New theoretical ISM-K2 Bayesian network model for evaluating vaccination effectiveness.

Aiming at the difficulty in obtaining a complete Bayesian network (BN) structure directly through search-scoring algorithms, authors attempted to incorporate expert judgment and historical data to construct an interpretive structural model with an ISM-K2 algorithm for evaluating vaccination effectiveness (VE). By analyzing the influenza vaccine data provided by Hunan Provincial Center for Disease Control and Prevention, risk factors influencing VE in each link in the process of "Transportation-Storage-Distribution-Inoculation" were systematically investigated. Subsequently, an evaluation index system of VE and an ISM-K2 BN model were developed. Findings include: (1) The comprehensive quality of the staff handling vaccines has a significant impact on VE; (2) Predictive inference and diagnostic reasoning through the ISM-K2 BN model are stable, effective, and highly interpretable, and consequently, the post-production supervision of vaccines is enhanced. The study provides a theoretical basis for evaluating VE and a scientific tool for tracking the responsibility of adverse events of ineffective vaccines, which has the value of promotion in improving VE and reducing the transmission rate of infectious diseases.

Including intangible costs into the cost-of-illness approach: a method refinement illustrated based on the PM2.5 economic burden in China.

The concentrations of particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) and 10 µm (PM10) is a widespread concern and has been demonstrated for 103 countries. During the past few years, the exposure-response function (ERf) has been widely used to estimate the health effects of air pollution. However, past studies are either based on the cost-of-illness or the willingness-to-pay approach, and therefore, either do not cover intangible costs or costs due to the absence of work. To address this limitation, a hybrid health effect and economic loss model is developed in this study. This novel approach is applied to a sample of environmental and cost data in China. First, the ERf is used to link PM2.5 concentrations to health endpoints of chronic mortality, acute mortality, respiratory hospital admission, cardiovascular hospital admission, outpatient visits-internal medicine, outpatient visits-pediatrics, asthma attack, acute bronchitis, and chronic bronchitis. Second, the health effect of PM2.5 is monetized into the economic loss. The mean economic loss due to PM2.5 was much heavier in the North than the South of China. Furthermore, the empirical results from 76 cities in China show that the health effects and economic losses were over 4.98 million cases and 382.30 billion-yuan in 2014 and decreased dramatically compared with those in 2013.

Detection of dependence patterns with delay.

The Unitary Events (UE) method is a popular and efficient method used this last decade to detect dependence patterns of joint spike activity among simultaneously recorded neurons. The first introduced method is based on binned coincidence count (Grün, 1996) and can be applied on two or more simultaneously recorded neurons. Among the improvements of the methods, a transposition to the continuous framework has recently been proposed by Muiño and Borgelt (2014) and fully investigated by Tuleau-Malot et al. (2014) for two neurons. The goal of the present paper is to extend this study to more than two neurons. The main result is the determination of the limit distribution of the coincidence count. This leads to the construction of an independence test between L≥2 neurons. Finally, we propose a multiple test procedure via a Benjamini and Hochberg approach (Benjamini and Hochberg, 1995). All the theoretical results are illustrated by a simulation study, and compared to the UE method proposed by Grün et al. (2002). Furthermore our method is applied on real data.

Rab35 regulates neurite outgrowth and cell shape.

Recent studies have identified Rab35 in the endocytic pathway and as a regulator of cytokinesis; however its molecular mechanisms are currently unknown. Here, we find that Rab35 colocalizes with actin filaments and with Cdc42, Rac1 and RhoA, and that Rab35 can activate Cdc42 both in vivo and in vitro. We find activated Rab35 stimulates neurite outgrowth in PC12 and N1E-115 cells via a Cdc42-dependent pathway and that siRNA knockdown of Rab35 activity abolishes neurite outgrowth in these cell lines. We conclude that one function of Rab35 is to regulate Rho-family GTPases and that this role has consequences for neurite outgrowth.

Lysobisphosphatidic acid controls endosomal cholesterol levels.

Most cell types acquire cholesterol by endocytosis of circulating low density lipoprotein, but little is known about the mechanisms of intra-endosomal cholesterol transport and about the primary cause of its aberrant accumulation in the cholesterol storage disorder Niemann-Pick type C (NPC). Here we report that lysobisphosphatidic acid (LBPA), an unconventional phospholipid that is only detected in late endosomes, regulates endosomal cholesterol levels under the control of Alix/AlP1, which is an LBPA-interacting protein involved in sorting into multivesicular endosomes. We find that Alix down-expression decreases both LBPA levels and the lumenal vesicle content of late endosomes. Cellular cholesterol levels are also decreased, presumably because the storage capacity of endosomes is affected and thus cholesterol clearance accelerated. Both lumenal membranes and cholesterol can be restored in Alix knockdown cells by exogenously added LBPA. Conversely, we also find that LBPA becomes limiting upon pathological cholesterol accumulation in NPC cells, because the addition of exogenous LBPA, but not of LBPA isoforms or analogues, partially reverts the NPC phenotype. We conclude that LBPA controls the cholesterol capacity of endosomes.

Diversity of raft-like domains in late endosomes.

BACKGROUND: Late endosomes, the last sorting station in the endocytic pathway before lysosomes, are pleiomorphic organelles composed of tubular elements as well as vesicular regions with a characteristic multivesicular appearance, which play a crucial role in intracellular trafficking. Here, we have investigated whether, in addition to these morphologically distinguishable regions, late endosomal membranes are additionally sub-compartmentalized into membrane microdomains. METHODOLOGY/PRINCIPAL FINDINGS: Using sub-organellar fractionation techniques, both with and without detergents, combined with electron microscopy, we found that both the limiting membrane of the organel and the intraluminal vesicles contain raft-type membrane domains. Interestingly, these differentially localized domains vary in protein composition and physico-chemical properties. CONCLUSIONS/SIGNIFICANCE: In addition to the multivesicular organization, we find that late endosomes contain cholesterol rich microdomains both on their limiting membrane and their intraluminal vesicles that differ in composition and properties. Implications of these findings for late endosomal functions are discussed.

Role of LBPA and Alix in multivesicular liposome formation and endosome organization.

What are the components that control the assembly of subcellular organelles in eukaryotic cells? Although membranes can clearly be distorted by cytosolic factors, very little is known about the intrinsic mechanisms that control the biogenesis, shape, and organization of organellar membranes. Here, we found that the unconventional phospholipid lysobisphosphatidic acid (LBPA) could induce the formation of multivesicular liposomes that resembled the multivesicular endosomes that exist where this lipid is found in vivo. This process depended on the same pH gradient that exists across endosome membranes in vivo and was selectively controlled by Alix. In turn, Alix regulated the organization of LBPA-containing endosomes in vivo.

Separation and characterization of late endosomal membrane domains.

Very little is known about the biophysical properties and the lipid or protein composition of membrane domains presumably present in endocytic and biosynthetic organelles. Here we analyzed the membrane composition of late endosomes by suborganellar fractionation in the absence of detergent. We found that the internal membranes of this multivesicular organelle can be separated from the limiting membrane and that each membrane population exhibited a defined composition. Our data also indicated that internal membranes may consist of at least two populations, containing primarily phosphatidylcholine or lysobisphosphatidic acid as major phospholipid, arguing for the existence of significant microheterogeneity within late endosomal membranes. We also found that lysobisphosphatidic acid exhibited unique pH-dependent fusogenic properties, and we speculated that this lipid is an ideal candidate to regulate the dynamic properties of this internal membrane mosaic.