Intron retention has long been an exemplar of regulated splicing with case studies of individual events serving as models that provided key mechanistic insights into the process of splicing control. ...In organisms such as plants and budding yeast, intron retention is well understood as a major mechanism of gene expression regulation. In contrast, in mammalian systems, the extent and functional significance of intron retention have, until recently, remained greatly underappreciated. Technical challenges to the global detection and quantitation of transcripts with retained introns have often led to intron retention being overlooked or dismissed as “noise”. Now, however, with the wealth of information available from high-throughput deep sequencing, combined with focused computational and statistical analyses, we are able to distinguish clear intron retention patterns in various physiological and pathological contexts. Several recent studies have demonstrated intron retention as a central component of gene expression programs during normal development as well as in response to stress and disease. Furthermore, these studies revealed various ways in which intron retention regulates protein isoform production, RNA stability and translation efficiency, and rapid induction of expression via post-transcriptional splicing of retained introns. In this review, we highlight critical findings from these transcriptomic studies and discuss commonalties in the patterns prevalent in intron retention networks at the functional and regulatory levels.
Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and ...differentiate to acquire the specialized morphological features of mature photoreceptor cells, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1−/− mice, which lack rod function and are a model of congenital stationary night blindness. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1−/− mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration.
Malaria-eliminating countries achieved remarkable success in reducing their malaria burdens between 2000 and 2010. As a result, the epidemiology of malaria in these settings has become more complex. ...Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics. The shift in the populations most at risk of malaria raises important questions for malaria-eliminating countries, since traditional control interventions are likely to be less effective. Approaches to elimination need to be aligned with these changes through the development and adoption of novel strategies and methods. Knowledge of the changing epidemiological trends of malaria in the eliminating countries will ensure improved targeting of interventions to continue to shrink the malaria map.
Hugh Sturrock and colleagues discuss the role of active case detection in low malaria transmission settings. They argue that the evidence for its effectiveness is sparse and that targeted mass drug ...administration should be evaluated as an alternative or addition to active case detection. Please see later in the article for the Editors' Summary
Human T-lymphotropic virus (HTLV) type I is the causative agent of HTLV-associated myelopathy (HAM)/tropical spastic paraparesis, and a number of HAM cases with HTLV-II infection have also been ...reported. However, despite some reports, it is unclear whether HTLV-I or -II infection is associated with other neurologic manifestations.
An analysis of medical histories and screening neurologic examinations from a prospective cohort of 153 HTLV-I, 388 HTLV-II, and 810 HTLV-seronegative individuals followed up for means of 11.5, 12.0, and 12.2 years was performed. Participants diagnosed with HAM were excluded. We calculated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race or ethnicity, income, educational attainment, body mass index, alcohol and cigarette consumption, injection drug use, diabetes, and hepatitis C virus status, using generalized estimating equations for repeated measures.
HTLV-I and -II participants were more likely than seronegative participants to have leg weakness (ORs 1.67 95% CI 1.28-2.18 and 1.44 1.16-1.78), impaired tandem gait (ORs 1.25 95% CI 1.07-1.47 and 1.45 1.27-1.64), Babinski sign (ORs 1.54 95% CI 1.13-2.08 and 1.51 1.18-1.93), impaired vibration sense (ORs 1.16 95% CI 1.01-1.33 and 1.27 1.14-1.42), and urinary incontinence (ORs 1.45 95% CI 1.23-1.72 and 1.70 1.50-1.93). For both HTLV-I and -II participants, higher odds of sensory neuropathy by monofilament examination were no longer significant after adjustment for confounding.
These results provide strong evidence that human T-lymphotropic virus (HTLV)-I and -II are associated with a spectrum of predominantly motor abnormalities in patients without overt HTLV-associated myelopathy. Further investigation of the clinical course and etiology of these abnormalities is warranted.
Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR ...scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.
Generation of CD8+ memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this ...process come from remains unclear. While CD8+ memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8+ effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate.
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•Unlike Teff cells, memory T cells do not acquire substantial amounts of long-chain FA•Glucose supports mitochondrial FAO and OXPHOS in memory T cells•Memory T cells use LAL-mediated cell-intrinsic lipolysis to mobilize FA for FAO•T cell-intrinsic lysosomal lipolysis is important for memory T cell development
CD8+ memory T cells engage fatty-acid oxidation (FAO); however, the source of fatty acids that fuel FAO is unclear. O’Sullivan et al. show that memory T cells rely on glucose, and cell-intrinsic lipolysis to mobilize substrates, for FAO.
The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified ...BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3' end of introns, with distance to the 3' splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models.
Context. Deep far-infrared (FIR) cosmological surveys are known to be affected by source confusion, causing issues when examining the main sequence (MS) of star forming galaxies. In the past this has ...typically been partially tackled by the use of stacking. However, stacking only provides the average properties of the objects in the stack. Aims. This work aims to trace the MS over 0.2 ≤ z < 6.0 using the latest de-blended Herschel photometry, which reaches ≈10 times deeper than the 5σ confusion limit in SPIRE. This provides more reliable star formation rates (SFRs), especially for the fainter galaxies, and hence a more reliable MS. Methods. We built a pipeline that uses the spectral energy distribution (SED) modelling and fitting tool CIGALE to generate flux density priors in the Herschel SPIRE bands. These priors were then fed into the de-blending tool XID+ to extract flux densities from the SPIRE maps. In the final step, multi-wavelength data were combined with the extracted SPIRE flux densities to constrain SEDs and provide stellar mass (M⋆) and SFRs. These M⋆ and SFRs were then used to populate the SFR-M⋆ plane over 0.2 ≤ z < 6.0. Results. No significant evidence of a high-mass turn-over was found; the best fit is thus a simple two-parameter power law of the form log(SFR) = αlog(M⋆) − 10.5 + β. The normalisation of the power law increases with redshift, rapidly at z ≲ 1.8, from 0.58 ± 0.09 at z ≈ 0.37 to 1.31 ± 0.08 at z ≈ 1.8. The slope is also found to increase with redshift, perhaps with an excess around 1.8 ≤ z < 2.9. Conclusions. The increasing slope indicates that galaxies become more self-similar as redshift increases. This implies that the specific SFR of high-mass galaxies increases with redshift, from 0.2 to 6.0, becoming closer to that of low-mass galaxies. The excess in the slope at 1.8 ≤ z < 2.9, if present, coincides with the peak of the cosmic star formation history.
Terrestrial ecosystems often vary dramatically in their responses to drought, but the reasons for this are unclear. With climate change forecasts for more frequent and extensive drought in the ...future, a more complete understanding of the mechanisms that determine differential ecosystem sensitivity to drought is needed. In 2012, the Central US experienced the fourth largest drought in a century, with a regional-scale 40 % reduction in growing season precipitation affecting ecosystems ranging from desert grassland to mesic tallgrass prairie. This provided an opportunity to assess ecosystem sensitivity to a drought of common magnitude in six native grasslands. We tested the prediction that drought sensitivity is inversely related to mean annual precipitation (MAP) by quantifying reductions in aboveground net primary production (ANPP). Long-term ANPP data available for each site (mean length = 16 years) were used as a baseline for calculating reductions in ANPP, and drought sensitivity was estimated as the reduction in ANPP per millimeter reduction in precipitation. Arid grasslands were the most sensitive to drought, but drought responses and sensitivity varied by more than twofold among the six grasslands, despite all sites experiencing 40 % reductions in growing season precipitation. Although drought sensitivity generally decreased with increasing MAP as predicted, there was evidence that the identity and traits of the dominant species, as well as plant functional diversity, influenced sensitivity. A more comprehensive understanding of the mechanisms leading to differences in drought sensitivity will require multi-site manipulative experiments designed to assess both biotic and abiotic determinants of ecosystem sensitivity.
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