Improving time-dependent parameters of magnetic field models

An important part of modelling the Earth's magnetic field is to accurately characterise its temporal variation, in particular the secular variation, and secular acceleration. These quantities are sensitive to the data selection and the time-dependent parameterisation and we present modifications to these strategies. When selecting satellite data for magnetic field modelling it is normal practice to use less disturbed data collected when the local time is between certain hours during the night and perhaps additionally when the data are not sunlit. However this approach results in gaps in the temporal data distribution which are likely to compromise the model parameters that depend on time. If the solar zenith angle is also a selection criterion, parameters which depend on location will also be compromised as an annual signal is introduced into the data distribution at high latitudes. Here we strive for a more continuous coverage in time. Rather than eliminating large amounts of data which are normally considered to be too noisy to include in the model, we downweight these data. This builds on work done previously involving small-scale noise

Investigation of acyl transfer auxiliary-assisted glycoconjugation for glycoprotein semi-synthesis

Homogeneous glycoprotein syntheses have become possible in the last decade due to advances in chemical ligation strategies, particularly Native Chemical Ligation (NCL). For native glycoproteins this still requires laborious and technically challenging syntheses of glycopeptide components, combined with multi-segment ligation reactions. Here we explore new reactions between sugar-linked acyl transfer auxiliaries and peptide thioesters. We show that native glycoproteins are difficult to produce using this approach but various related analogues are accessible. The results show that site-specific neoglycoconjugation is a viable route to simply glycosylated proteins, which may be extended using well-documented enzymatic processes

Peptide Fragments of a β-Defensin Derivative with Potent Bactericidal Activity

β-Defensins are known to be both antimicrobial and able to chemoattract various immune cells. Although the sequences of paralogous genes are not highly conserved, the core defensin structure is retained. Defb14-1C(V) has bactericidal activity similar to that of its parent peptide (murine β-defensin Defb14) despite all but one of the canonical six cysteines being replaced with alanines. The 23-amino-acid N-terminal half of Defb14-1C(V) is a potent antimicrobial while the C-terminal half is not. Here, we use a library of peptide derivatives to demonstrate that the antimicrobial activity can be localized to a particular region. Overlapping fragments of the N-terminal region were tested for their ability to kill Gram-positive and Gram-negative bacteria. We demonstrate that the most N-terminal fragments (amino acids 1 to 10 and 6 to 17) are potent antimicrobials against Gram-negative bacteria whereas fragments based on sequence more C terminal than amino acid 13 have very poor activity against both Gram-positive and -negative types. We further test a series of N-terminal deletion peptides in both their monomeric and dimeric forms. We find that bactericidal activity is lost against both Gram types as the deletion region increases, with the point at which this occurs varying between bacterial strains. The dimeric form of the peptides is more resistant to the peptide deletions, but this is not due just to increased charge. Our results indicate that the primary sequence, together with structure, is essential in the bactericidal action of this β-defensin derivative peptide and importantly identifies a short fragment from the peptide that is a potent bactericide

The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator

Mdc1 is a large modular phosphoprotein scaffold that maintains signaling and repair complexes at double-stranded DNA break sites. Mdc1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with the tail of γH2AX following DNA damage, but the role of the N-terminal forkhead-associated (FHA) domain remains unclear. We show that a major binding target of the Mdc1 FHA domain is a previously unidentified DNA damage and ATM-dependent phosphorylation site near the N-terminus of Mdc1 itself. Binding to this motif stabilizes a weak self-association of the FHA domain to form a tight dimer. X-ray structures of free and complexed Mdc1 FHA domain reveal a ‘head-to-tail' dimerization mechanism that is closely related to that seen in pre-activated forms of the Chk2 DNA damage kinase, and which both positively and negatively influences Mdc1 FHA domain-mediated interactions in human cells prior to and following DNA damag

The Human Cathelicidin LL-37 Has Antiviral Activity against Respiratory Syncytial Virus

Respiratory syncytial virus is a leading cause of lower respiratory tract illness among infants, the elderly and immunocompromised individuals. Currently, there is no effective vaccine or disease modifying treatment available and novel interventions are urgently required. Cathelicidins are cationic host defence peptides expressed in the inflamed lung, with key roles in innate host defence against infection. We demonstrate that the human cathelicidin LL-37 has effective antiviral activity against RSV in vitro, retained by a truncated central peptide fragment. LL-37 prevented virus-induced cell death in epithelial cultures, significantly inhibited the production of new infectious particles and diminished the spread of infection, with antiviral effects directed both against the viral particles and the epithelial cells. LL-37 may represent an important targetable component of innate host defence against RSV infection. Prophylactic modulation of LL-37 expression and/or use of synthetic analogues post-infection may represent future novel strategies against RSV infection

Audio-Visual Speech Timing Sensitivity Is Enhanced in Cluttered Conditions

Events encoded in separate sensory modalities, such as audition and vision, can seem to be synchronous across a relatively broad range of physical timing differences. This may suggest that the precision of audio-visual timing judgments is inherently poor. Here we show that this is not necessarily true. We contrast timing sensitivity for isolated streams of audio and visual speech, and for streams of audio and visual speech accompanied by additional, temporally offset, visual speech streams. We find that the precision with which synchronous streams of audio and visual speech are identified is enhanced by the presence of additional streams of asynchronous visual speech. Our data suggest that timing perception is shaped by selective grouping processes, which can result in enhanced precision in temporally cluttered environments. The imprecision suggested by previous studies might therefore be a consequence of examining isolated pairs of audio and visual events. We argue that when an isolated pair of cross-modal events is presented, they tend to group perceptually and to seem synchronous as a consequence. We have revealed greater precision by providing multiple visual signals, possibly allowing a single auditory speech stream to group selectively with the most synchronous visual candidate. The grouping processes we have identified might be important in daily life, such as when we attempt to follow a conversation in a crowded room

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%–11.2% (reference value  6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder