Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1

Microcephalin‐1 (MCPH1) exists as 2 isoforms that regulate cyclin‐dependent kinase‐1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin‐dependent kinase‐1–dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase‐promoting complex/cyclosome–CDH1 E3 ligase complex. Anaphase‐promoting complex/cyclosome–CDH1 target proteins generally have D‐Box or KEN‐Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D‐Box dependent, whereas the short isoform was KEN‐Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.—Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform‐specific degradation by APC/C‐CDH1. FASEB J. 33, 2796–2808 (2019). www.fasebj.or

Measurements and Modeling of Transient Blood Flow Perturbations Induced by Brief Somatosensory Stimulation

Proper interpretation of BOLD fMRI and other common functional imaging methods requires an understanding of neurovascular coupling. We used laser speckle-contrast optical imaging to measure blood-flow responses in rat somatosensory cortex elicited by brief (2 s) forepaw stimulation. Results show a large increase in local blood flow speed followed by an undershoot and possible late-time oscillations. The blood flow measurements were modeled using the impulse response of a simple linear network, a four-element windkessel. This model yielded excellent fits to the detailed time courses of activated regions. The four-element windkessel model thus provides a simple explanation and interpretation of the transient blood-flow response, both its initial peak and its late-time behavior

Jobseekers Regime and Flexible New Deal, the Six Month Offer and Support for the Newly Unemployed evaluations: An early process study

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Prostate cancer survivorship essentials framework: guidelines for practitioners

© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd Objective: To develop contemporary and inclusive prostate cancer survivorship guidelines for the Australian setting. Participants and Methods: A four-round iterative policy Delphi was used, with a 47-member expert panel that included leaders from key Australian and New Zealand clinical and community groups and consumers from diverse backgrounds, including LGBTQIA people and those from regional, rural and urban settings. The first three rounds were undertaken using an online survey (94–96% response) followed by a fourth final face-to-face panel meeting. Descriptors for men’s current prostate cancer survivorship experience were generated, along with survivorship elements that were assessed for importance and feasibility. From these, survivorship domains were generated for consideration. Results: Six key descriptors for men’s current prostate cancer survivorship experience that emerged were: dealing with side effects; challenging; medically focused; uncoordinated; unmet needs; and anxious. In all, 26 survivorship elements were identified within six domains: health promotion and advocacy; shared management; vigilance; personal agency; care coordination; and evidence-based survivorship interventions. Consensus was high for all domains as being essential. All elements were rated high on importance but consensus was mixed for feasibility. Seven priorities were derived for immediate action. Conclusion: The policy Delphi allowed a uniquely inclusive expert clinical and community group to develop prostate cancer survivorship domains that extend beyond traditional healthcare parameters. These domains provide guidance for policymakers, clinicians, community and consumers on what is essential for step change in prostate cancer survivorship outcomes

In vivo multiphoton microscopy beyond 1 mm in the brain

The ability to visualize deep brain structures in vivo with high spatial resolution is of rising interest to investigate neuronal physiology and cerebral vasculature. Optical imaging offers non-invasive, high-resolution in vivo microscopy techniques to observe brain tissue and its surrounding environment. Two-photon fluorescence laser- scanning microscopy (2PM) can overcome depth limitations by using nonlinear excitation. The ideal approach for deep imaging in brain is to use both high energy pulses and longer excitation wavelengths. Please click Additional Files below to see the full abstract

Dimensions and Global Twist of Single-Layer DNA Origami Measured by Small-Angle X-ray Scattering

The rational design of complementary DNA sequences can be used to create nanostructures that self-assemble with nanometer precision. DNA nanostructures have been imaged by atomic force microscopy and electron microscopy. Small-angle X-ray scattering (SAXS) provides complementary structural information on the ensemble-averaged state of DNA nanostructures in solution. Here we demonstrate that SAXS can distinguish between different single-layer DNA origami tiles that look identical when immobilized on a mica surface and imaged with atomic force microscopy. We use SAXS to quantify the magnitude of global twist of DNA origami tiles with different crossover periodicities: these measurements highlight the extreme structural sensitivity of single-layer origami to the location of strand crossovers. We also use SAXS to quantify the distance between pairs of gold nanoparticles tethered to specific locations on a DNA origami tile and use this method to measure the overall dimensions and geometry of the DNA nanostructure in solution. Finally, we use indirect Fourier methods, which have long been used for the interpretation of SAXS data from biomolecules, to measure the distance between DNA helix pairs in a DNA origami nanotube. Together, these results provide important methodological advances in the use of SAXS to analyze DNA nanostructures in solution and insights into the structures of single-layer DNA origami

Asymmetric interference between cognitive task components and concurrent sensorimotor coordination

Everyday cognitive tasks are frequently performed under dual-task conditions alongside continuous sensorimotor coordinations (CSC) such as driving, walking, or balancing. Observed interference in these dual-task settings is commonly attributed to demands on executive function or attentional resources, but the time-course and reciprocity of interference are not well understood at the level of information-processing components. Here, we used electrophysiology to study the detailed chronometry of dual-task interference between a visual oddball task and a continuous visuomanual tracking task. The oddball task's electrophysiological components were linked to underlying cognitive processes, and the tracking task served as a proxy for the continuous cycle of state-monitoring and adjustment inherent to CSCs. Dual-tasking interfered with the oddball task's accuracy and attentional processes (attenuated P2 and P3b magnitude, and parietal alpha-band ERD), but errors in tracking due to dual-tasking accrued at a later time-scale, and only in trials in which the target stimulus appeared and its tally had to be incremented. Interference between cognitive tasks and CSCs can be asymmetric in terms of timing as well as affected information-processing components

Enabling mechanical separation of enantiomers through controlled batchwise concomitant crystallization : digital design and experimental validation

In the pharmaceutical industry the separation of chiral molecules is important due to the different physiochemical properties that the enantiomers of a chiral drug possess. Therefore, resolution techniques are used to separate such enantiomers from one another. In particular, preferential crystallization is a common technique used to separate conglomerate-forming compounds, due to its high selectivity. However, the efficient separation of enantiomers in a batchwise preferential crystallization process through seeding with the preferred enantiomer alone is still inefficient, since unwanted nucleation of the counter enantiomer is inevitable. Here, we demonstrate a model-based digital design for the separation of enantiomers for a conglomerate-forming compound (asparagine monohydrate), by using mechanical separation by sieving after crystallization, whereby the separation is enabled by a designed bias in the crystal size distributions of each enantiomer. This bias is created by a concomitant crystallization of both enantiomers using optimized seeding and cooling profiles obtained from a population balance model. In this way, a high level of control is achieved over a batchwise preferential crystallization process, since the crystallization of both enantiomers is controlled. We show that, through this separation method, material with impurity levels as low as 6 wt % can be obtained. To our knowledge this is the first demonstration of modeling such a process to separate enantiomers of a conglomerate-forming compound

An analysis of identical single-nucleotide polymorphisms genotyped by two different platforms

The overlap of 94 single-nucleotide polymorphisms (SNP) among the 4,720 and 11,120 SNPs contained in the linkage panels of Illumina and Affymetrix, respectively, allows an assessment of the discrepancy rate produced by these two platforms. Although the no-call rate for the Affymetrix platform is approximately 8.6 times greater than for the Illumina platform, when both platforms make a genotypic call, the agreement is an impressive 99.85%. To determine if disputed genotypes can be resolved without sequencing, we studied recombination in the region of the discrepancy for the most discrepant SNP rs958883 (typed by Illumina) and tsc02060848 (typed by Affymetrix). We find that the number of inferred recombinants is substantially higher for the Affymetrix genotypes compared to the Illumina genotypes. We illustrate this with pedigree 10043, in which 3 of 7 versus 0 of 7 offspring must be double recombinants using the genotypes from the Affymetrix and the Illumina platforms, respectively. Of the 36 SNPs with one or more discrepancies, we identified a subset that appears to cluster in families. Some of this clustering may be due to the presence of a second segregating SNP that obliterates a XbaI site (the restriction enzyme used in the Affymetrix platform), resulting in a fragment too long (>1,000 bp) to be amplified

Draft Aphaenogaster genomes expand our view of ant genome size variation across climate gradients

Given the abundance, broad distribution, and diversity of roles that ants play in many ecosystems, they are an ideal group to serve as ecosystem indicators of climatic change. At present, only a few whole-genome sequences of ants are available (19 of \u3e16,000 species), mostly from tropical and sub-tropical species. To address this limited sampling, we sequenced genomes of temperate-latitude species from the genus Aphaenogaster, a genus with important seed dispersers. In total, we sampled seven colonies of six species: Aphaenogaster ashmeadi, Aphaenogaster floridana, Aphaenogaster fulva, Aphaenogaster miamiana, Aphaenogaster picea, and Aphaenogaster rudis. The geographic ranges of these species collectively span eastern North America from southern Florida to southern Canada, which encompasses a latitudinal gradient in which many climatic variables are changing rapidly. For the six genomes, we assembled an average of 271,039 contigs into 47,337 scaffolds. The Aphaenogaster genomes displayed high levels of completeness with 96.1% to 97.6% of Hymenoptera BUSCOs completely represented, relative to currently sequenced ant genomes which ranged from 88.2% to 98.5%. Additionally, the mean genome size was 370.5 Mb, ranging from 310.3 to 429.7, which is comparable to that of other sequenced ant genomes (212.8-396.0 Mb) and flow cytometry estimates (210.7-690.4 Mb). In an analysis of currently sequenced ant genomes and the new Aphaenogaster sequences, we found that after controlling for both spatial autocorrelation and phylogenetics ant genome size was marginally correlated with sample site climate similarity. Of all examined climate variables, minimum temperature, and annual precipitation had the strongest correlations with genome size, with ants from locations with colder minimum temperatures and higher levels of precipitation having larger genomes. These results suggest that climate extremes could be a selective force acting on ant genomes and point to the need for more extensive sequencing of ant genomes