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Calcium fluoride is the ultimate source of all fluorochemicals. Current synthetic approaches rely on the use of HF, generated from naturally occurring fluorspar and sulfuric acid. Methods for constructing E–F bonds directly from CaF2have long been frustrated by its high lattice energy, low solubility and impaired fluoride ion nucleophilicity. Little fundamental understanding of the reactivity of Ca–F moieties is available to guide methodology development; well-defined molecular species containing Ca–F bonds are extremely rare, and existing examples are strongly aggregated and evidence no nucleophilic fluoride delivery. Here, by contrast, we show that by targeting anionic systems of the type [Ln(X)2CaF]−, monomeric calcium fluoride complexes containing single Ca–F bonds can be synthesized, including via routes involving fluoride abstraction from existing C–F bonds. Comparative structural and spectroscopic studies of mono- and dinuclear systems allow us to define structure–activity relationships for E–F bond formation from molecular calcium fluorides.

Rare diseases (RD) have a prevalence of not more than 1/2000 persons in the European population, and are characterised by the difficulty experienced in obtaining a correct and timely diagnosis. According to Orphanet, 72.5% of RD have a genetic origin although 35% of them do not yet have an identified causative gene. A significant proportion of patients suspected to have a genetic RD receive an inconclusive exome/genome sequencing. Working towards the International Rare Diseases Research Consortium (IRDiRC)’s goal for 2027 to ensure that all people living with a RD receive a diagnosis within one year of coming to medical attention, the Solve-RD project aims to identify the molecular causes underlying undiagnosed RD. As part of this strategy, we developed a phenotypic similarity-based variant prioritization methodology comparing submitted cases with other submitted cases and with known RD in Orphanet. Three complementary approaches based on phenotypic similarity calculations using the Human Phenotype Ontology (HPO), the Orphanet Rare Diseases Ontology (ORDO) and the HPO-ORDO Ontological Module (HOOM) were developed; genomic data reanalysis was performed by the RD-Connect Genome-Phenome Analysis Platform (GPAP). The methodology was tested in 4 exemplary cases discussed with experts from European Reference Networks. Variants of interest (pathogenic or likely pathogenic) were detected in 8.8% of the 725 cases clustered by similarity calculations. Diagnostic hypotheses were validated in 42.1% of them and needed further exploration in another 10.9%. Based on the promising results, we are devising an automated standardized phenotypic-based re-analysis pipeline to be applied to the entire unsolved cases cohort.

The article enumerates five of the most important things that school leaders should know about and be able to do with data. Topics include the uses of data for educators, the need for everyone for data to answer questions and make informed decisions, and different concepts represented by privacy, security, and confidentiality.

Recent technological developments may facilitate the description of evolutionary relationships and population genetic structure as well as other information relevant to fisheries management by using readily available natural history collections. Contemporary sequence capture and short‐read sequencing methods offer opportunities to analyze highly fragmented DNA from formalin‐fixed specimens so long as enough DNA of sufficient quality is recovered. We compared two protocols developed to extract DNA from formalin‐fixed tissues using specimens of three freshwater fishes: the Southern Brook Lamprey Ichthyomyzon gagei, Slimy Sculpin Cottus cognatus, and Brown Trout Salmo trutta. Extractions were attempted using hot alkali digestion with and without buffer wash pretreatments to compare the DNA concentration, purity, and fragment length of DNA recovered between extraction protocols, tissue types (muscle and caudal fin tissue for Brown Trout and Slimy Sculpin), and preservation periods (5 or 7 years for Southern Brook Lamprey). Likelihood models generally did not detect DNA quantity differences between extraction protocols nor tissue types; however, 6.0–8.7× more DNA was recovered from Slimy Sculpin caudal fins than from muscle tissue. Extraction protocol had mixed effects on DNA purity; the wash protocol outperformed the no‐wash protocol for Slimy Sculpin and Brown Trout, but the reverse was true for the lamprey. Purer DNA was recovered from the caudal fins; however, fragment lengths were generally greater from muscle tissue for both ray‐finned species. Our results suggest that the best tissue for sampling may depend on the quality metric considered most important for a study's objectives and that omitting time‐consuming tissue wash steps can yield DNA of quantity and quality comparable to DNA from more complex methods. Regardless of species, the DNA extracted from most samples using both protocols met quantity and quality thresholds that are likely to result in short‐read sequencing success. These results provide optimism for unlocking the wealth of genetic information in natural history collections for use in fisheries management and conservation genomics. Impact statementContemporary sequence capture and short‐read sequencing methods may facilitate inference of evolutionary relationships, population genetic structure, and other information relevant to fisheries management from formalin‐fixed natural history collections as long as enough DNA of sufficient quality is recovered. We assessed extraction protocols for two ray‐finned fishes and one lamprey, and determined factors likely to result in sequencing success. Contemporary sequence capture and short‐read sequencing methods may facilitate inference of evolutionary relationships, population genetic structure, and other information relevant to fisheries management from formalin‐fixed natural history collections as long as enough DNA of sufficient quality is recovered. We assessed extraction protocols for two ray‐finned fishes and one lamprey, and determined factors likely to result in sequencing success.

The Enhanced Recovery After Surgery (ERAS) protocol represents an advancement in perioperative care to reduce surgical stress and accelerate recovery. This meta-analysis evaluates the effectiveness of ERAS in pancreatic surgery.

Platooning is a cooperative driving technology for driving in a longitudinal formation. Vehicle-to-vehicle (V2V) communication is the key enabling technology. Platooning is considered to be a closed application between well-known participants that use V2V data for their operation. For the deployment of platooning, multi-brand, i.e. interoperable, solutions are paramount. To achieve this, the European ENSEMBLE (ENabling SafE Multi-Brand pLatooning for Europe) project has been conducted. In this project, multi-brand specifications have been harmonized to a set of common specifications and requirements for a generic Platooning Support Function (PSF). Part of the specifications is a common interaction protocol, which also encompasses security features. A reference design has been developed to initially check the specifications. It consists of a detailed design of the common functionality and includes software and communication sub-system hardware prototypes. This reference design has also been used as benchmark for brand-specific implementations, e.g. in communication plug tests. Daimler Truck included the reference design directly in their PSF implementation, which gave the opportunity to continuously develop the reference design during the project. In this paper, the ‘final’ reference design is described as implemented in the Daimler truck, which took part in the verification, validation and demonstration of multi-brand platooning together with six other truck manufacturers.

The reactions of anionic aluminium or gallium nucleophiles {K[E(NON)]}2(E = Al, 1; Ga, 2; NON = 4,5-bis(2,6-diisopropylanilido)-2,7-ditert-butyl-9,9-dimethylxanthene) with beryllocene (BeCp2) led to the displacement of one cyclopentadienyl ligand at beryllium and the formation of compounds containing Be–Al or Be–Ga bonds (NON)EBeCp (E = Al, 3; Ga, 4). The Be–Al bond in the beryllium–aluminyl complex [2.310(4) Å] is much shorter than that found in the small number of previous examples [2.368(2) to 2.432(6) Å], and quantum chemical calculations suggest the existence of a non-nuclear attractor (NNA) for the Be–Al interaction. This represents the first example of a NNA for a heteroatomic interaction in an isolated molecular complex. As a result of this unusual electronic structure and the similarity in the Pauling electronegativities of beryllium and aluminium, the charge at the beryllium center (+1.39) in 3is calculated to be less positive than that of the aluminium center (+1.88). This calculated charge distribution suggests the possibility for nucleophilic behavior at beryllium and correlates with the observed reactivity of the beryllium–aluminyl complex with N,N′-diisopropylcarbodiimide─the electrophilic carbon center of the carbodiimide undergoes nucleophilic attack by beryllium, thereby yielding a beryllium–diaminocarbene complex.

How well do futures prices forecast the spot price of crude oil? Contrary to the established view, futures prices significantly improve upon the accuracy of monthly no-change forecasts. This results from two innovations. First, we document that independent of the construction of futures-based forecasts, longer-horizon futures prices have become better predictors of crude oil spot prices since the mid-2000s. Second, we show that futures curves constructed using end-of-month prices instead of average prices have consistently been able to generate large accuracy-improvements for short-horizon forecasts of average prices. These findings are remarkably robust and apply to all major crude oil benchmarks.

Demographic parameters are key to understanding population dynamics. Here, we analyse the survival and reproduction of the German wolf population in the 20 years following recolonization. Specifically, we analysed the effects of environmental, ecological and individual characteristics on 1) survival probability of the population; 2) annual survival rates of age classes; 3) reproduction probability; and 4) reproductive output, measured as the number of detected pups/juveniles. Using Cox proportional hazards model, we estimated a median survival time of circa three years for wolves. Annual survival probabilities were found to be 0.75 for juveniles, 0.75 for subadults and 0.88 for adults. Survival was lower for juveniles in winter and for subadult males in summer, probably associated with dispersal events. Low habitat suitability was clearly associated with lower survival in juveniles and subadults, but not in adults. Local territory density was related to increased survival. Reproduction probability within a territory was 0.88, but explanatory variables had no effect. Reproductive output was four pups/juveniles on average, positively related to habitat suitability and female experience, but negatively related to territory density. Survival values were very high for the species when compared to other regions. We hypothesize that carrying capacity has not been reached in the study area, thus the survival may decrease in the future if the landscape becomes saturated. Furthermore, our results highlight a spatial pattern in survival and reproduction, with area of better habitat suitability favouring faster population growth. Thus, targeting conservation measures to low habitat suitability areas will have a strong population effect on the short term by boosting survival and reproduction of the individuals, while long‐term viability should be carefully planned with high suitability areas in mind, as those contain the territories with higher survival and reproduction potential.

Background:Host genetic factors play a major role with respect to susceptibility to infections. Many polymorphisms of the Toll-like receptors (TLRs), members of the innate immune response, are directly associated with the clinical outcomes following infection. The 2848 G/A variant (rs352140) of the TLR9gene is associated with increased TLR9 expression. However, the impact of the genotypes of this SNP on HIV+, HCV+, and HCV+/HIV+ individuals is still debated.Materials and Methods:This study investigated the 2848 G/A polymorphism in HCV infection, HIV infection, and HCV/HIV co-infection in a large sample of Brazilians (n= 1,182). Groups were initially compared without considering stratification by ethnicity and subsequently stratifying individuals between whites and non-whites.Results:Considering non-white individuals, a significant difference between the HIV+/HCV+ group and controls was observed with the GG genotype serving as a protective factor (p= 0.023). Additionally, significant allelic differences were observed between the HCV+ group and controls (p= 0.042); between the HIV+/HCV+ group and controls (p= 0.011); and between the HIV+/HCV+ group and HIV+ individuals (p= 0.047). However, all significant results were lost following adjustment for multiple comparisons (p> 0.05).Conclusion:Although our initial results indicated a potential influence of the rs352140 genotype on host altered susceptibility to viral infections, following correction for multiple comparisions the standard (p< 0.05) for statistical association was lost. This may be due to insufficient sample size as we were examining many different associations. Thus, a larger study is warranted to further pursue this topic.

Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE®) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient’s data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.

The article offers information on importance to use data to assess student growth. Topics discussed include information on importance of growth data to measure of student growth in their accountability system under the Every Student Succeeds Act ; information on Student Growth Percentile (SGP) that reflects whether or not a student does better than his or her peers; and need to demonstrate the value of data for meeting goals by modeling effective data use.

ABSTRACTRedirection of immune cells to efficiently eliminate tumor cells holds great promise. Natural killer cells (NK), macrophages, or T cells are specifically engaged with target cells expressing markers after infection or neoplastic transformation, resulting in their activation and subsequent killing of those targets. Multiple strategies to redirect immunity have been developed in the past two decades, but they have technical hurdles or cause undesirable side-effects, as exemplified by the T cell-based chimeric antigen receptor approaches (CAR-T therapies) or bispecific T cell engager platforms. Our first-in-class bispecific antibody redirecting innate immune cells to tumors (AFM13, a CD30/CD16A-specific innate immune cell engager) has shown signs of clinical efficacy in CD30-positive lymphomas and the potential to be safely administered, indicating a wider therapeutic window compared to T cell engaging therapies. AFM13 is the most advanced candidate from our fit-for-purpose redirected optimized cell killing (ROCK®) antibody platform, which comprises a plethora of CD16A-binding innate immune cell engagers with unique properties. Here, we discuss aspects of this modular platform, including the advantages of innate immune cell engagement over classical monoclonal antibodies and other engager concepts. We also present details on its potential to engineer a fit-for-purpose innate immune cell engager format that can be equipped with unique CD16A domains, modules that influence pharmacokinetic properties and molecular architectures that influence the activation of immune effectors, as well as tumor targeting. The ROCK® platform is aimed at the activation of innate immunity for the effective lysis of tumor cells and holds the promise of overcoming limitations of other approaches that redirect immune cells by widening the therapeutic window.

•Tick-human interactions evoke complex chemokines-mediated inflammatory reactions.•Host genetics influence the susceptibility to TBEV infection and disease progression.•CD209, GSTM1, IL-10, IL-28B, MMP9, OAS2, OAS3and TLR3genes impact on TBEV infection.•CCR5 protein/gene and CCR5 ligands mediate the immune response against TBEV infection.•CCR5Δ32 modifies the CCR5-mediated immune response against TBEV infection.

ABSTRACTA challenge when developing therapeutic antibodies is the identification of candidates with favorable pharmacokinetics (PK) early in development. A key determinant of immunoglobulin (IgG) serum half‑life in vivois the efficiency of pH-dependent binding to the neonatal Fc receptor (FcRn). Numerous studies have proposed techniques to assess FcRn binding of IgG-based therapeutics in vitro, enabling prediction of serum half-life prior to clinical assessment. FcRn high-performance liquid chromatography (HPLC) assays FcRn binding of therapeutic IgGs across a pH gradient, allowing the correlation of IgG column retention time to the half‑life of a therapeutic IgG in vivo. However, as FcRn retention time cannot be directly compared to an in vivoparameter, modifications to FcRn-HPLC are required to enable interpretation of the data within a physiological context, to provide more accurate estimations of serum half-life. This study presents an important modification to this method, FcRn-pH-HPLC, which reproducibly measures FcRn dissociation pH, allowing correlation with previously established half-lives of therapeutic antibodies. Furthermore, the influence of incorporating various antibody modifications, binding modules, and their orientations within IgGs and bispecifics on FcRn dissociation pH was evaluated using antibodies from the redirected optimized cell killing (ROCK®) platform. Target and effector antigen-binding domain sequences, their presentation format and orientation within a bispecific antibody alter FcRn retention; tested Fc domain modifications and incorporating stabilizing disulfide bonds had minimal effect. This study may inform the generation of mono-, bi- and multi-specific antibodies with tailored half-lives based on FcRn binding properties in vitro, to differentiate antibody-based therapeutic candidates with optimal developability.

Over‐deepened basins exist throughout the Alpine realm. Improving our knowledge on these basins is of high social relevance, since these areas are often well‐populated and they possess, for instance, unusual hydrological settings. Nonetheless, geophysical and sedimentological investigations of over‐deepened basins are rare. We analyse the sedimentary succession of such a basin, the Tannwald Basin, through geological interpretation of seismic reflection profiles. The basin is located approximately 60 km north of the European Alps. It was incised into Tertiary molasse sediments by the Rhine Glacier and later filled by glacial, fluvial, and lacustrine deposits of 250 m thickness. The Leibniz Institute for Applied Geophysics acquired a grid of five high‐resolution seismic reflection lines that imaged till the deepest parts of the Tannwald Basin. The seismic profiles, processed to a pre‐stack depth migration level, allow a detailed geological interpretation that is calibrated with the help of a nearby borehole. We determine the structure and the seismic facies of the sediment succession in the basin and presume the following hypothesis of the evolution of the basin: sub‐glacial erosion comprises the excavation of the over‐deepened basin as well as detachment of large fragments of molasse material. These molasse slabs were deposited within the basin in a layer of basal till that graded upwards in water‐lain till and fine‐grained deposits. During the last two glaciations, the basinal structure became buried by till sequences and glacio‐fluvial sediments.

Kurzfassung:In der vorliegenden Arbeit wird die Gliederung des Quartärs, wie sie in der Stratigraphischen Tabelle von Deutschland 2016 (STD 2016) vorgenommen wurde, erläutert. Im Allgemeinen werden nur Veränderungen gegenüber der STD 2002 kommentiert, für detaillierte Erläuterungen und Literatur siehe Doppler et al. (2011), Ellwanger et al. (2011), Litt et al. (2005), Litt (2007a), Preusser et al. (2011), Van Husen & Reitner (2011) sowie die entsprechenden Definitionen im LithoLex (litholex.bgr.de).Abstract:This paper comments on the stratigraphic division of the Quaternary as made in the Stratigraphic Table of Germany 2016 (STD 2016). In general only modifications to STD 2002 are illustrated, for detailed explanations and references see Doppler et al. (2011), Ellwanger et al. (2011), Litt et al. (2005), Litt (2007a), Preusser et al. (2011), Van Husen & Reitner (2011) and the corresponding definitions in LithoLex (litholex.bgr.de).

Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism, and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned.

ABSTRACTMost analyses of public opinion polling focus on questions of bias or accuracy. In contrast, this study assumes the validity of polling and instead investigates polling data as a form of rhetorical argument. While ancient and modern traditions conceive of doxaas unstated collective opinion, modern opinion polling represents a transformation of the concept of doxain deliberative democracies. By analyzing specific polls, polling data is shown to advance implicit claims about public policy and good governance. Thus, polling data do not embody an objective empirical artifact, but rather a form of deliberative argumentation that is at odds with democratic life. The study concludes by advocating a revitalization of the public culture of contestation and by discussing more indirect, intuitive means of assessing larger opinion trends.

In hippocampal neurons, Ras and Rab interactor 1 (RIN1) hinders the formation of stable synaptic connections by increasing dendritic filopodial motility and regulates long-term depression by enhancing AMPA receptor endocytosis.

This study describes the development of α-bisabolol-loaded lipid-core nanocapsules (α-BLNC) and Cocoa-theospheres (α-BCT), aiming oral use for gastroprotection. α-Bisabolol was efficiently encapsulated in high drug loading (25%) in lipid-core nanocapsules and cocoa-theospheres. Laser diffraction analysis showed nanometric and unimodal distributions (mean diameters of 216 and 148 nm, respectively). The gastroprotective indexes in rats for the ethanol-induced ulcers were 0.11 (α-BCT), 0.68 (blank-CT), 0.29 (α-BLNC) and 0.37 (blank-LNC), while for the indomethacin-induced ulcer model, the results were 37.33 (α-BCT), 48.14 (blank-CT), 31.33 (α-BLNC) and 45.33 (blank-LNC). SEM analysis of the stomach mucosa showed more homogenous and cohesive coatings for α-BLNC and α-BCT treatments in comparison with the blank formulations. In histological evaluations, protection against the tissue damage and Periodic Acid-Schiff-positive increase were observed after the pretreatment with α-bisabolol nanoparticles in ethanol and indomethacin-induced ulcers. α-Bisabolol-loaded in cocoa-theospheres provided a gastroprotective effect absent in blank-cocoa-theospheres, while the drug-loaded lipid-core nanocapsules maintained the gastroprotective effect observed for blank lipid-core nanocapsules, which are per seantioxidant agents. The nanoencapsulation enabled a dose reduction of α-bisabolol. Moreover, lipid-core nanocapsules and cocoa-theospheres have mucoadhesive properties even though they present diverse supramolecular structures. Both lipid-core nanocapsules and cocoa-theospheres are promising platforms for the development of prophylactic formulations.

We hypothesized that the use of oxygen supplementation during aerobic exercise induces less DNA damage than exercise alone. The aim of this study is to assess the level of DNA damage induced by physical exercise with and without oxygen supplementation in chronic obstructive pulmonary diseases (COPD) patients. Peripheral blood was collected before and after aerobic exercise in two conditions: (I) aerobic exercise without oxygen supplementation (AE group) and (II) with oxygen supplementation (AE-O2group). Lymphocytes were collected to perform the alkaline version of the Comet Assay. To assess the susceptibility to exogenous DNA damage, the lymphocytes were treated with methyl methanesulphonate (MMS) for 1-h or 3-h. After 3-h treatment, the percentage of residual damage was calculated assuming the value of 1-h MMS treatment as 100%. AE group showed lower induced damage (1 h of MMS treatment) and consequently less DNA repair compared to AE-O2group. AE-O2group showed an increase in the induced DNA damage (1 h of MMS treatment) and an increased DNA repair capacity. Within the AE-O2group, in the post-exercise situation the induced DNA damage after 1 h of MMS treatment was higher (p= 0.01) than in the pre-exercise. COPD patients who performed physical exercise associated with oxygen supplementation had a better response to DNA damage induced by MMS and a better DNA repair when compared to the condition of physical exercise without oxygen supplementation. UNISC N374.298. Registered 04 JUN 2013 (retrospectively registered).

Tuberculosis (TB), Lung Cancer (LC) and Chronic Obstructive Pulmonary Diseases (COPD) affect millions of individuals worldwide. Monitoring of DNA damage in pathological situations has been investigated because it can add a new dimension to clinical expression and may represent a potential target for therapeutic intervention. The aim of this study was to evaluate DNA damage and the frequency of cellular abnormalities in TB, LC and COPD patients by comparing them to healthy subjects. The detection of DNA damage by a buccal micronucleus cytome assay was investigated in patients with COPD (n= 28), LC (n= 18) and TB (n= 22) and compared to control individuals (n= 17). The COPD group had a higher frequency of apoptotic cells compared to TB and LC group. The TB group showed a higher frequency of DNA damage, defect in cytokinesis, apoptotic and necrotic cells. Patients with LC had low frequency of chromosomal aberrations than TB and COPD patients. COPD patients showed cellular abnormalities that corresponded to cell death by apoptosis and necrosis, while patients with TB presented defects in cytokinesis and dysfunctions in DNA repair that resulted in the formation of micronucleus (MN) besides apoptotic and necrotic cells. Patients with COPD, TB and LC had a low frequency of permanent DNA damage.

To harness the potent tumor-killing capacity of T cells for the treatment of CD19+malignancies, we constructed AFM11, a humanized tetravalent bispecific CD19/CD3 tandem diabody (TandAb) consisting solely of Fv domains. The molecule exhibits good manufacturability and stability properties. AFM11 has 2 binding sites for CD3 and 2 for CD19, an antigen that is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies. Comparison of the binding and cytotoxicity of AFM11 with those of a tandem scFv bispecific T cell engager (BiTE) molecule targeting the same antigens revealed that AFM11 elicited more potent in vitro B cell lysis. Though possessing high affinity to CD3, the TandAb mediates serial-killing of CD19+cells with little dependence of potency or efficacy upon effector:target ratio, unlike the BiTE. The advantage of the TandAb over the BiTE was most pronounced at lower effector:target ratios. AFM11 mediated strictly target-dependent T cell activation evidenced by CD25 and CD69 induction, proliferation, and cytokine release, notwithstanding bivalent CD3 engagement. In a NOD/scid xenograft model, AFM11 induced dose-dependent growth inhibition of Raji tumors in vivo, and radiolabeled TandAb exhibited excellent localization to tumor but not to normal tissue. After intravenous administration in mice, half-life ranged from 18.4 to 22.9 h. In a human ex vivoB-cell chronic lymphocytic leukemia study, AFM11 exhibited substantial cytotoxic activity in an autologous setting. Thus, AFM11 may represent a promising therapeutic for treatment of CD19+malignancies with an advantageous safety risk profile and anticipated dosing regimen.

The most common fixed offshore wind turbine (OWT) types are steel monopiles, jackets, tripods, and gravity-based structures (GBS). The fatigue analysis is a governing limit for these structures due to their dynamic behavior when subjected to wind and wave loads. In this article, the conceptual design, geotechnical capacity verification, and hydrodynamic load model effects on the fatigue damage of a GBS are assessed. The study is conducted for water depths ranging from 10 to 40 m, considering a parked and an operating wind turbine. The turbine model is based on the DTU’s (Technical University of Denmark) 10 MW reference OWT, and the dynamic analyses are conducted in the SIMA-RIFLEX software. Due to the large dimension of the GBS, the hydrodynamic model used to calculate the loads must be carefully chosen not to make the structure unfeasible. Among the available models, Morison's equation and the one derived from MacCamy–Fuchs' theory are the most widely used. Results show that the Brazilian environmental condition associated with MacCamy–Fuchs' model can provide a significant damage reduction for the 40 m water depth model when the turbine is both in parked and operational modes. In shallow waters (up to 25 m), the hydrodynamic forces are lower, and the turbine operation strongly influences the GBS response. However, in this case, the use of MacCamy–Fuchs’ theory can still significantly reduce the resulting fatigue damage.

The avian utricle, a vestibular organ of the inner ear, displays turnover of sensory hair cells throughout life. This is in sharp contrast to the mammalian utricle, which shows limited regenerative capacity. Here, we use single-cell RNA sequencing to identify distinct marker genes for the different sensory hair cell subtypes of the chicken utricle, which we validated in situ. We provide markers for spatially distinct supporting cell populations and identify two transitional cell populations of dedifferentiating supporting cells and developing hair cells. Trajectory reconstruction resulted in an inventory of gene expression dynamics of natural hair cell generation in the avian utricle.

By the end of 2011 Africa had 23.5 million HIV infected people and 72% of the new HIV cases globally (UNAIDS, 2012). The mainly sexual transmission of HIV in the African context is associated with stigma especially among women (Rankin et al., 2005). HIV/AIDS stigma includes negative behaviors, denial, secrecy, fear and self-blame related to the disease (Deacon, Stephney & Proslendis, 2005). HIV/AIDS stigma is associated with sexual promiscuity, hinders disclosure of serostatus, and affects uptake of preventive programs (Zungu-Dirwayi, 2004). Though there is an acknowledgement of the negative effects of HIV/AIDS stigma, there is little research that has been conducted on this pertinent issue on the African continent with the largest number of HIV infected and affected people globally. Prevention of new HIV infections require the acknowledgement of the fact that stigma is attached to disclosure of status yet seropositive people still engage in risky behaviors (Prince et al., 2006). Therefore there is need to design strategies to counteract the negative effects associated to HIV/AIDS stigma at all levels.

Independent self-construals in Western cultures may promote analytic information processing and low field dependence, while interdependent self-construals in Eastern cultures may foster holistic information processing and high field dependence. To examine these ideas, the social orientation and cognitive style of 254 introductory psychology students were measured. Multiple regression analyses indicated a non-significant relationship between the participants' social orientation and cognitive style (R2s ranged from .00 to .01, 95% confidence intervals for R2ranged from .00 to .05). These findings indicate that the hypothesis that collectivism and individualism are associated with differences in information processing between individuals needs further scrutiny. The possible reasons for the lack of association between social orientation and cognitive style are discussed.