Dexamethasone down-regulates ABCG2 expression levels in breast cancer cells

The breast cancer resistance protein ABCG2 effluxes a variety of drugs and is believed to play an important role in multidrug resistance to chemotherapy. We show here for the first time that dexamethasone (DEX) and progesterone (PROG) are able to strongly inhibit ABCG2 expression in progesterone receptor (PR)-positive MCF7 and PR-negative MDA-MB-231 breast cells. In contrast, in the latter cells stably-transfected with progesterone receptor isoforms A and B, ABCG2 expression was strongly up-regulated by DEX and PROG. In addition, two other ligands of Pregnane X Receptor (PXR) and/or Glucocorticoid Receptor (GR) were also able to down-regulate ABCG2 expression in PXR- and GR-positive MCF7 cells. ABCG2 expression regulation by DEX likely resulted from the activation of PR-, PXR-, and/or GR-signaling pathways. ABCG2 expression inhibition by DEX was associated with increased sensitivity to mitoxantrone, a known ABCG2 substrate. The findings suggest that DEX may be useful in improving drug efficacy under certain conditions.     

Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.     

Low serum urate levels are associated to female gender in multiple sclerosis patients

Background

Urate is a natural antioxidant and may prevent CNS tissue damage and the clinical manifestations of experimental autoimmune encephalitis. Results from clinical studies are conflicting and the contribution of urate to the pathogenesis of Multiple Sclerosis (MS) remains uncertain.

Objective

To evaluate serum urate levels in MS patients and their relationships with clinical, demographic and MRI variables.

Methods

Levels of non-fasting serum uric acid and creatinine were determined by an automated enzymatic assay and glomerular filtration rate was assessed in 245 MS patients, in 252 age/sex-matched neurological controls (NC) and in 59 Healthy controls (HC).

Results

Median serum urate levels did not differ between MS patients (3.8 mg/dL), HC (4.0 mg/dl) and NC (4.0 mg/dL). Serum urate levels were lower in females than in males in all groups (p = <0.0001). In female-MS, serum urate levels (3.2 mg/dL) were lower compared to those in female HC (3.8; p = 0.01) and NC (3.5 mg/dL; p = 0.02), whereas in male-MS they(4.8 mg/dL) did not differ from those in male HC (4.5 mg/dl) and NC (4.8 mg/dL). Urate concentrations trended to be lower in Clinically isolated syndromes suggestive of MS (3.7 mg/dL) and in relapsing MS (3.7 mg/dL), compared to patients with progressive MS (4.4 mg/dL; p = 0.06), and in patients with an annual relapse rate (ARR) >2 (3.3 mg/dL) than in those with an ARR ≤2: 3.9 mg/dL; p = 0.05). Significant lower serum urate levels were found in females than in males in all clinical MS subtypes (p<0.01), separately evaluated. Female sex (beta: −0.53; p<0.00001) was the most significant determinant of serum urate concentrations in MS patients on multivariate regression analysis.

Conclusions

Our findings suggest that low urate levels could be of significance in predominantly inflammatory phases of MS even at the early stage and mainly in females.     

Spermiogenesis in Three Species of Whitefly (Homoptera, Aleyrodidae)

Aflagellate and immotile spermatozoa of three species of whitefly, Bemisia tabaci, Dialeroudes citri and Trialeroudes vaporariorum (Aleyrodidae), are described. In these three species, axoneme and mitochondria are present in the early spermatid, but degenerate in the later stages. The acrosome has arborescent appendages that almost completely surround the spermatozoan. In D. citri the acrosomal projections are more elongated and branched than in T. vaporariorum and B. tabaci . Nuclear and cell elongation appear to occur in the absence of microtubules.     

Alterations in Postural Control during the World's Most Challenging Mountain Ultra-Marathon

We investigated postural control (PC) effects of a mountain ultra-marathon (MUM): a 330-km trail run with 24000 m of positive and negative change in elevation. PC was assessed prior to (PRE), during (MID) and after (POST) the MUM in experienced ultra-marathon runners (n = 18; finish time = 126±16 h) and in a control group (n = 8) with a similar level of sleep deprivation. Subjects were instructed to stand upright on a posturographic platform over a period of 51.2 seconds using a double-leg stance under two test conditions: eyes open (EO) and eyes closed (EC). Traditional measures of postural stability (center of pressure trajectory analysis) and stabilogram-diffusion analysis (SDA) parameters were analysed. For the SDA, a significantly greater short-term effective diffusion was found at POST compared with PRE in the medio-lateral (ML; Dxs) and antero-posterior (AP) directions (Dys) in runners (p<0.05) The critical time interval (Ctx) in the ML direction was significantly higher at MID (p<0.001) and POST (p<0.05) than at PRE in runners. At MID (p<0.001) and POST (p<0.05), there was a significant difference between the two groups. The critical displacement (Cdx) in the ML was significantly higher at MID and at POST (p<0.001) compared with PRE for runners. A significant difference in Cdx was observed between groups in EO at MID (p<0.05) and POST (p<0.005) in the ML direction and in EC at POST in the ML and AP directions (p<0.05).Our findings revealed significant effects of fatigue on PC in runners, including, a significant increase in Ctx (critical time in ML plan) in EO and EC conditions. Thus, runners take longer to stabilise their body at POST than at MID. It is likely that the mountainous characteristics of MUM (unstable ground, primarily uphill/downhill running, and altitude) increase this fatigue, leading to difficulty in maintaining balance.     

Fully Automated Segmentation of the Pons and Midbrain Using Human T1 MR Brain Images

Purpose

This paper describes a novel method to automatically segment the human brainstem into midbrain and pons, called LABS: Landmark-based Automated Brainstem Segmentation. LABS processes high-resolution structural magnetic resonance images (MRIs) according to a revised landmark-based approach integrated with a thresholding method, without manual interaction.

Methods

This method was first tested on morphological T1-weighted MRIs of 30 healthy subjects. Its reliability was further confirmed by including neurological patients (with Alzheimer''s Disease) from the ADNI repository, in whom the presence of volumetric loss within the brainstem had been previously described. Segmentation accuracies were evaluated against expert-drawn manual delineation. To evaluate the quality of LABS segmentation we used volumetric, spatial overlap and distance-based metrics.

Results

The comparison between the quantitative measurements provided by LABS against manual segmentations revealed excellent results in healthy controls when considering either the midbrain (DICE measures higher that 0.9; Volume ratio around 1 and Hausdorff distance around 3) or the pons (DICE measures around 0.93; Volume ratio ranging 1.024–1.05 and Hausdorff distance around 2). Similar performances were detected for AD patients considering segmentation of the pons (DICE measures higher that 0.93; Volume ratio ranging from 0.97–0.98 and Hausdorff distance ranging 1.07–1.33), while LABS performed lower for the midbrain (DICE measures ranging 0.86–0.88; Volume ratio around 0.95 and Hausdorff distance ranging 1.71–2.15).

Conclusions

Our study represents the first attempt to validate a new fully automated method for in vivo segmentation of two anatomically complex brainstem subregions. We retain that our method might represent a useful tool for future applications in clinical practice.     

Variation in Butterfly Larval Acoustics as a Strategy to Infiltrate and Exploit Host Ant Colony Resources

About 10,000 arthropods live as ants'' social parasites and have evolved a number of mechanisms allowing them to penetrate and survive inside the ant nests. Many of them can intercept and manipulate their host communication systems. This is particularly important for butterflies of the genus Maculinea, which spend the majority of their lifecycle inside Myrmica ant nests. Once in the colony, caterpillars of Maculinea “predatory species” directly feed on the ant larvae, while those of “cuckoo species” are fed primarily by attendance workers, by trophallaxis. It has been shown that Maculinea cuckoo larvae are able to reach a higher social status within the colony''s hierarchy by mimicking the acoustic signals of their host queen ants. In this research we tested if, when and how myrmecophilous butterflies may change sound emissions depending on their integration level and on stages of their life cycle. We studied how a Maculinea predatory species (M. teleius) can acoustically interact with their host ants and highlighted differences with respect to a cuckoo species (M. alcon). We recorded sounds emitted by Maculinea larvae as well as by their Myrmica hosts, and performed playback experiments to assess the parasites'' capacity to interfere with the host acoustic communication system. We found that, although varying between and within butterfly species, the larval acoustic emissions are more similar to queens'' than to workers'' stridulations. Nevertheless playback experiments showed that ant workers responded most strongly to the sounds emitted by the integrated (i.e. post-adoption) larvae of the cuckoo species, as well as by those of predatory species recorded before any contact with the host ants (i.e. in pre-adoption), thereby revealing the role of acoustic signals both in parasite integration and in adoption rituals. We discuss our findings in the broader context of parasite adaptations, comparing effects of acoustical and chemical mimicry.     

Morphometric Changes of the Corpus Callosum in Congenital Blindness

We examined the effects of visual deprivation at birth on the development of the corpus callosum in a large group of congenitally blind individuals. We acquired high-resolution T1-weighted MRI scans in 28 congenitally blind and 28 normal sighted subjects matched for age and gender. There was no overall group effect of visual deprivation on the total surface area of the corpus callosum. However, subdividing the corpus callosum into five subdivisions revealed significant regional changes in its three most posterior parts. Compared to the sighted controls, congenitally blind individuals showed a 12% reduction in the splenium, and a 20% increase in the isthmus and the posterior part of the body. A shape analysis further revealed that the bending angle of the corpus callosum was more convex in congenitally blind compared to the sighted control subjects. The observed morphometric changes in the corpus callosum are in line with the well-described cross-modal functional and structural neuroplastic changes in congenital blindness.     

GLUT4 Defects in Adipose Tissue Are Early Signs of Metabolic Alterations in Alms1GT/GT,a Mouse Model for Obesity and Insulin Resistance

Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alström Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alström mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alström mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.