BackgroundHIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. The mechanisms of suppression are incompletely understood. Modulation of HIV-1 replication by miRNAs has been reported, but the role of small RNAs in ES is unknown. Using samples from a well-characterized ES cohort, untreated viremic patients, and uninfected controls, we explored the PBMC miRNA profile and probed the relationships of miRNA expression, CD4+ T-cell counts, and viral load.ResultsmiRNA profiles, obtained using multiple acquisition, data processing, and analysis methods, distinguished ES and uninfected controls from viremic HIV-1-infected patients. For several miRNAs, however, ES and viremic patients shared similar expression patterns. Differentially expressed miRNAs included those with reported roles in HIV-1 latency (miR-29 family members, miRs -125b and -150). Others, such as miR-31 and miR-31*, had no previously reported connection with HIV-1 infection but were found here to differ significantly with uncontrolled HIV-1 replication. Correlations of miRNA expression with CD4+ T-cell count and viral load were found, and we observed that ES with low CD4+ T-cell counts had miRNA profiles more closely related to viremic patients than controls. However, expression patterns indicate that miRNA variability cannot be explained solely by CD4+ T-cell variation.ConclusionsThe intimate involvement of miRNAs in disease processes is underscored by connections of miRNA expression with the HIV disease clinical parameters of CD4 count and plasma viral load. However, miRNA profile changes are not explained completely by these variables. Significant declines of miRs-125b and -150, among others, in both ES and viremic patients indicate the persistence of host miRNA responses or ongoing effects of infection despite viral suppression by ES. We found no negative correlations with viral load in viremic patients, not even those that have been reported to silence HIV-1 in vitro, suggesting that the effects of these miRNAs are exerted in a focused, cell-type-specific manner. Finally, the observation that some ES with low CD4 counts were consistently related to viremic patients suggests that miRNAs may serve as biomarkers for risk of disease progression even in the presence of viral suppression.

Scale sensilla are small tactile mechanosensory organs located on the head scales of many squamate reptiles (lizards and snakes). In sea snakes and sea kraits (Elapidae: Hydrophiinae), these scale organs are presumptive scale sensilla that purportedly function as both tactile mechanoreceptors and potentially as hydrodynamic receptors capable of sensing the displacement of water. We combined scanning electron microscopy, silicone casting of the skin and quadrate sampling with a phylogenetic analysis to assess morphological variation in sensilla on the postocular head scale(s) across four terrestrial, 13 fully aquatic and two semi-aquatic species of elapids. Substantial variation exists in the overall coverage of sensilla (0.8–6.5%) among the species sampled and is broadly overlapping in aquatic and terrestrial lineages. However, two observations suggest a divergent, possibly hydrodynamic sensory role of sensilla in sea snake and sea krait species. First, scale sensilla are more protruding (dome-shaped) in aquatic species than in their terrestrial counterparts. Second, exceptionally high overall coverage of sensilla is found only in the fully aquatic sea snakes, and this attribute appears to have evolved multiple times within this group. Our quantification of coverage as a proxy for relative ‘sensitivity’ represents the first analysis of the evolution of sensilla in the transition from terrestrial to marine habitats. However, evidence from physiological and behavioural studies is needed to confirm the functional role of scale sensilla in sea snakes and sea kraits.

Morphological variation among the viviparous sea snakes (Hydrophiinae), a clade of fully aquatic elapid snakes, includes an extreme “microcephalic” ecomorph that has a very small head atop a narrow forebody, while the hind body is much thicker (up to three times the forebody girth). Previous research has demonstrated that this morphology has evolved at least nine times as a consequence of dietary specialization on burrowing eels, and has also examined morphological changes to the vertebral column underlying this body shape. The question addressed in this study is what happens to the skull during this extreme evolutionary change? Here we use X-ray micro-computed tomography and geometric morphometric methods to characterize cranial shape variation in 30 species of sea snakes. We investigate ontogenetic and evolutionary patterns of cranial shape diversity to understand whether cranial shape is predicted by dietary specialization, and examine whether cranial shape of microcephalic species may be a result of heterochronic processes. We show that the diminutive cranial size of microcephalic species has a convergent shape that is correlated with trophic specialization to burrowing prey. Furthermore, their cranial shape is predictable for their size and very similar to that of juvenile individuals of closely related but non-microcephalic sea snakes. Our findings suggest that heterochronic changes (resulting in pedomorphosis) have driven cranial shape convergence in response to dietary specializations in sea snakes.

IntroductionThe use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals.Materials and MethodsA set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed.ResultsNone of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count.DiscussionNo associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.

Eilenodontines are one of the oldest radiation of herbivorous lepidosaurs (snakes, lizards and tuatara) characterized by batteries of wide teeth with thick enamel that bear mammal-like wear facets. Unlike most reptiles, eilenodontines have limited tooth replacement, making dental longevity particularly important to them. We use both X-ray and neutron computed tomography to examine a fossil tooth from the eilenodontine Eilenodon (Late Jurassic, USA). Of the two approaches, neutron tomography was more successful and facilitated measurements of enamel thickness and distribution. We find the enamel thickness to be regionally variable, thin near the cusp tip (0.10 mm) but thicker around the base (0.15–0.30 mm) and notably greater than that of other rhynchocephalians such as the extant Sphenodon (0.08–0.14 mm). The thick enamel in Eilenodon would permit greater loading, extend tooth lifespan and facilitate the establishment of wear facets that have sharp edges for orally processing plant material such as horsetails (Equisetum). The shape of the enamel dentine junction indicates that tooth development in Eilenodon and Sphenodon involved similar folding of the epithelium but different ameloblast activity.

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Many aquatic insects utilise air bubbles on the surface of their bodies to supply O 2 while they dive. The bubbles can simply store O 2 , as in the case of an 'air store', or they can act as a physical 'gas gill', extracting O 2 from the water. Backswimmers of the genus Anisops augment their air store with O 2 from haemoglobin cells located in the abdomen. The O 2 release from the haemoglobin helps stabilise bubble volume, enabling backswimmers to remain near neutrally buoyant for a period of the dive. It is generally assumed that the backswimmer air store does not act as a gas gill and that gas exchange with the water is negligible. This study combines measurements of dive characteristics under different exotic gases (N 2 , He, SF 6 , CO) with mathematical modelling, to show that the air store of the backswimmer Anisops deanei does exchange gases with the water. Our results indicate that approximately 20% of O 2 consumed during a dive is obtained directly from the water. Oxygen from the water complements that released from the haemoglobin, extending the period of near-neutral buoyancy and increasing dive duration.

To investigate the dosimetric effect of intended beam interruption during volumetric modulated arc therapy (VMAT) with flattening filter free (FFF) beam for exploring the possibility of deep inspiration breath hold stereotactic body radiation therapy (SBRT). A total of ten SBRT plans with 6 and 10 MV FFF beams were retrospectively selected. All plans consisted of four partial arcs, except one plan with six partial arcs. We delivered the plans using a Varian Truebeam™ with three different scenarios; without interruption (0int), with one intentional interruption (1int), or with two intentional interruptions (2int), per each partial arc. The treatment log files were exported from the treatment console, and the variations in delivered MU were evaluated at the beam interruption angles. The dose distributions were also measured using a 3D cylindrical diode array detector, ArcCHECK™. The 2D global gamma evaluations were performed, compared to the planned dose distribution, with 3%/3 and 4%/2 mm passing criterion. The dose difference (DD) was also determined between uninterrupted and interrupted data with 3, 2, 1, and 0.5% of global maximum dose. The interruption caused a total increase of 0.14 ± 0.05% and 0.25 ± 0.08% of the total planned MU, ranging from 1746 to 3261 MU, at the interrupted angles in 1int and 2int, respectively. All global gamma passing rates satisfied our clinical threshold of 90%, and the differences of passing rates were less than 0.3% on average with both criterions. All measured 1int and 2int data were within 3% DD from 0int measured data. For 6 MV FFF beams, the average passing rate with 2, 1, and 0.5% DD were 99.9 ± 0.2%, 92.3 ± 12.0%, and 81.9 ± 24.9%, respectively, between 0int and 1int, and 99.8 ± 0.4%, 92.1%12.4%, and 80.7 ± 26.5%, respectively, between 0int and 2int. For 10 MV FFF beams, the average passing rate with 2, 1, and 0.5% DD were 100.0 ± 0.2%, 95.4 ± 9.4% and 87.0 ± 19.8%, respectively, between 0int and 1int, and 99.9 ± 0.3%, 95.4 ± 9.7%, and 87.2 ± 21.3% between 0int and 2int. The dosimetric impact of beam interruption was investigated with small field and high dose rate FFF-VMAT SBRT plans. The delivered dose distributions with up to 12 interruptions per plan were still clinically acceptable. Only minimal changes were observed in Gamma, DD, and log file analysis.