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"Jordan, Paul"
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How to start, carry on and end conversations : scripts for social situations for people on the autism spectrum
\"In this book, Paul Jordan, who is on the autism spectrum, explains how to make sense of everyday social situations you might encounter at school, university or in other group settings. He reveals how, with the use of just 65 simple words, it is possible to create 'scripts for thinking' that break conversations down into small chunks and help you to think of what to say, whether you are speaking to a fellow student, starting a conversation with a new friend, calling out bullies or answering a teacher's question.\"--Amazon.com.
Book
Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase
Paramyxoviruses represent a family of RNA viruses causing significant human diseases. These include measles virus, the most infectious virus ever reported, in addition to parainfluenza virus, and other emerging viruses. Paramyxoviruses likely share common replication machinery but their mechanisms of RNA biosynthesis activities and details of their complex polymerase structures are unknown. Mechanistic and functional details of a paramyxovirus polymerase would have sweeping implications for understanding RNA virus replication and for the development of new antiviral medicines. To study paramyxovirus polymerase structure and function, we expressed an active recombinant Nipah virus (NiV) polymerase complex assembled from the multifunctional NiV L protein bound to its phosphoprotein cofactor. NiV is an emerging highly pathogenic virus that causes severe encephalitis and has been declared a global public health concern due to its high mortality rate. Using negative-stain electron microscopy, we demonstrated NiV polymerase forms ring-like particles resembling related RNA polymerases. We identified conserved sequence elements driving recognition of the 3'-terminal genomic promoter by NiV polymerase, and leading to initiation of RNA synthesis, primer extension, and transition to elongation mode. Polyadenylation resulting from NiV polymerase stuttering provides a mechanistic basis for transcription termination. It also suggests a divergent adaptation in promoter recognition between pneumo- and paramyxoviruses. The lack of available antiviral therapy for NiV prompted us to identify the triphosphate forms of R1479 and GS-5734, two clinically relevant nucleotide analogs, as substrates and inhibitors of NiV polymerase activity by delayed chain termination. Overall, these findings provide low-resolution structural details and the mechanism of an RNA polymerase from a previously uncharacterized virus family. This work illustrates important functional differences yet remarkable similarities between the polymerases of nonsegmented negative-strand RNA viruses.
Journal Article
Jordan
\"This is the only Jordan guide with Arabic script next to every place name and with expanded coverage of adventure pursuits including trekking by horse or camal, hiking, canyoning and ecotourism opportunities.\"--Publisher's description.
BOOK
Nucleosides for the treatment of respiratory RNA virus infections
Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.
Journal Article
Oscar G. Rejlander : artist photographer
A fascinating survey of the varied career of an inventive and influential 19th-century photographer, from allegorical montage to Darwin's catalogue of emotions. Oscar G. Rejlander (1813-1875) was a Swedish-born photographer who pioneered the genre of art photography. He is best known for combining negatives to form elaborate allegorical compositions and for his ability to communicate expression through his photographic studies and portraits. His influence shines in the works of other important photographers of the day. This catalogue accompanies the first major retrospective on this vital yet understudied figure and considers the whole range of his activities, including his work as a painter and printmaker. Lori Pauli introduces Rejlander with a comprehensive survey of his life and career. Three essays follow, from leading scholars in the field of 19th-century photography, with topics ranging from Rejlander's engagement with Victorian painting, to his studio and working methods, to his artistic circle and work with Charles Darwin. Engagingly written and beautifully illustrated, this publication fills a void in scholarship on Rejlander; it also sheds light more broadly on the intersection of art and science and the uses of photography in Victorian culture, as well as the history of photography and its impact on Victorian culture.
BOOK
Self-assembling biomolecular catalysts for hydrogen production
The chemistry of highly evolved protein-based compartments has inspired the design of new catalytically active materials that self-assemble from biological components. A frontier of this biodesign is the potential to contribute new catalytic systems for the production of sustainable fuels, such as hydrogen. Here, we show the encapsulation and protection of an active hydrogen-producing and oxygen-tolerant [NiFe]-hydrogenase, sequestered within the capsid of the bacteriophage P22 through directed self-assembly. We co-opted
Escherichia coli
for biomolecular synthesis and assembly of this nanomaterial by expressing and maturing the EcHyd-1 hydrogenase prior to expression of the P22 coat protein, which subsequently self assembles. By probing the infrared spectroscopic signatures and catalytic activity of the engineered material, we demonstrate that the capsid provides stability and protection to the hydrogenase cargo. These results illustrate how combining biological function with directed supramolecular self-assembly can be used to create new materials for sustainable catalysis.
The encapsulation and stabilization of an oxygen tolerant [NiFe]-hydrogenase, sequestered within the bacteriophage P22 capsid, has now been achieved through a directed self-assembly process. Probing the catalytic activity and infrared spectroscopic signatures of the bio-inspired assembly shows that the capsid provides stability and protection to the hydrogenase cargo.
Journal Article
Establishment and Characterization of Mild Atopic Dermatitis in the DNCB-Induced Mouse Model
In dermatological research, 2,4-dinitrochlorbenzene (DNCB)-induced atopic dermatitis (AD) is a standard model as it displays many disease-associated characteristics of human AD. However, the reproducibility of the model is challenging due to the lack of information regarding the methodology and the description of the phenotype and endotype of the mimicked disease. In this study, a DNCB-induced mouse model was established with a detailed procedure description and classification of the AD human-like skin type. The disease was induced with 1% DNCB in the sensitization phase and repeated applications of 0.3% and 0.5% DNCB in the challenging phase which led to a mild phenotype of AD eczema. Pathophysiological changes of the dorsal skin were measured: thickening of the epidermis and dermis, altered skin barrier proteins, increased TH1 and TH2 cytokine expression, a shift in polyunsaturated fatty acids, increased pro-resolving and inflammatory mediator formation, and dysregulated inflammation-associated gene expression. A link to type I allergy reactions was evaluated by increased mast cell infiltration into the skin accompanied by elevated IgE and histamine levels in plasma. As expected for mild AD, no systemic inflammation was observed. In conclusion, this experimental setup demonstrates many features of a mild human-like extrinsic AD in murine skin.
Journal Article
Differential impact of 5-lipoxygenase-activating protein antagonists on the biosynthesis of leukotrienes and of specialized pro-resolving mediators
Lipoxygenases (LOX) transform arachidonic acid (AA, C20:4) and docosahexaenoic acid (DHA, C22:6) into bioactive lipid mediators (LMs) that comprise not only pro-inflammatory leukotrienes (LTs) but also the specialized pro-resolving mediators (SPMs) that promote inflammation resolution and tissue regeneration. The 5-LOX-activating protein (FLAP) is known to provide AA as a substrate to 5-LOX for generating LTs, such as LTB 4 , a potent chemoattractant and activator of phagocytes. Notably, 5-LOX is also involved in the biosynthesis of certain SPMs, namely, lipoxins and D-resolvins, implying a role of FLAP in SPM formation. FLAP antagonists have been intensively developed as LT biosynthesis inhibitors, but how they impact SPM formation is a matter of debate. Here, we show that FLAP antagonism suppresses the conversion of AA by 5-LOX to LT and lipoxins, while the conversion of DHA to SPM is unaffected. Screening of multiple prominent FLAP antagonists for their effects on LM formation in human M1- and M2-monocyte-derived macrophages by comprehensive LM profiling showed that all nine compounds reduced the production of 5-LOX-derived LTs but increased the formation of SPMs from DHA, e.g., resolvin D5. Some FLAP antagonists, especially those that contain an indole or benzimidazole moiety, even elicited SPM formation in resting M2-monocyte-derived macrophages. Intriguingly, in coincubations of human neutrophils and platelets that produce substantial AA-derived lipoxin and DHA-derived RvD5, FLAP antagonism abolished lipoxin formation, but resolvin D5 levels remained unaffected. Conclusively, antagonism of FLAP suppresses the conversion of AA by 5-LOX to LTs and lipoxins but not the conversion of DHA by 5-LOX to SPM, which should be taken into account for the development of such compounds as anti-inflammatory drugs.
Journal Article
Listen to the residents! How to develop sustainable and successful urban mobility concepts
Background
Urbanization is progressing rapidly, with over 65% of the world’s population projected to live in urban areas by 2050. This population shift is expected to lead to several environmental and social challenges. As a result, many urban development projects are being implemented with accompanying mobility concepts. However, there is limited knowledge regarding mobility services that meet the residents’ needs. This understanding is essential for advancing new mobility concepts in urban areas that consider the respective socioecological context. Therefore, this paper is dedicated to exploring and exemplifying the mobility behaviors and personas prevalent in nascent urban areas.
Results
For this purpose, a quantitative survey was carried out (
n
= 376) to measure mobility behavior and 11 specific mobility needs in three nascent urban quarters in Germany and Austria. The highest-rated mobility needs across quarters were reliability, convenience, and safety. In contrast, the least important mobility needs were orientation, social recognition, and entertainment. A cluster analysis of mobility needs and behaviors (using Ward’s method and k-means) suggests the prevalence of five mobility personas. While the personas differed by demographics and mobility behavior, they were similarly distributed across quarters.
Conclusions
In summary, this article highlights which mobility needs should be addressed and proposes strategies for targeting individual mobility personas. Overall, mobility concepts should prioritize reliable, shared transportation, as many individuals continue to rely on car ownership due to a lack of reliable alternatives. Therefore, the findings help facilitate the transition to more sustainable and socially acceptable forms of mobility in urban areas.
Journal Article
A Phase I Study to Assess the Effect of Speed of Injection on Pain, Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers
Gantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab.
This randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated.
Immediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups.
Subcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009.
Journal Article