Evolution of human immunodeficiency virus type 1 in a patient with cross-reactive neutralizing activity in serum

Analysis of longitudinally obtained HIV-1 env sequences from an individual with reported cross-reactive neutralizing activity revealed that the majority of viral variants obtained from serum between 4 and 7 years after seroconversion were unable to persist in peripheral blood. Here we show that these viral variants were more sensitive to autologous serum neutralization, had shorter envelopes with fewer potential N-linked glycosylation sites, and showed lower replication kinetics than successfully evolving HIV-1 variants. These data reflect the host selection pressures on phenotypic characteristics of HIV-1 and illustrate in detail the dynamic interaction between HIV-1 and its host's humoral immune responses.     

A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions

Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher''s exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.     

Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta‐analysis

We conducted a meta‐analysis of randomized trials in which the effects of treatment with antidepressant medication were compared to the effects of combined pharmacotherapy and psychotherapy in adults with a diagnosed depressive or anxiety disorder. A total of 52 studies (with 3,623 patients) met inclusion criteria, 32 on depressive disorders and 21 on anxiety disorders (one on both depressive and anxiety disorders). The overall difference between pharmacotherapy and combined treatment was Hedges' g = 0.43 (95% CI: 0.31‐0.56), indicating a moderately large effect and clinically meaningful difference in favor of combined treatment, which corresponds to a number needed to treat (NNT) of 4.20. There was sufficient evidence that combined treatment is superior for major depression, panic disorder, and obsessive‐compulsive disorder (OCD). The effects of combined treatment compared with placebo only were about twice as large as those of pharmacotherapy compared with placebo only, underscoring the clinical advantage of combined treatment. The results also suggest that the effects of pharmacotherapy and those of psychotherapy are largely independent from each other, with both contributing about equally to the effects of combined treatment. We conclude that combined treatment appears to be more effective than treatment with antidepressant medication alone in major depression, panic disorder, and OCD. These effects remain strong and significant up to two years after treatment. Monotherapy with psychotropic medication may not constitute optimal care for common mental disorders.     

Decrease in Vitamin D Status in the Greenlandic Adult Population from 1987–2010

Background

Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food.

Objective

To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005–2010.

Design

A total of 2877 randomly selected Inuit (≥18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status.

Results

The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005–2010 was lowest among the 18–29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005–2010 (32%–58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18–29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2–57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking (−11.6%; CI: −16.2; −6.9), BMI (−0.6%; CI: −1.1; −0.2) and latitude (−0.7% per degree increase; CI: −1.3; −0.2) were associated with decreased concentrations.

Conclusion

We identified a remarkable decrease in vitamin D status from 1987 to 2005–2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered.     

Molecular Epidemiological Survey of Listeria monocytogenes in Seafoods and Seafood-Processing Plants

To evaluate the role of seafoods in the epidemiology of human listeriosis and the role of the processing environment as a source of Listeria monocytogenes in seafood products, 305 L. monocytogenes isolates were characterized by multilocus enzyme electrophoresis using 21 genetic loci and restriction enzyme analysis of total DNA. Forty-four isolates were recovered from patients in Norway; 93 were isolated from seafoods, seafood-processing environments, and seawater from 55 different producers; and the remaining 168 isolates originated from six seafood-processing plants and one transport terminal examined in detail for L. monocytogenes. The patient isolates fell into 11 electrophoretic types, with four of them being responsible for 77% of the listeriosis cases in 1992 to 1996. Isolates from Norwegian seafoods and processing environments showed great genetic diversity, indicating that seafoods and seafood-processing environments do not offer a niche for specific L. monocytogenes strains. On the other hand, isolates from individual processing plants were genetically more homogenous, showing that plants are likely to be colonized with specific subclones of L. monocytogenes. The isolation of identical subclones of L. monocytogenes from both human patients and seafoods, including ready-to-eat products, suggests that such products may have been possible sources for listeriosis cases in Norway.     

The index herd with PMWS in Sweden: Presence of serum amyloid A,circovirus 2 viral load and antibody levels in healthy and PMWS-affected pigs

Background  

Postweaning Multisystemic Wasting Syndrome (PMWS) is an emerging disease in pigs of multifactorial origin, but associated to porcine circovirus type 2 (PCV2) infection. PMWS was first diagnosed in Sweden at a progeny test station that received pigs aged five weeks from 19 different nucleus herds on the day after weaning. The objective of this study was to examine, for the first time in an index outbreak of PMWS, the relationship between PCV2 virus, antibodies to PCV2 and serum amyloid a (SAA) in sequentially collected serum samples from pigs with and without signs of PMWS.     

The Breast Cancer-Associated Glycoforms of MUC1, MUC1-Tn and sialyl-Tn,Are Expressed in COSMC Wild-Type Cells and Bind the C-Type Lectin MGL

Aberrant glycosylation occurs in the majority of human cancers and changes in mucin-type O-glycosylation are key events that play a role in the induction of invasion and metastases. These changes generate novel cancer-specific glyco-antigens that can interact with cells of the immune system through carbohydrate binding lectins. Two glyco-epitopes that are found expressed by many carcinomas are Tn (GalNAc-Ser/Thr) and STn (NeuAcα2,6GalNAc-Ser/Thr). These glycans can be carried on many mucin-type glycoproteins including MUC1. We show that the majority of breast cancers carry Tn within the same cell and in close proximity to extended glycan T (Galβ1,3GalNAc) the addition of Gal to the GalNAc being catalysed by the T synthase. The presence of active T synthase suggests that loss of the private chaperone for T synthase, COSMC, does not explain the expression of Tn and STn in breast cancer cells. We show that MUC1 carrying both Tn or STn can bind to the C-type lectin MGL and using atomic force microscopy show that they bind to MGL with a similar deadadhesion force. Tumour associated STn is associated with poor prognosis and resistance to chemotherapy in breast carcinomas, inhibition of DC maturation, DC apoptosis and inhibition of NK activity. As engagement of MGL in the absence of TLR triggering may lead to anergy, the binding of MUC1-STn to MGL may be in part responsible for some of the characteristics of STn expressing tumours.     

Short period leaf movements in Oxalis regnellii

Oxalis regnellii Mig. is a trifoliate plant, and the three leaflets usually show synchronized up and down movements with a circadian period of 26–27 h. The three leaflets can also perform desynchronized ultradian oscillations, and we report on such rhythms under different conditions. A study of the occurrence of ultradian leaf movement rhythms as a function of irradiance is presented. At an irradiance of approximately 1 μW cm⁻², the occurrence was maximal and ca 30%. The periods varied from 5 to 15 h. Four other cases of ultradian rhythms in different conditions are also presented. In one case spontaneous ultradian rhythms occurred, and in another, two of the leaflets showed ultradian rhythms when the third leaflet had received a light pulse. In two more cases, the three leaflets on a leaf were separated by physical cuts along the petiole between the pulvini; in both cases the period was approximately 5 h. Possible mechanisms to explain the ultradian rhythms in Oxalis regnelli are discussed.     

Lipophilic prodrugs and formulations of conventional (deoxy)nucleoside and fluoropyrimidine analogs in cancer

Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations, several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half-life, change the biodistribution, and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Encapsulating drugs in nanoparticles or liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. In this review, we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems.