promote transmission of and infection by Y. pestis.

The micro-SDLA balloonborne diode laser spectrometer was flown twice from Bauru (22° S, Brazil) in February 2004 during HIBISCUS to yield in situ H2O measurements in the Upper Troposphere (UT) and Lower Stratosphere (LS) and in particular in the Tropical Tropopause Layer (TTL). The overall TTL was found warmer (with a subsaturated cold point near –79°C) and the LS moister compared to former measurements obtained in tropical oceanic conditions. The use of specific balloons with a slow descent, combined with the high-resolution of the laser sensor, allowed us to observe in situ in the UT, the TTL and the LS several thin layers correlated on H2O, CH4, O3, temperature and PV. A component of these layers is associated with the isentropic transport into the UT- LS of extratropical stratospheric air masses. Moreover, the examination of temperature and tracer (CH4, O3) profiles gives insights on the potential contribution of convective transport of H2O in the TTL.