VLA-4 as a Central Target for Modulating Neuroinflammatory Disorders

The complex steps leading to the central nervous system (CNS) inflammation and the progress to neuroinflammatory and neurodegenerative disorders have opened up new research and intervention avenues. This review focuses on the therapeutic targeting of the VLA-4 integrin to discuss the clear-cut effect on immune cell trafficking into brain tissues. Besides, we explore the possibility that blocking VLA-4 may have a relevant impact on nonmigratory activities of immune cells, such as antigen presentation and T-cell differentiation, during the neuroinflammatory process. Lastly, the recent refinement of computational techniques is highlighted as a way to increase specificity and to reduce the detrimental side effects of VLA-4 immunotherapies aiming at developing better clinical interventions.

UMIc: A Preprocessing Method for UMI Deduplication and Reads Correction

A recent refinement in high-throughput sequencing involves the incorporation of unique molecular identifiers (UMIs), which are random oligonucleotide barcodes, on the library preparation steps. A UMI adds a unique identity to different DNA/RNA input molecules through polymerase chain reaction (PCR) amplification, thus reducing bias of this step. Here, we propose an alignment free framework serving as a preprocessing step of fastq files, called UMIc, for deduplication and correction of reads building consensus sequences from each UMI. Our approach takes into account the frequency and the Phred quality of nucleotides and the distances between the UMIs and the actual sequences. We have tested the tool using different scenarios of UMI-tagged library data, having in mind the aspect of a wide application. UMIc is an open-source tool implemented in R and is freely available from https://github.com/BiodataAnalysisGroup/UMIc.

Latent-Variable Non-Autoregressive Neural Machine Translation with Deterministic Inference Using a Delta Posterior

Although neural machine translation models reached high translation quality, the autoregressive nature makes inference difficult to parallelize and leads to high translation latency. Inspired by recent refinement-based approaches, we propose LaNMT, a latent-variable non-autoregressive model with continuous latent variables and deterministic inference procedure. In contrast to existing approaches, we use a deterministic inference algorithm to find the target sequence that maximizes the lowerbound to the log-probability. During inference, the length of translation automatically adapts itself. Our experiments show that the lowerbound can be greatly increased by running the inference algorithm, resulting in significantly improved translation quality. Our proposed model closes the performance gap between non-autoregressive and autoregressive approaches on ASPEC Ja-En dataset with 8.6x faster decoding. On WMT'14 En-De dataset, our model narrows the gap with autoregressive baseline to 2.0 BLEU points with 12.5x speedup. By decoding multiple initial latent variables in parallel and rescore using a teacher model, the proposed model further brings the gap down to 1.0 BLEU point on WMT'14 En-De task with 6.8x speedup.

The Lingering of the Literal in Some Poems of Emily Dickinson

Dickinson is known for her adventurous metaphors (‘Risk is the hair that holds the tun’, ‘Hope is the thing with feathers’), but also—and one might think paradoxically—for her attachment to the literal, to the thing that remains stubbornly itself (in this refusal of transcendence critics sometimes contrast her with Emerson, for whom the whole world is ‘emblematic’). This chapter seeks to account for this apparent paradox from the perspective of relevance theory’s so-called ‘deflationary’ account of metaphors. That account is briefly introduced, along with Robyn Carston’s recent refinement of it, according to which under certain circumstances the literal or encyclopaedic component used to produce an ad hoc concept ‘lingers’ beyond its interpretive resolution. A close reading of four Dickinson poems reveals them to be rich in ‘the lingering of the literal’, though in each case the literal vestige takes a different—and sometimes surprising—form.

Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

Canaloplasty: A Minimally Invasive and Maximally Effective Glaucoma Treatment

Canaloplasty is a highly effective, minimally invasive, surgical technique indicated for the treatment of open-angle glaucoma that works by restoring the function of the eye’s natural outflow system. The procedure’s excellent safety profile and long-term efficacy make it a viable option for the majority of glaucoma patient types. It can be used in conjunction with existing drug based glaucoma treatments, after laser or other types of incisional surgery, and does not preclude or affect the outcome of future surgery. Numerous scientific studies have shown Canaloplasty to be safe and effective in lowering IOP whilst reducing medication dependence. A recent refinement of Canaloplasty, known as ab-interno Canaloplasty (ABiC), maintains the IOP-lowering and safety benefits of traditional (ab-externo) Canaloplasty using a more efficient, simplified surgical approach. This paper presents a review of Canaloplasty indications, clinical data, and complications, as well as comparisons with traditional incisional glaucoma techniques. It also addresses the early clinical evidence for ABiC.

LIMIT MULTIPLICITIES FOR PRINCIPAL CONGRUENCE SUBGROUPS OF AND

We study the limiting behavior of the discrete spectra associated to the principal congruence subgroups of a reductive group over a number field. While this problem is well understood in the cocompact case (i.e., when the group is anisotropic modulo the center), we treat groups of unbounded rank. For the groups $\text{GL}(n)$ and $\text{SL}(n)$ we show that the suitably normalized spectra converge to the Plancherel measure (the limit multiplicity property). For general reductive groups we obtain a substantial reduction of the problem. Our main tool is the recent refinement of the spectral side of Arthur’s trace formula obtained in [Finis, Lapid, and Müller, Ann. of Math. (2) 174(1) (2011), 173–195; Finis and Lapid, Ann. of Math. (2) 174(1) (2011), 197–223], which allows us to show that for $\text{GL}(n)$ and $\text{SL}(n)$ the contribution of the continuous spectrum is negligible in the limit.

INITIAL REVIEW OF THE BIOSTRATIGRAPHY AND PETROLEUM SYSTEMS AROUND THE TASMAN SEA HYDROCARBON-PRODUCING BASINS

Understanding the genesis and habitat of hydrocarbons in a sedimentary basin takes knowledge of that basin at many levels, from basic infill geology to petroleum systems, plays, prospects and detailed sequence stratigraphy. While geophysics can define the basins and their internal structures, biostratigraphy and paleogeography provide greater understanding of basin geology. Micropaleontology and palynology are the chief tools that we need to define both the environment and dimension of time.As an example, the reconstruction of the Tasman Sea region to the mid-Cretaceous (ca 120 Ma) shows that the hydrocarbon-producing Gippsland and Taranaki petroleum basins developed at similar latitudes and in similar geological contexts. Other basins within the region have been lightly explored and need evaluation as to the value of further exploration.As paleontology has developed separately in Australia and New Zealand, comparison of biostratigraphic zones and their chronostratigraphy is critical to understand the similarity or otherwise of the sedimentary record of the two regions. Recent refinement of the NZ timescale and comparative studies on Gippsland Basin wells by NZ paleontologists have provided some key insights that enable us to compare the geological history of both regions more closely, and to recognise similarities in petroleum systems that may enhance petroleum prospects on both sides of the Tasman Sea.

Towards GIS Mapping and Spatial Modelling of Archaeological Sites in the Southeast Queensland Bioregion

<p>In the early 1980s a strategic approach to the description, assessment and management of cultural heritage places using biogeographical boundaries was developed in Queensland. A recent refinement correlates sites on the Environmental Protection Agency's Indigenous Sites Database with environmental variables for the Moreton Basin Province of the Southeast Queensland Bioregion. Archaeological sites in the province are correlated with distance to water, elevation and particular geological and vegetation types. These correlations may reflect either real relationships or biases in the data. Preliminary correlative models developed are not considered substitutes for further inventory surveys and ongoing model refinement. The development of such models is considered useful in providing initial understanding of site distribution patterns.</p>