Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

During apoptosis, pro‐apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP. Such caspase‐independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS‐STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS‐STING signalling pathway. Using super‐resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP. In a temporal manner, we find that following MOMP, BAX/BAK‐mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK‐dependent MOMP. Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase‐independent cell death.     

Unexpected opioid activity in a known class of drug

Tifluadom, although structurally a 1,4 benzodiazepine, has no affinity for the 3H-flunitrazepam binding site, but is a potent displacer of 3H-bremazocine from its opioid binding site. Tifluadom is characterised as an opiate kappa-receptor agonist in vitro and in vivo with potent analgesic activity in animals and no dependence potential.     

Covariate-dependent age-at-onset distributions for Huntington disease.

A combined logistic regression and life-table analysis is presented on age-at-onset data for Huntington disease. Covariates included in the analysis were sex of the at-risk individual, parental age at onset, and sex of transmitting parent. Parental age at onset and parental sex were found to be significant covariates for age at onset in the offspring, and the appropriate logistic regression functions are calculated by maximum likelihood methods. These regression functions permit a more precise evaluation of carrier risks and likelihoods than hitherto was possible by simple computational means. We further introduce a novel method to account for sibship correlations in the significance assessment, using log-likelihood differences between different models.     

The postantennal organ: A specialized unicellular sensory input to the protocerebrum in apterygotan insects (Collembola)

Summary A postantennal organ occurs in three different families in Collembola. In spite of considerable diversity in their outer structures, the organs manifest many similarities in their internal structure (pore system with pores of about 50–100 Å diameter, a single sensory cell with two branching ciliary outer segments, reduction of the outer receptor lymph cavity and occurrence of an electron dense secretion around the dendrites). A tendency towards an enlargement of the outer surface of the organ and towards an incorporation of the sensory cell into the protocerebrum appears to be correlated with adaptations to a strict euedaphic life. An appropriate stimulus for the organ cannot be derived from the structure unequivocally, however, it could be hygro-, chemo- or thermosensitive. Perforated surface and number of pores in the postantennal organ correspond to the values found in insect sensory hairs.     

Broad spectrum action of phenazine against active and dormant structures of fungal pathogens and root knot nematode

Antifungal antibiotic from Pseudomonas chlororaphis isolate PA23 was identified as Phenazine using TLC and HPLC. Phenazine recorded the highest inhibition zone of 21?mm with 35.55% percent inhibition of mycelial growth of Pythium aphanidermatum over control. It had a significant effect on the hyphal morphology of P. aphanidermatum and on spore germination of Botryodiplodia theobromae and Alternaria solani. Disorganization of hyphal morphology of P. aphanidermatum includes vacuolization, cell content degeneration and hyphal lysis. Similarly interaction of phenazine with Rhizoctonia solani resulted in abnormal swelling of hyphal tips was noticed in the hyphal tips. Similarly the germination of sclerotia of Macrophomina phaseolina, R. solani and Sclerotium rolfsii were completely inhibited by phenazine at a concentration 50?μl. Incubation of the eggs of the root knot nematode Meloidogyne incognita in 30?μl concentration of phenazine, completely suppressed the hatching of juveniles.     

Effects of Wheat and Oat-Based Whole Grain Foods on Serum Lipoprotein Size and Distribution in Overweight Middle Aged People: A Randomised Controlled Trial

Introduction

Epidemiological studies suggest three daily servings of whole-grain foods (WGF) might lower cardiovascular disease risk, at least partly by lowering serum lipid levels. We have assessed the effects of consuming three daily portions of wholegrain food (provided as wheat or a mixture of wheat and oats) on lipoprotein subclass size and concentration in a dietary randomised controlled trial involving middle aged healthy individuals.

Methods

After a 4-week run-in period on a refined diet, volunteers were randomly allocated to a control (refined diet), wheat, or wheat + oats group for 12 weeks. Our servings were determined in order to significantly increase the intakes of non starch polysaccharides to the UK Dietary Reference Value of 18 g per day in the whole grain groups (18.5 g and 16.8 g per day in the wheat and wheat + oats groups respectively in comparison with 11.3 g per day in the control group). Outcome measures were serum lipoprotein subclasses'' size and concentration. Habitual dietary intake was assessed prior and during the intervention. Of the 233 volunteers recruited, 24 withdrew and 3 were excluded.

Results

At baseline, significant associations were found between lipoprotein size and subclasses'' concentrations and some markers of cardiovascular risk such as insulin resistance, blood pressure and serum Inter cellular adhesion molecule 1 concentration. Furthermore, alcohol and vitamin C intake were positively associated with an anti-atherogenic lipoprotein profile, with regards to lipoprotein size and subclasses'' distribution. However, none of the interventions with whole grain affected lipoprotein size and profile.

Conclusion

Our results indicate that three portions of wholegrain foods, irrelevant of the type (wheat or oat-based) do not reduce cardiovascular risk by beneficially altering the size and distribution of lipoprotein subclasses.

Trial Registration

www.Controlled-Trials.com ISRCTN 27657880.     

Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals

The management of overweight subjects by interventions aimed at reducing inflammation is highly desirable. To date, observational studies have identified a link between increased dietary antioxidant intake and reduced cardiovascular morbidity. However, direct trial evidence regarding the ability of antioxidants to influence inflammation is lacking. Therefore, this study examined lycopene's ability to lower systemic and high-density lipoprotein (HDL)-associated inflammation in moderately overweight middle-aged subjects. Serum was collected before and after a 12-week intervention from 54 moderately overweight, middle-aged individuals. Subjects were randomised to one of three groups: control diet (< 10 mg lycopene/week), lycopene-rich diet (224–350 mg lycopene/week) and lycopene supplement (70 mg lycopene/week). HDL was subfractionated into HDL_2&3 by rapid ultracentrifugation. Compliance was monitored by assessing lycopene concentration in serum and HDL_2&3. Systemic and HDL-associated inflammation was assessed by measuring serum amyloid A (SAA) levels. HDL functionality was determined by monitoring the activities of paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT). Lycopene increased in serum and HDL_2&3 following both lycopene interventions (P<.001, for all), while SAA decreased in serum following the lycopene supplement and in HDL₃ following both lycopene interventions (P<.05 for all). PON-1 activity increased in serum and HDL_2&3 in both lycopene groups (P<.05, for all). Furthermore, the activity of CETP decreased in serum following the lycopene supplement, while the activity of LCAT increased in serum and HDL₃ following both lycopene interventions (P<.05 for all). These results demonstrate that in moderately overweight, middle-aged subjects, increasing lycopene intake leads to changes to HDL_2&3, which we suggest enhanced their antiatherogenic properties. Overall, these results show the heart-protective properties of increased lycopene intake.     

CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions

The chemokine receptor CCR7 represents an important determinant for circulating lymphocytes to enter lymph nodes (LN) via high endothelial venules. High endothelial venules also represent the major site of entry for plasmacytoid dendritic cells (pDC). In the steady-state, murine pDC have been suggested to home to LN engaging the chemokine receptors CXCR3, CXCR4, and CCR5, whereas responsiveness to CCR7 ligands is thought to be acquired only upon activation. In this study, we show that already resting pDC express minute amounts of CCR7 that suffice to trigger migration to CCL19/CCL21 in vitro. Upon activation with TLR ligands, CCR7 levels on pDC are strongly increased. Notably, CCR7-deficient mice display substantially reduced pDC counts in LN but not in bone marrow and spleen. Adoptive cell transfer experiments revealed that under both steady-state as well as inflammatory conditions, the homing of CCR7-deficient pDC is severely impaired, indicating that the reduced cell counts of naive pDC observed in CCR7(-/-) mice reflect an intrinsic homing defect of pDC. Together, these observations provide strong evidence that similar to naive lymphocytes, nonstimulated pDC exploit CCR7 to gain entry into LN. This adds to the repertoire of chemokine receptors permitting them to enter diverse tissues.