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

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

Environmental Exposure, Obesity, and Parkinson’s Disease: Lessons from Fat and Old Worms

BACKGROUND: A common link has been exposed, namely, that metal exposure plays a role in obesity and in Parkinson's disease (PD). This link may help to elucidate mechanisms of neurotoxicity. OBJECTIVE: We reviewed the utility of the nematode, Caenorhabditis elegans, as a model organism to study neurodegeneration in obesity and Parkinson's disease (PD), with an emphasis on the neurotransmitter, dopamine (DA). DATA SOURCES: A PubMed literature search was performed using the terms "obesity" and any of the following: "C. elegans," "central nervous system," "neurodegeneration," "heavy metals," "dopamine" or "Parkinson's disease." We reviewed the identified studies, including others cited therein, to summarize the current evidence of neurodegeneration in obesity and PD, with an emphasis on studies carried out in C. elegans and environmental toxins in the etiology of both diseases. DATA EXTRACTION AND DATA SYNTHESIS: Heavy metals and DA have both been linked to diet-induced obesity, which has led to the notion that the mechanism of environmentally induced neurodegeneration in PD may also apply to obesity. C. elegans has been instrumental in expanding our mechanism-based knowledge of PD, and this species is emerging as a good model of obesity. With well-established toxicity and neurogenetic assays, it is now feasible to explore the putative link between metal- and chemical-induced neurodegeneration. CONCLUSIONS: One side effect of an aging population is an increase in the prevalence of obesity, metabolic disorders, and neurodegenerative orders, diseases that are likely to co-occur. Environmental toxins, especially heavy metals, may prove to be a previously neglected part of the puzzle

Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Alogliptin in Patients With Type 2 Diabetes and Inadequate Glycemic Control: A randomized, double-blind, placebo-controlled study

OBJECTIVE—To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes

Triple combination of insulin glargine, sitagliptin and metformin in type 2 diabetes : the EASIE post-hoc analysis and extension trial

Q3Q1Aim We examined the effects of adding glargine to metformin–sitagliptin (MS + G) or sitagliptin to metformin–glargine (MG + S) therapy in type 2 diabetic persons uncontrolled after 24-week MS or MG dual therapy. Methods Subjects with A1c ≥ 7% on MS or MG treatment were respectively given glargine (0.2 U/kg starting dose) or sitagliptin (100 mg daily) for 12 weeks. The primary endpoint was number of subjects attaining A1c goal defined as < 7%. Results After receiving 24-week MS or MG dual therapy in the original EASIE Study, 42% (104/248) on MS and 68% (152/224) on MG attained A1c < 7% (p < 0.0001). The reduction in A1c was negatively associated with baseline fasting blood glucose (FBG) only in the MG group. Reduction in A1c was not related to baseline postprandial blood glucose (PPBG) in either the MG or MS group. Amongst 194 eligible patients, 57.7% (n = 111) entered the 12-week extension trial [MS + G:74/131, 57.3%; MG + S:37/63, 58.7%) with 55 (51.9%) subjects attaining goal [MS + G:59.2%; MG + S:37.1%] at week 12. The final insulin dosage was similar in both groups [MS + G: 0.46 U/kg; MG + S: 0.45 U/kg] with a higher rate of hypoglycemia in the MG + S (6.5 events/patient-year) than the MS + G group (3.2 events/patient-year), although neither group had severe hypoglycemia. Conclusion In metformin-treated type 2 diabetes patients, high fasting BG predicted greater A1c reductions with the addition of glargine, but not with sitagliptin. In subjects uncontrolled with 6-month dual therapy of MS or MG, 50% attained A1c < 7% with triple therapy of MS + G or MG + S in 12 weeks. The increased rate of hypoglycemia with MG + S (but not with MS + G) underlines the need to take measures to avoid the hypoglycemia

Multifaceted determinants for achieving glycemic control the international diabetes management practice study (IDMPS)

OBJECTIVE - The International Diabetes Mellitus Practice Study is a 5-year survey documenting changes in diabetes treatment practice in developing regions. RESEARCH DESIGN AND METHODS - Logistic regression analysis was used to identify factors for achieving A1C <7% in 11,799 patients (1,898 type 1 diabetic and 9,901 type 2 diabetic) recruited by 937 physicians from 17 countries in Eastern Europe (n = 3,519), Asia (n = 5,888), Latin America (n = 2,116), and Africa (n = 276). RESULTS - Twenty-two percent of type 1 diabetic and 36% of type 2 diabetic patients never had A1C measurements. In those with values for A1C, blood pressure, and LDL cholesterol, 7.5% of type 1 diabetic (n = 696) and 3.6% of type 2 diabetic (n = 3,896) patients attained all three recommended targets (blood pressure < 130/80 mmHg, LDL cholesterol <100 mg/dl, and A1C <7%). Self-monitoring of blood glucose was the only predictor for achieving the A1C goal in type 1 diabetes (odds ratios: Asia 2.24, Latin America 3.55, and Eastern Europe 2.42). In type 2 diabetes, short disease duration (Asia 0.97, Latin America 0.97, and Eastern Europe 0.82) and treatment with few oral glucose-lowering drugs (Asia 0.64, Latin America 0.76, and Eastern Europe 0.62) were predictors. Other region-specific factors included lack of microvascular complications and old age in Latin America and Asia; health insurance coverage and specialist care in Latin America; lack of obesity and self-adjustment of insulin dosages in Asia; and training by a diabetes educator, self-monitoring of blood glucose in patients who self-adjusted insulin, and lack of macrovascular complications in Eastern Europe. CONCLUSIONS - In developing countries, factors pertinent to patients, doctors, and health care systems all impact on glycemic control.Facultad de Ciencias Médica

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

Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins' defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents

Gaps and barriers in the control of blood glucose in people with type 2 diabetes

Background: Glycaemic control is suboptimal in a large proportion of people with type 2 diabetes who are consequently at an increased and avoidable risk of potentially severe complications. We sought to explore attitudes and practices among healthcare professionals that may contribute to suboptimal glycaemic control through a review of recent relevant publications in the scientific literature. Methods: An electronic search of the PubMed database was performed to identify relevant publications from January 2011 to July 2015. The electronic search was complemented by a manual search of abstracts from key diabetes conferences in 2014/2015 available online. Results: Recently published data indicate that glycaemic control is suboptimal in a substantial proportion (typically 40%-60%) of people with diabetes. This is the case across geographic regions and in both low- and higher-income countries. Therapeutic inertia appears to be an important contributor to poor glycaemic control in up to half of people with type 2 diabetes. In particular, prescribers are often willing to tolerate extended periods of 'mild' hyperglycaemia as well as having low expectations for their patients. There are often delays of 3 years or longer in initiating or intensifying glucose-lowering therapy when needed. Conclusion: Many people with type 2 diabetes are failed by current management, with approximately half not achieving or maintaining appropriate target blood glucose levels, leaving these patients at increased and avoidable risk of serious complications. Review criteria: The methodology of this review article is detailed in the 'Methods' section

SMF-1, SMF-2 and SMF-3 DMT1 Orthologues Regulate and Are Regulated Differentially by Manganese Levels in C. elegans

Manganese (Mn) is an essential metal that can exert toxic effects at high concentrations, eventually leading to Parkinsonism. A major transporter of Mn in mammals is the divalent-metal transporter (DMT1). We characterize here DMT1-like proteins in the nematode C. elegans, which regulate and are regulated by Mn and iron (Fe) content. We identified three new DMT1-like genes in C. elegans: smf-1, smf-2 and smf-3. All three can functionally substitute for loss of their yeast orthologues in S. cerevisiae. In the worm, deletion of smf-1 or smf-3 led to an increased Mn tolerance, while loss of smf-2 led to increased Mn sensitivity. smf mRNA levels measured by QRT-PCR were up-regulated upon low Mn and down-regulated upon high Mn exposures. Translational GFP-fusions revealed that SMF-1 and SMF-3 strongly localize to partially overlapping apical regions of the gut epithelium, suggesting a differential role for SMF-1 and SMF-3 in Mn nutritional intake. Conversely, SMF-2 was detected in the marginal pharyngeal epithelium, possibly involved in metal-sensing. Analysis of metal content upon Mn exposure in smf mutants revealed that SMF-3 is required for normal Mn uptake, while smf-1 was dispensable. Higher smf-2 mRNA levels correlated with higher Fe content, supporting a role for SMF-2 in Fe uptake. In smf-1 and smf-3 but not in smf-2 mutants, increased Mn exposure led to decreased Fe levels, suggesting that both metals compete for transport by SMF-2. Finally, SMF-3 was post-translationally and reversibly down-regulated following Mn-exposure. In sum, we unraveled a complex interplay of transcriptional and post-translational regulations of 3 DMT1-like transporters in two adjacent tissues, which regulate metal-content in C. elegans