The MST of symmetric disk graphs is light

AbstractSymmetric disk graphs are often used to model wireless communication networks. Given a set S of n points in Rd (representing n transceivers) and a transmission range assignment r:S→R, the symmetric disk graph of S (denoted SDG(S)) is the undirected graph over S whose set of edges is E={(u,v)|r(u)⩾|uv| and r(v)⩾|uv|}, where |uv| denotes the Euclidean distance between points u and v. We prove that the weight of the MST of any connected symmetric disk graph over a set S of n points in the plane, is only O(logn) times the weight of the MST of the complete Euclidean graph over S. We then show that this bound is tight, even for points on a line.Next, we prove that if the number of different ranges assigned to the points of S is only k, k≪n, then the weight of the MST of SDG(S) is at most 2k times the weight of the MST of the complete Euclidean graph. Moreover, in this case, the MST of SDG(S) can be computed efficiently in time O(knlogn).We also present two applications of our main theorem, including an alternative proof of the Gap Theorem, and a result concerning range assignment in wireless networks.Finally, we show that in the non-symmetric model (where E={(u,v)|r(u)⩾|uv|}), the weight of a minimum spanning subgraph might be as big as Ω(n) times the weight of the MST of the complete Euclidean graph

Bounded-Angle Spanning Tree: Modeling Networks with Angular Constraints

We introduce a new structure for a set of points in the plane and an angle $\alpha$, which is similar in flavor to a bounded-degree MST. We name this structure $\alpha$-MST. Let $P$ be a set of points in the plane and let $0 < \alpha \le 2\pi$ be an angle. An $\alpha$-ST of $P$ is a spanning tree of the complete Euclidean graph induced by $P$, with the additional property that for each point $p \in P$, the smallest angle around $p$ containing all the edges adjacent to $p$ is at most $\alpha$. An $\alpha$-MST of $P$ is then an $\alpha$-ST of $P$ of minimum weight. For $\alpha < \pi/3$, an $\alpha$-ST does not always exist, and, for $\alpha \ge \pi/3$, it always exists. In this paper, we study the problem of computing an $\alpha$-MST for several common values of $\alpha$. Motivated by wireless networks, we formulate the problem in terms of directional antennas. With each point $p \in P$, we associate a wedge $W_p$ of angle $\alpha$ and apex $p$. The goal is to assign an orientation and a radius $r_p$ to each wedge $W_p$, such that the resulting graph is connected and its MST is an $\alpha$-MST. (We draw an edge between $p$ and $q$ if $p \in W_q$, $q \in W_p$, and $|pq| \le r_p, r_q$.) Unsurprisingly, the problem of computing an $\alpha$-MST is NP-hard, at least for $\alpha=\pi$ and $\alpha=2\pi/3$. We present constant-factor approximation algorithms for $\alpha = \pi/2, 2\pi/3, \pi$. One of our major results is a surprising theorem for $\alpha = 2\pi/3$, which, besides being interesting from a geometric point of view, has important applications. For example, the theorem guarantees that given any set $P$ of $3n$ points in the plane and any partitioning of the points into $n$ triplets, one can orient the wedges of each triplet {\em independently}, such that the graph induced by $P$ is connected. We apply the theorem to the {\em antenna conversion} problem

Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of Insulin Glargine and Lixisenatide, Compared with Basal-Bolus Regimen in Patients with Type 2 Diabetes: Propensity Score Matched Analysis

INTRODUCTION: Basal-bolus (BB) regimens are generally used to intensify basal insulin therapy in patients with type 2 diabetes (T2D) not meeting glycemic targets. However, drawbacks include multiple injection burden and risk of weight gain and hypoglycemia. A once-daily titratable fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi) may provide a simple, well-tolerated, and efficacious alternative. We compared these treatments in a post hoc propensity score matched analysis using randomized trial data. METHODS: From the LixiLan-L study, 195 patients who had been randomized to iGlarLixi were matched for age, sex, race, T2D duration, baseline body mass index, glycated hemoglobin (HbA1c), fasting plasma glucose, insulin dose, and metformin use to 195 patients who had been randomized to a BB regimen in the GetGoal Duo-2 trial. RESULTS: At study end, estimated treatment differences for reduction in HbA1c and weight change, and ratio of hypoglycemia events per patient-year (BB vs iGlarLixi) were − 0.28% (standard error 0.08, P = 0.0002), − 1.32 kg (standard error 0.30, P < 0.0001), and 2.85 (P < 0.0001), respectively, all favoring iGlarLixi over BB. Also, proportions of patients reaching individual and composite goals (HbA1c < 7% [< 53 mmol/mol], no weight gain, and no hypoglycemia) were higher in the iGlarLixi compared with the BB treatment group. Gastrointestinal side effects were more common with iGlarLixi. CONCLUSIONS: In patients with T2D inadequately controlled on basal insulin, iGlarLixi offers an effective alternative to BB regimen for reducing HbA1c, without increased risk of hypoglycemia and weight gain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02058160 (LixiLan-L trial); NCT01768559 (GetGoal Duo-2 trial)

Unmasking silent neurotoxicity following developmental exposure to environmental toxicants

AbstractSilent neurotoxicity, a term introduced approximately 25years ago, is defined as a persistent change to the nervous system that does not manifest as overt evidence of toxicity (i.e. it remains clinically unapparent) unless unmasked by experimental or natural processes. Silent neurotoxicants can be challenging for risk assessors, as the multifactorial experiments needed to reveal their effects are seldom conducted, and they are not addressed by current study design guidelines. This topic was the focus of a symposium addressing the interpretation and use of silent neurotoxicity data in human health risk assessments of environmental toxicants at the annual meeting of the Developmental Neurotoxicology Society (previously the Neurobehavioral Teratology Society) on June 30th, 2014. Several factors important to the design and interpretation of studies assessing the potential for silent neurotoxicity were discussed by the panelists and audience members. Silent neurotoxicity was demonstrated to be highly specific to the characteristics of the animals being examined, the unmasking agent tested, and the behavioral endpoint(s) evaluated. Overall, the experimental examples presented highlighted a need to consider common adverse outcomes and common biological targets for chemical and non-chemical stressors, particularly when the exposure and stressors are known to co-occur. Risk assessors could improve the evaluation of silent neurotoxicants in assessments through specific steps from researchers, including experiments to reveal the molecular targets and mechanisms that may result in specific types of silent neurotoxicity, and experiments with complex challenges reminiscent of the human situation

Stressed-Induced TMEM135 Protein Is Part of a Conserved Genetic Network Involved in Fat Storage and Longevity Regulation in Caenorhabditis elegans

Disorders of mitochondrial fat metabolism lead to sudden death in infants and children. Although survival is possible, the underlying molecular mechanisms which enable this outcome have not yet been clearly identified. Here we describe a conserved genetic network linking disorders of mitochondrial fat metabolism in mice to mechanisms of fat storage and survival in Caenorhabditis elegans (C. elegans). We have previously documented a mouse model of mitochondrial very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency.[1] We originally reported that the mice survived birth, but, upon exposure to cold and fasting stresses, these mice developed cardiac dysfunction, which greatly reduced survival. We used cDNA microarrays[2], [3], [4] to outline the induction of several markers of lipid metabolism in the heart at birth in surviving mice. We hypothesized that the induction of fat metabolism genes in the heart at birth is part of a regulatory feedback circuit that plays a critical role in survival.[1] The present study uses a dual approach employing both C57BL/6 mice and the nematode, C. elegans, to focus on TMEM135, a conserved protein which we have found to be upregulated 4.3 (±0.14)-fold in VLCAD-deficient mice at birth. Our studies have demonstrated that TMEM135 is highly expressed in mitochondria and in fat-loaded tissues in the mouse. Further, when fasting and cold stresses were introduced to mice, we observed 3.25 (±0.03)- and 8.2 (±0.31)- fold increases in TMEM135 expression in the heart, respectively. Additionally, we found that deletion of the tmem135 orthologue in C. elegans caused a 41.8% (±2.8%) reduction in fat stores, a reduction in mitochondrial action potential and decreased longevity of the worm. In stark contrast, C. elegans transgenic animals overexpressing TMEM-135 exhibited increased longevity upon exposure to cold stress. Based on these results, we propose that TMEM135 integrates biological processes involving fat metabolism and energy expenditure in both the worm (invertebrates) and in mammalian organisms. The data obtained from our experiments suggest that TMEM135 is part of a regulatory circuit that plays a critical role in the survival of VLCAD-deficient mice and perhaps in other mitochondrial genetic defects of fat metabolism as well

COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence

Occupational, residential, dietary and environmental exposures to mixtures of synthetic anthropogenic chemicals after World War II have a strong relationship with the increase of chronic diseases, health cost and environmental pollution. The link between environment and immunity is particularly intriguing as it is known that chemicals and drugs can cause immunotoxicity (e.g., allergies and autoimmune diseases). In this review, we emphasize the relationship between long-term exposure to xenobiotic mixtures and immune deficiency inherent to chronic diseases and epidemics/pandemics. We also address the immunotoxicologic risk of vulnerable groups, taking into account biochemical and biophysical properties of SARS-CoV-2 and its immunopathological implications. We particularly underline the common mechanisms by which xenobiotics and SARS-CoV-2 act at the cellular and molecular level. We discuss how long-term exposure to thousand chemicals in mixtures, mostly fossil fuel derivatives, exposure toparticle matters, metals, ultraviolet (UV)–B radiation, ionizing radiation and lifestyle contribute to immunodeficiency observed in the contemporary pandemic, such as COVID-19, and thus threaten global public health, human prosperity and achievements, and global economy. Finally, we propose metrics which are needed to address the diverse health effects of anthropogenic COVID-19 crisis at present and those required to prevent similar future pandemics

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies

Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.publishedVersio

Depleted uranium is not toxic to rat brain endothelial (RBE4) cells

Abstract: Studies on Gulf War veterans with depleted uranium (DU) fragments embedded in their soft tissues have led to suggestions of possible DU-induced neurotoxicity. We investigated DU uptake into cultured rat brain endothelial cells (RBE4). Following the determination that DU readily enters RBE4 cells, cytotoxic effects were analyzed using assays for cell volume increase, heat shock protein 90 (Hsp90) expression, 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) reduction, and lactate dehydrogenase (LDH) activity. The results of these studies show that uptake of the U 3 O 8 uranyl chloride form of DU into RBE4 cells is efficient, but there are little or no resulting cytotoxic effects on these cells as detected by common biomarkers. Thus, the present experimental paradigm is rather reassuring and provides no indication for overt cytotoxicity in endothelial cells exposed to DU. Index Entries: Depleted uranium (DU); heavey metal toxicity; blood-brain barrier; endothelium. Article: INTRODUCTION Depleted uranium (DU) is a component of military munitions and is therefore the subject of important toxicity studies. Specifically, the possibility of DU neurotoxicity is under investigation. DU is a dense heavy metal used without reserve in many military applications. Chemically similar to natural uranium, but depleted of much of the radioactivity of the 235 U and 234 U isotopes, DU is a low-specific-activity metal that has several advantages for use as weapons material. Neurotoxicity could potentially arise from the chemical or radioactive properties of DU, and the level of neurotoxicity is as yet undetermined (1-3). Gulf War veterans with DU fragments embedded in their soft tissues were studied and the results suggested that there might be DU-associated effects on behavior and cognition (1-4). Rats embedded with DU fragments accumulated uranium in a range of tissues, with early levels highest in the kidney and a gradual increase in bone accumulation. Brain tissues were found to have far lower levels, with the hippocampus showing high levels among the brain regions following physiologically relevant exposures and cerebellum accumulating the highest levels upon extremely high exposure levels For a blood-borne contaminant to cause neurotoxicity, it must first cross the blood-brain barrier (BBB). This barrier protects the central nervous system (CNS) from toxicants in the blood, and its ability to protect against metal neurotoxicity was reviewed by Zheng et al. (7). The capillaries of the brain are lined with endothelial cells acting as the first line of defense in the BBB. The high degree of tightness of the junctions that link the endothelial cells virtually prevents any paracellular passage from occurring in physiological conditions. In addition, several transport proteins can increase the brain-to-blood efflux of various compounds (e.g., Pglycoproteins or multidrug resistance proteins [MDR] of the ATP-binding cassette [ABC]) (7). The molecula

Brain Uptake, Retention, and Efflux of Aluminum and Manganese

My colleagues and I investigated the sites and mechanisms of aluminum (Al) and manganese (Mn) distribution through the blood-brain barrier (BBB). Microdialysis was used to sample non-protein-bound Al in the extracellular fluid (ECF) of blood (plasma) and brain. Brain ECF Al appearance after intravenous Al citrate injection was too rapid to attribute to diffusion or to transferrin-receptor-mediated endocytosis, suggesting another carrier-mediated process. The brain:blood ECF Al concentration ratio was 0.15 at constant blood and brain ECF Al concentrations, suggesting carrier-mediated brain Al efflux. Pharmacological manipulations suggested the efflux carrier might be a monocarboxylate transporter (MCT). However, the lack of Al 14C-citrate uptake into rat erythrocytes suggested it is not a good substrate for isoform MCT1 or for the band 3 anion exchanger. Al 14C-citrate uptake into murine-derived brain endothelial cells appeared to be carrier mediated, Na independent, pH independent, and energy dependent. Uptake was inhibited by substrate/inhibitors of the MCT and organic anion transporter families. Determination of 26Al in rat brain at various times after intravenous 26Al suggested a prolonged brain 26Al half-life. It appears that Al transferrin and Al citrate cross the BBB by different mechanisms, that much of the Al entering brain ECF is rapidly effluxed, probably as Al citrate, but that some Al is retained for quite some time. Brain influx of the Mn2+ ion and Mn citrate, determined with the in situ brain perfusion technique, was greater than that attributable to diffusion, suggesting carrier-mediated uptake. Mn citrate uptake was approximately 3-fold greater than the Mn2+ ion, suggesting it is a primary Mn species entering the brain. After Mn2+ ion, Mn citrate, or Mn transferrin injection into the brain, brain Mn efflux was not more rapid than that predicted from diffusion. The BBB permeation of Al and Mn is mediated by carriers that may help regulate their brain concentrations