top of page
Published Science
Click Search to Filter.
Total Entries: 10690
Title:
Cavemen's diet really did just consist of eating meat, researchers claim
Authors:
Abstract:
They were less interested in fruit and vegetables
Published:
March 22, 2019
Title:
Interleukin-18 up-regulates amino acid transporters and facilitates amino acid–induced mTORC1 activation in natural killer cells
Authors:
Almutairi, Saeedah Musaed; Ali, Alaa Kassim; He, William; Yang, Doo-Seok; Ghorbani, Peyman; Wang, Lisheng; Fullerton, Morgan D.; Lee, Seung-Hwan
Abstract:
Upon inflammation, natural killer (NK) cells undergo metabolic changes to support their high energy demand for effector function and proliferation. The metabolic changes are usually accompanied by an increase in the expression of nutrient transporters, leading to increased nutrient uptake. Among various cytokines inducing NK cell proliferation, the mechanisms underlying the effect of interleukin (IL)-18 in promoting NK cell proliferation are not completely understood. Here, we demonstrate that IL-18 is a potent cytokine that can enhance the expression of the nutrient transporter CD98/LAT1 for amino acids independently of the mTORC1 pathway and thereby induce a dramatic metabolic change associated with increased proliferation of NK cells. Notably, treatment of IL-18–stimulated NK cells with leucine activates the metabolic sensor mTORC1, indicating that the high expression of amino acid transporters induces amino acid–driven mTORC1 activation. Inhibition of the amino acid transporter CD98/LAT1 abrogated the leucine-driven mTORC1 activation and reduced NK cell effector function. Taken together, our study identified a novel role of IL-18 in up-regulating nutrient transporters on NK cells and thereby inducing metabolic changes, including the mTORC1 activation by amino acids.
Published:
March 22, 2019
Title:
Dietary lysozyme supplementation contributes to enhanced intestinal functions and gut microflora of piglets
Authors:
Xiong, Xia; Zhou, Jian; Liu, Hongnan; Tang, Yulong; Tan, Bie; Yin, Yulong
Abstract:
Lysozyme plays a significant role in defense against bacterial pathogens and in regulating the interactions between gut microbiota and host immune systems. Here, the effects of dietary lysozyme on the intestinal development, immunity, and colonic microbiota of piglets were comprehensively evaluated. Twenty-four seven-day-old piglets from Landrace × Yorkshire sows (n = 8 per group) received no supplementation (group A, the control), 0.5 g kg-1 lysozyme (group B), or 1.0 g kg-1 lysozyme (group C). After the 14-day treatment, piglets supplemented with 1.0 g kg-1 lysozyme had higher average weaning weight, jejunal villus height (VH), and ileal lymphocyte counts than those in the control groups (P < 0.005). Serum total protein and albumin were significantly up-regulated (P < 0.005) and immunoglobulin G tended to increase in the 0.5 g kg-1 lysozyme group (P = 0.065). Bacteroidetes, Proteobacteria, and Fibrobacteres all showed a significant increase in relative abundance after lysozyme treatment at the highest dosage (P
Published:
March 20, 2019
Title:
Mental Disorders and Suicide Attempts in the Pregnancy and Postpartum Periods Compared with Non-Pregnancy: A Population-Based Study
Authors:
Mota, Natalie P.; Chartier, Mariette; Ekuma, Okechukwu; Nie, Yao; Hensel, Jennifer M.; MacWilliam, Leonard; McDougall, Chelsey; Vigod, Simone; Bolton, James M.
Abstract:
Published:
March 20, 2019
Title:
Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer
Authors:
Reina-Campos, Miguel; Linares, Juan F.; Duran, Angeles; Cordes, Thekla; L'Hermitte, Antoine; Badur, Mehmet G.; Bhangoo, Munveer S.; Thorson, Phataraporn K.; Richards, Alicia; Rooslid, Tarmo; Garcia-Olmo, Dolores C.; Nam-Cha, Syongh Y.; Salinas-Sanchez, Antonio S.; Eng, Ken; Beltran, Himisha; Scott, David A.; Metallo, Christian M.; Moscat, Jorge; Diaz-Meco, Maria T.
Abstract:
Summary Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
Published:
March 18, 2019
Title:
Serine and Methionine Metabolism: Vulnerabilities in Lethal Prostate Cancer
Authors:
Gao, Xia; Locasale, Jason W.; Reid, Michael A.
Abstract:
Altered metabolism is a common feature of new and recurring malignancy. In this issue of Cancer Cell, Reina-Campos and colleagues report upregulation of the serine, glycine, one-carbon (SGOC) metabolic network is required for neuroendocrine prostate cancer, a castration-resistant aggressive form of the disease, and presents a targetable vulnerability.
Published:
March 18, 2019
Title:
Stable isotopes reveal patterns of diet and mobility in the last Neandertals and first modern humans in Europe
Authors:
Wißing, Christoph; Rougier, Hélène; Baumann, Chris; Comeyne, Alexander; Crevecoeur, Isabelle; Drucker, Dorothée G.; Gaudzinski-Windheuser, Sabine; Germonpré, Mietje; Gómez-Olivencia, Asier; Krause, Johannes; Matthies, Tim; Naito, Yuichi I.; Posth, Cosimo; Semal, Patrick; Street, Martin; Bocherens, Hervé
Abstract:
Correlating cultural, technological and ecological aspects of both Upper Pleistocene modern humans (UPMHs) and Neandertals provides a useful approach for achieving robust predictions about what makes us human. Here we present ecological information for a period of special relevance in human evolution, the time of replacement of Neandertals by modern humans during the Late Pleistocene in Europe. Using the stable isotopic approach, we shed light on aspects of diet and mobility of the late Neandertals and UPMHs from the cave sites of the Troisième caverne of Goyet and Spy in Belgium. We demonstrate that their diet was essentially similar, relying on the same terrestrial herbivores, whereas mobility strategies indicate considerable differences between Neandertal groups, as well as in comparison to UPMHs. Our results indicate that UPMHs exploited their environment to a greater extent than Neandertals and support the hypothesis that UPMHs had a substantial impact not only on the population dynamics of large mammals but also on the whole structure of the ecosystem since their initial arrival in Europe.
Published:
March 14, 2019
Title:
Integrated Lipidomics and Metabolomics Analysis of Tears in Multiple Sclerosis: An Insight into Diagnostic Potential of Lacrimal Fluid
Authors:
Cicalini, Ilaria; Rossi, Claudia; Pieragostino, Damiana; Agnifili, Luca; Mastropasqua, Leonardo; di Ioia, Maria; De Luca, Giovanna; Onofrj, Marco; Federici, Luca; Del Boccio, Piero
Abstract:
Metabolomics based on mass spectrometry represents an innovative approach to characterize multifactorial diseases, such as multiple sclerosis (MuS). To date, the most important biomarker source for MuS diagnosis is the cerebrospinal fluid. However, an important goal for research is to identify new molecules in more easily accessible biological fluids. A very interesting biofluid in MuS is represented by tears, considered as an intermediate fluid between the cerebrospinal fluid and serum. In this work, we developed a merged strategy for the analysis of lipids containing choline by Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS), as well as for the targeted analysis of free carnitine, acylcarnitines and aminoacids by direct infusion mass spectrometry. Samples for both metabolomics and lipidomics approaches were obtained in a single extraction procedure from tears of patients affected by MuS and healthy controls. Tear lipidomics showed 30 phospholipids significantly modulated and, notably, many sphingomyelins resulted lower in MuS. Moreover, the metabolomics approach carried out both on tears and serum highlighted the diagnostic potential of specific aminoacids and acylcarnitines. In conclusion, the metabolic profiling of tears appears to reflect the pathological conditions of the central nervous system, suggesting that the molecular repository of tears can be considered as a source of potential biomarkers for MuS.
Published:
March 13, 2019
Title:
Naked Liquid Marbles: A Robust Three-Dimensional Low-Volume Cell-Culturing System
Authors:
Chen, Mo; Shah, Megha P.; Shelper, Todd B.; Nazareth, Lynn; Barker, Matthew; Tello Velasquez, Johana; Ekberg, Jenny A. K.; Vial, Marie-Laure; St John, James A.
Abstract:
Three-dimensional (3D) multicellular structures allow cells to behave and interact with each other in a manner that mimics the in vivo environment. In recent years, many 3D cell culture methods have been developed with the goal of producing the most in vivo-like structures possible. Whilst strongly preferable to conventional cell culture, these approaches are often poorly reproducible, time-consuming, expensive, and labor-intensive and require specialized equipment. Here, we describe a novel 3D culture platform, which we have termed the naked liquid marble (NLM). Cells are cultured in a liquid drop (the NLM) in superhydrophobic-coated plates, which causes the cells to naturally form 3D structures. Inside the NLMs, cells are free to interact with each other, forming multiple 3D spheroids that are uniform in size and shape in less than 24 h. We showed that this system is highly reproducible, suitable for cell coculture, compound screening, and also compatible with laboratory automation systems. The low cost of production, small volume of each NLM, and production via automated liquid handling make this 3D cell-culturing system particularly suitable for high-throughput screening assays such as drug testing as well as numerous other cell-based research applications.
Published:
March 13, 2019
Title:
The Effect of Low-Carbohydrate and Low-Fat Diets on Pain in Individuals with Knee Osteoarthritis
Authors:
Strath, Larissa J; Jones, Catherine D; Philip George, Alan; Lukens, Shannon L; Morrison, Shannon A; Soleymani, Taraneh; Locher, Julie L; Gower, Barbara A; Sorge, Robert E
Abstract:
Objective. Osteoarthritis is the most prominent form of arthritis, affecting approximately 15% of the population in the United States. Knee osteoarthritis (KOA) has become one of the leading causes of disability in older adults. Besides knee replacement, there are no curative treatments for KOA, so persistent pain is commonly treated with opioids, acetaminophen, and nonsteroidal anti-inflammatory drugs. However, these drugs have many unpleasant side effects, so there is a need for alternative forms of pain management. We sought to test the efficacy of a dietary intervention to reduce KOA. Design. A randomized controlled pilot study to test the efficacy of two dietary interventions. Subjects. Adults 65–75 years of age with KOA. Methods. Participants were asked to follow one of two dietary interventions (low-carbohydrate [LCD], low-fat [LFD]) or continue to eat as usual (control [CTRL]) over 12 weeks. Functional pain, self-reported pain, quality of life, and depression were assessed every three weeks. Serum from before and after the diet intervention was analyzed for oxidative stress. Results. Over a period of 12 weeks, the LCD reduced pain intensity and unpleasantness in some functional pain tasks, as well as self-reported pain, compared with the LFD and CTRL. The LCD also significantly reduced oxidative stress and the adipokine leptin compared with the LFD and CTRL. Reduction in oxidative stress was related to reduced functional pain. Conclusions. We present evidence suggesting that oxidative stress may be related to functional pain, and lowering it through our LCD intervention could provide relief from pain and be an opioid alternative.
Published:
March 13, 2019
Title:
Tubulin βII and βIII Isoforms as the Regulators of VDAC Channel Permeability in Health and Disease
Authors:
Puurand, Marju; Tepp, Kersti; Timohhina, Natalja; Aid, Jekaterina; Shevchuk, Igor; Chekulayev, Vladimir; Kaambre, Tuuli
Abstract:
In recent decades, there have been several models describing the relationships between the cytoskeleton and the bioenergetic function of the cell. The main player in these models is the voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. At the same time, high-energy phosphates are channeled out and directed to cellular energy transfer networks. Regulation of these energy fluxes is controlled by β-tubulin, bound to VDAC. It is also thought that β-tubulin‒VDAC interaction modulates cellular energy metabolism in cancer, e.g., switching from oxidative phosphorylation to glycolysis. In this review we focus on the described roles of unpolymerized αβ-tubulin heterodimers in regulating VDAC permeability for adenine nucleotides and cellular bioenergetics. We introduce the Mitochondrial Interactosome model and the function of the βII-tubulin subunit in this model in muscle cells and brain synaptosomes, and also consider the role of βIII-tubulin in cancer cells.
Published:
March 13, 2019
Title:
Exceptionally high δ15N values in collagen single amino acids confirm Neandertals as high-trophic level carnivores
Authors:
Jaouen, Klervia; Richards, Michael P.; Cabec, Adeline Le; Welker, Frido; Rendu, William; Hublin, Jean-Jacques; Soressi, Marie; Talamo, Sahra
Abstract:
Isotope and archeological analyses of Paleolithic food webs have suggested that Neandertal subsistence relied mainly on the consumption of large herbivores. This conclusion was primarily based on elevated nitrogen isotope ratios in Neandertal bone collagen and has been significantly debated. This discussion relies on the observation that similar high nitrogen isotopes values could also be the result of the consumption of mammoths, young animals, putrid meat, cooked food, freshwater fish, carnivores, or mushrooms. Recently, compound-specific C and N isotope analyses of bone collagen amino acids have been demonstrated to add significantly more information about trophic levels and aquatic food consumption. We undertook single amino acid C and N isotope analysis on two Neandertals, which were characterized by exceptionally high N isotope ratios in their bulk bone or tooth collagen. We report here both C and N isotope ratios on single amino acids of collagen samples for these two Neandertals and associated fauna. The samples come from two sites dating to the Middle to Upper Paleolithic transition period (Les Cottés and Grotte du Renne, France). Our results reinforce the interpretation of Neandertal dietary adaptations as successful top-level carnivores, even after the arrival of modern humans in Europe. They also demonstrate that high δ15N values of bone collagen can solely be explained by mammal meat consumption, as supported by archeological and zooarcheological evidence, without necessarily invoking explanations including the processing of food (cooking, fermenting), the consumption of mammoths or young mammals, or additional (freshwater fish, mushrooms) dietary protein sources.
Published:
March 12, 2019
Title:
Fiber and Colon Cancer, Part 2
Authors:
Morgan
Abstract:
A few years back I wrote an in depth blog post about the questionable role of fiber in preventing colorectal cancer based on the results of several clinical trials. find that post here. If you have…
Published:
March 12, 2019
Title:
p53 β-hydroxybutyrylation attenuates p53 activity
Authors:
Liu, Kun; Li, Fangzhou; Sun, Qianqian; Lin, Ning; Han, Haichao; You, Kaiqiang; Tian, Feng; Mao, Zebin; Li, Tingting; Tong, Tanjun; Geng, Meiyu; Zhao, Yingming; Gu, Wei; Zhao, Wenhui
Abstract:
p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that β-hydroxybutyrate (BHB) induces β-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by γ-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.
Published:
March 11, 2019
Title:
Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers
Authors:
Takamatsu, Hitoshi; Yamamoto, Ken-Ichi; Tomonobu, Nahoko; Murata, Hitoshi; Inoue, Yusuke; Yamauchi, Akira; Sumardika, I. Wayan; Youyi, Chen; Kinoshita, Rie; Yamamura, Masahiro; Fujiwara, Hideyo; Mitsui, Yosuke; Araki, Kota; Futami, Junichiro; Saito, Ken; Iioka, Hidekazu; Ruma, I. Made Winarsa; Putranto, Endy Widya; Nishibori, Masahiro; Kondo, Eisaku; Yamamoto, Yasuhiko; Toyooka, Shinichi; Sakaguchi, Masakiyo
Abstract:
The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is cross-talking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE-positive expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we hence investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.
Published:
March 8, 2019
Title:
PALEOLITHIC KETOGENIC DIET (PKD) AS A STAND-ALONE THERAPY IN CANCER: CASE STUDIES
Authors:
Clemens, Zsofia; Dabóczi, Andrea; Tóth, Csaba
Abstract:
Outlook for cancer patients remains poor despite ”best available treatment” which includes surgery, chemotherapy and radiotherapy in most solid cancers. Genetic profiling, attempts to use matched chemotherapy and the use of high-cost biological therapies, so far, did result in no major breakthrough (1). Metabolic therapies have been suggested as a promising alternative option. Yet, clinical group studies that have been published, provide next to no evidence for a benefit in hard clinical endpoints of cancer. Previously, we put forward (2) that the apparent ineffectivity of the ketogenic diet in cancer is likely due to two factors. First, all published studies included cancer patients that also used chemo- and/or radiation therapy. Second, all group studies used the classical version of the ketogenic diet which is based on vegetable oils and dairy, an evolutionary maladapted, erroneous version of the ketogenic diet.
Published:
March 8, 2019
Title:
The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring
Authors:
Sebastiani, Giorgia; Herranz Barbero, Ana; Borrás-Novell, Cristina; Alsina Casanova, Miguel; Aldecoa-Bilbao, Victoria; Andreu-Fernández, Vicente; Pascual Tutusaus, Mireia; Ferrero Martínez, Silvia; Gómez Roig, María Dolores; García-Algar, Oscar
Abstract:
Vegetarian and vegan diets have increased worldwide in the last decades, according to the knowledge that they might prevent coronary heart disease, cancer, and type 2 diabetes. Althought plant-based diets are at risk of nutritional deficiencies such as proteins, iron, vitamin D, calcium, iodine, omega-3, and vitamin B12, the available evidence shows that well planned vegetarian and vegan diets may be considered safe during pregnancy and lactation, but they require a strong awareness for a balanced intake of key nutrients. A review of the scientific literature in this field was performed, focusing specifically on observational studies in humans, in order to investigate protective effects elicited by maternal diets enriched in plant-derived foods and possible unfavorable outcomes related to micronutrients deficiencies and their impact on fetal development. A design of pregestational nutrition intervention is required in order to avoid maternal undernutrition and consequent impaired fetal growth.
Published:
March 6, 2019
Title:
Genomic evidence for shared common ancestry of East African hunting-gathering populations and insights into local adaptation
Authors:
Scheinfeldt, Laura B.; Soi, Sameer; Lambert, Charla; Ko, Wen-Ya; Coulibaly, Aoua; Ranciaro, Alessia; Thompson, Simon; Hirbo, Jibril; Beggs, William; Ibrahim, Muntaser; Nyambo, Thomas; Omar, Sabah; Woldemeskel, Dawit; Belay, Gurja; Froment, Alain; Kim, Junhyong; Tishkoff, Sarah A.
Abstract:
Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genome-wide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a hunting-gathering (HG) lifestyle. We observe that genetic structure in Africa is broadly correlated not only with geography, but to a lesser extent, with linguistic affiliation and subsistence strategy. Four East African HG (EHG) populations that are geographically distant from each other show evidence of common ancestry: the Hadza and Sandawe in Tanzania, who speak languages with clicks classified as Khoisan; the Dahalo in Kenya, whose language has remnant clicks; and the Sabue in Ethiopia, who speak an unclassified language. Additionally, we observed common ancestry between central African rainforest HGs and southern African San, the latter of whom speak languages with clicks classified as Khoisan. With the exception of the EHG, central African rainforest HGs, and San, other HG groups in Africa appear genetically similar to neighboring agriculturalist or pastoralist populations. We additionally demonstrate that infectious disease, immune response, and diet have played important roles in the adaptive landscape of African history. However, while the broad biological processes involved in recent human adaptation in Africa are often consistent across populations, the specific loci affected by selective pressures more often vary across populations.
Published:
March 5, 2019
Title:
PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin
Authors:
Besse-Patin, Aurèle; Jeromson, Stewart; Levesque-Damphousse, Philipa; Secco, Blandine; Laplante, Mathieu; Estall, Jennifer L.
Abstract:
Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.
Published:
March 5, 2019
Title:
Anti-influenza activity of elderberry (Sambucus nigra)
Authors:
Torabian, Golnoosh; Valtchev, Peter; Adil, Qayyum; Dehghani, Fariba
Abstract:
Elderberry extract is effective in treatment of flu. This study aimed to determine the mechanism of action of elderberry and its primary active compound, cyanidin 3-glucoside (cyn 3-glu), against influenza virus. The direct effect was studied via hemagglutination inhibition assay, plaque reduction assay, and flow cytometry analysis. In addition, to assess the indirect immunomodulatory effect, the modulation of pro-inflammatory cytokines was evaluated. Elderberry showed mild inhibitory effect at the early stages of the influenza virus cycle, with considerably stronger effect (therapeutic index of 12 ± 1.3) in the post-infection phase. Our data further support both direct effects of elderberry extract by blocking viral glycoproteins as well as indirect effects by increased expression of IL-6, IL-8, and TNF. Cyn 3-glu despite demonstrating a similar direct mechanism of action (IC50 of 0.069 mg/ml) compared to the elderberry juice, did not affect the expression of pro-inflammatory cytokines. In conclusion, elderberry exhibits multiple modes of therapeutic action against influenza infection.
Published:
March 1, 2019
Title:
Characterizing Developmental Trajectories and the Role of Neuropsychiatric Genetic Risk Variants in Early-Onset Depression
Authors:
Rice, Frances; Riglin, Lucy; Thapar, Ajay K.; Heron, Jon; Anney, Richard; O’Donovan, Michael C.; Thapar, Anita
Abstract:
OBJECTIVE To test the hypothesis that there are distinct trajectories of depressive symptoms and that genetic liability for neurodevelopmental psychiatric disorders (eg, schizophrenia, attention deficit/hyperactivity disorder [ADHD]), as well as for major depressive disorder (MDD), contribute to early-onset depression. DESIGN, SETTING, AND PARTICIPANTS The Avon Longitudinal Study of Parents and Children is an ongoing, prospective, longitudinal, population-based cohort that has been collecting data since September 6, 1990, including data on 7543 adolescents with depressive symptoms at multiple time points. The present study was conducted between November 10, 2017, and August 14, 2018. MAIN OUTCOMES AND MEASURES Trajectories based on self-reported depressive symptoms dichotomized by the clinical cutpoint; MDD, schizophrenia, and ADHD polygenic risk score (PRS) were predictors. RESULTS In 7543 adolescents with depression data on more than 1 assessment point between a mean (SD) age of 10.64 (0.25) years and 18.65 (0.49) years (3568 [47.3%] male; 3975 [52.7%] female), 3 trajectory classes were identified: persistently low (73.7%), later-adolescence onset (17.3%), and early-adolescence onset (9.0%). The later-adolescence–onset class was associated with MDD genetic risk only (MDD PRS: odds ratio [OR], 1.27; 95% CI, 1.09-1.48; P = .003). The early-adolescence–onset class was also associated with MDD genetic risk (MDD PRS: OR, 1.24; 95% CI, 1.06-1.46; P = .007) but additionally with genetic risk for neurodevelopmental disorders (schizophrenia PRS: OR, 1.22; 95% CI, 1.04-1.43; P = .01; ADHD PRS: OR, 1.32; 95% CI, 1.13-1.54; P < .001) and childhood ADHD (χ 2 1 = 6.837; P = .009) and neurodevelopmental traits (pragmatic language difficulties: OR, 1.31; P = .004; social communication difficulties: OR, 0.68; P
Published:
March 1, 2019
Title:
M1 macrophage mediated increased reactive oxygen species (ROS) influence wound healing via the MAPK signaling in vitro and in vivo
Authors:
Deng, Zheng; Shi, Fei; Zhou, Zheng; Sun, Feng; Sun, Meng-Hao; Sun, Qian; Chen, Lei; Li, Deng; Jiang, Chen-Yi; Zhao, Rui-Zhe; Cui, Di; Wang, Xing-Jie; Jing, Yi-Feng; Xia, Shu-Jie; Han, Bang-Min
Abstract:
Thulium laser resection of the prostate (TmLRP), a major treatment for benign prostatic hyperplasia (BPH), has several postoperative complications that affect the patients' quality of life. The aim of this study was to investigate the effect of the M1 macrophage-secreted reactive oxygen species (ROS) on prostatic wound healing, and the role of MAPK signaling in this process. A co-culture model in vitro was established using macrophages and prostate epithelial or stromal cells. Cell proliferation, migration, apoptosis, MAPK pathway-related gene expression levels were evaluated by standard assays. In addition, an in vivo model of prostatectomy was established in beagles by subjecting them to TmLRP, and were either treated with N-acetyl-L-cysteine (NAC) and or placebo. Wound healing and re-epithelialization were analyzed histopathologically in both groups, in addition to macrophage polarization, oxidative stress levels and MAPK pathway-related proteins expressions. Intracellular ROS levels were significantly increased in the prostate epithelial and stromal cells following co-culture with M1-like macrophages and H2O2 exposure via MAPK activation, which affected their proliferation, migration and apoptosis, and delayed the wound healing process. The cellular functions and wound healing capacity of the prostate cells were restored by blocking or clearing the macrophage-secreted ROS. In the beagle model, increased ROS levels impaired cellular functions, and appropriate removing ROS accelerated the wound healing process.
Published:
March 1, 2019
Title:
Protective effects of alogliptin against TNF-α-induced degradation of extracellular matrix in human chondrocytes
Authors:
Zhang, Panpan; Chen, Yuhua; Zhao, Huafei; Du, Hao
Abstract:
Osteoarthritis (OA) is a common debilitating disease most prevalent among the elderly population worldwide. Excessive degradation of the articular extracellular matrix is a pivotal event in the development of OA. Preventative treatments against the destruction of type II collagen and aggrecan, the two main components of the articular extracellular matrix, may serve as a novel therapy against the progression of OA. In the current study, we investigated whether the DPP-4 inhibitor alogliptin could prevent degradation of the articular extracellular matrix in human primary chondrocytes. Pretreatment with alogliptin successfully prevented degradation of type II collagen and aggrecan in a dose-dependent manner by reducing increased expression of MMP-1, -3, and -13 as well as ADAMTS-4 and -5 induced by treatment with TNF-α. Furthermore, pretreatment with alogliptin also reduced TNF-α-induced expression of IKKα/β, IκBα and NF-κB in human primary chondrocytes. This suggests that DPP-4 inhibitors such as alogliptin may be used as an effective preventative therapy against continued destruction of the articular extracellular matrix in OA.
Published:
March 1, 2019
Title:
Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs
Authors:
Gok Yavuz, Betul; Gunaydin, Gurcan; Gedik, M. Emre; Kosemehmetoglu, Kemal; Karakoc, Derya; Ozgur, Figen; Guc, Dicle
Abstract:
Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.
Published:
February 28, 2019
Title:
Identification of potential human urinary biomarkers for tomato juice intake by mass spectrometry-based metabolomics
Authors:
Hövelmann, Yannick; Jagels, Annika; Schmid, Robin; Hübner, Florian; Humpf, Hans-Ulrich
Abstract:
PURPOSE: Dietary biomarkers allow the accurate and objective determination of the dietary intake of humans and can thus be valuable for investigating the relation between consumption of foods and biochemical as well as physiological responses. The objective of this study was the identification of potential urinary biomarkers for consumption of tomato juice. METHODS: In the course of a dietary intervention study, the human urine metabolome of a study cohort was compared between a tomato-free diet and after intake of tomato juice by application of an LC-HRMS-based metabolomics approach. The data acquisition was achieved using an orbitrap mass spectrometer, followed by multistage data processing and univariate as well as multivariate statistical analysis to identify discriminating features. RESULTS: Statistical analysis revealed several unique features detectable after tomato juice intake. The most discriminating markers were putatively identified as hydroxylated and sulfonated metabolites of esculeogenin B, aglycone of the steroidal glycoalkaloid esculeoside B recently found in tomato juice. Furthermore, the β-carboline alkaloids tangutorid E and F and glucuronidated derivatives thereof were identified in urine. CONCLUSIONS: Steroidal glycoalkaloids in tomato juice are cleaved after ingestion, and hydroxylated and sulfonated metabolites of their aglycones might serve as urinary biomarkers for tomato juice intake. Similarly, β-carboline alkaloids and glucuronidated derivatives were identified as potential urinary biomarkers. Both the aglycones of the steroidal alkaloids and the β-carboline alkaloids might exhibit biological activities worth investigating.
Published:
February 28, 2019
Title:
Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
Authors:
Halbrook, Christopher J.; Pontious, Corbin; Kovalenko, Ilya; Lapienyte, Laura; Dreyer, Stephan; Lee, Ho-Joon; Thurston, Galloway; Zhang, Yaqing; Lazarus, Jenny; Sajjakulnukit, Peter; Hong, Hanna S.; Kremer, Daniel M.; Nelson, Barbara S.; Kemp, Samantha; Zhang, Li; Chang, David; Biankin, Andrew; Shi, Jiaqi; Frankel, Timothy L.; Crawford, Howard C.; Morton, Jennifer P.; Pasca di Magliano, Marina; Lyssiotis, Costas A.
Abstract:
Summary Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.
Published:
February 28, 2019
Title:
A Plant-Based Meal Stimulates Incretin and Insulin Secretion More Than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study
Authors:
Kahleova, Hana; Tura, Andrea; Klementova, Marta; Thieme, Lenka; Haluzik, Martin; Pavlovicova, Renata; Hill, Martin; Pelikanova, Terezie
Abstract:
Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p
Published:
February 26, 2019
Title:
Low-Dose Methotrexate for the Prevention of Atherosclerotic Events
Authors:
Ridker, Paul M; Everett, Brendan M.; Pradhan, Aruna; MacFadyen, Jean G.; Solomon, Daniel H.; Zaharris, Elaine; Mam, Virak; Hasan, Ahmed; Rosenberg, Yves; Iturriaga, Erin; Gupta, Milan; Tsigoulis, Michelle; Verma, Subodh; Clearfield, Michael; Libby, Peter; Goldhaber, Samuel Z.; Seagle, Roger; Ofori, Cyril; Saklayen, Mohammad; Butman, Samuel; Singh, Narendra; Le May, Michel; Bertrand, Olivier; Johnston, James; Paynter, Nina P.; Glynn, Robert J.
Abstract:
Published:
February 21, 2019
Title:
Convergent gene losses illuminate metabolic and physiological changes in herbivores and carnivores
Authors:
Hecker, Nikolai; Sharma, Virag; Hiller, Michael
Abstract:
The repeated evolution of dietary specialization represents a hallmark of mammalian ecology. To detect genomic changes that are associated with dietary adaptations, we performed a systematic screen for convergent gene losses associated with an obligate herbivorous or carnivorous diet in 31 placental mammals. For herbivores, our screen discovered the repeated loss of the triglyceride lipase inhibitor PNLIPRP1, suggesting enhanced triglyceride digestion efficiency. Furthermore, several herbivores lost the pancreatic exocytosis factor SYCN, providing an explanation for continuous pancreatic zymogen secretion in these species. For carnivores, we discovered the repeated loss of the hormone-receptor pair INSL5–RXFP4 that regulates appetite and glucose homeostasis, which likely relates to irregular feeding patterns and constant gluconeogenesis. Furthermore, reflecting the reduced need to metabolize plant-derived xenobiotics, several carnivores lost the xenobiotic receptors NR1I3 and NR1I2. Finally, the carnivore-associated loss of the gastrointestinal host defense gene NOX1 could be related to a reduced gut microbiome diversity. By revealing convergent gene losses associated with differences in dietary composition, feeding patterns, and gut microbiomes, our study contributes to understanding how similar dietary specializations evolved repeatedly in mammals.
Published:
February 19, 2019
Title:
Higher Non-processed Red Meat Consumption Is Associated With a Reduced Risk of Central Nervous System Demyelination
Authors:
Black, Lucinda J.; Bowe, Gabrielle S.; Pereira, Gavin; Lucas, Robyn M.; Dear, Keith; van der Mei, Ingrid; Sherriff, Jill L.
Abstract:
The evidence associating red meat consumption and risk of multiple sclerosis is inconclusive. We tested associations between red meat consumption and risk of a first clinical diagnosis of central nervous system demyelination (FCD), often presaging a diagnosis of multiple sclerosis. We used food frequency questionnaire data from the 2003–2006 Ausimmune Study, an incident, matched, case-control study examining environmental risk factors for FCD. We calculated non-processed and processed red meat density (g/1,000 kcal/day). Conditional logistic regression models (with participants matched on age, sex, and study region) were used to estimate odds ratios (ORs), 95% confidence intervals (95% CI) and p-values for associations between non-processed (n = 689, 250 cases, 439 controls) and processed (n = 683, 248 cases, 435 controls) red meat density and risk of FCD. Models were adjusted for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, race, education, body mass index and dietary misreporting. A one standard deviation increase in non-processed red meat density (22 g/1,000 kcal/day) was associated with a 19% reduced risk of FCD (AOR = 0.81; 95%CI 0.68, 0.97; p = 0.02). When stratified by sex, higher non-processed red meat density (per 22 g/1,000 kcal/day) was associated with a 26% reduced risk of FCD in females (n = 519; AOR = 0.74; 95%CI 0.60, 0.92; p = 0.01). There was no statistically significant association between non-processed red meat density and risk of FCD in males (n = 170). We found no statistically significant association between processed red meat density and risk of FCD. Further investigation is warranted to understand the important components of a diet that includes non-processed red meat for lower FCD risk.
Published:
February 19, 2019
Title:
Alcohol and delirium tremens: effects of average number of drinks per day and beverage type
Authors:
Sørensen, H. J.; Holst, C.; Knop, J.; Mortensen, E. L.; Tolstrup, J. S.; Becker, U.
Abstract:
Objective: Associations of amount of alcohol intake and beverage type with the risk of delirium tremens (DT) have not been studied. This longitudinal study investigated if the average number of drinks per day and beverage type predict DT. Methods: A cohort of 3 582 alcohol-dependent men and women aged 19–82 without previous DT were interviewed about alcohol intake and beverage type at baseline in 1994–2005 and followed through record linkage in Danish nationwide registers to identify incident DT. Data were analyzed by means of Cox regression models. Results: An average number of drinks per day of 20–30 or >30 was associated with hazard ratios (HRs) of 1.38 (95% CI 1.03–1.84) and 1.64 (95% CI 1.19–2.27) relative to the reference category (1–9 drinks). Independently of amount consumed and covariates (age, gender, civil status and work status), beverage type (spirits vs. mixed alcohol) was associated with a HR of 1.63 (95% CI 1.08–2.46). Male gender was robustly associated with increased risk (HR = 1.62 (95% CI 1.25–2.08). Conclusions: In alcohol-dependent men and women, daily alcohol intake above a threshold of 20 beverages or 240 g alcohol and a preference for spirits increase the risk of developing DT.
Published:
February 17, 2019
Title:
A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy
Authors:
Hajek, Peter; Phillips-Waller, Anna; Przulj, Dunja; Pesola, Francesca; Myers Smith, Katie; Bisal, Natalie; Li, Jinshuo; Parrott, Steve; Sasieni, Peter; Dawkins, Lynne; Ross, Louise; Goniewicz, Maciej; Wu, Qi; McRobbie, Hayden J.
Abstract:
BACKGROUND E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments. METHODS We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a secondgeneration refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms. RESULTS A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P
Published:
February 14, 2019
Title:
Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism
Authors:
Kim, Minjoong; Gwak, Jihye; Hwang, Sunsook; Yang, Seungyeon; Jeong, Seung Min
Abstract:
Cancer cells exhibit metabolic dependence on mitochondrial glutamine metabolism that provides them with the substrates required for rapid proliferation. Despite the extensive efforts to target this glutamine addiction for therapeutic purposes, the adaptive metabolic responses and the mechanisms whereby cells maintain their unlimited growth remain areas of active investigation. Here we report that mitochondrial glutamate-pyruvate transaminase 2 (GPT2) contributes to cell survival and growth by sustaining the tricarboxylic acid (TCA) cycle anaplerosis after the inhibition of glutaminase (GLS), the first enzyme for mitochondrial glutamine metabolism. We found that elevated reactive oxygen species upon GLS inhibition induce GPT2 expression via activating transcription factor 4. Moreover, inhibition of GPT2 synergized with suppression of GLS activity to induce a pronounced reduction in proliferation and an increase in cell death of cancer cells. Our data uncover GPT2 as an important component of the adaptive metabolic response for glutamine deprivation and indicate that targeting this pathway in combination with GLS inhibition may be an effective therapeutic approach for cancer treatment.
Published:
February 14, 2019
Title:
Assessment of a Personalized Approach to Predicting Postprandial Glycemic Responses to Food Among Individuals Without Diabetes
Authors:
Mendes-Soares, Helena; Raveh-Sadka, Tali; Azulay, Shahar; Edens, Kim; Ben-Shlomo, Yatir; Cohen, Yossi; Ofek, Tal; Bachrach, Davidi; Stevens, Josh; Colibaseanu, Dorin; Segal, Lihi; Kashyap, Purna; Nelson, Heidi
Abstract:
Emerging evidence suggests that postprandial glycemic responses (PPGRs) to food may be influenced by and predicted according to characteristics unique to each individual, including anthropometric and microbiome variables. Interindividual diversity in PPGRs to food requires a personalized approach for the maintenance of healthy glycemic levels.To describe and predict the glycemic responses of individuals to a diverse array of foods using a model that considers the physiology and microbiome of the individual in addition to the characteristics of the foods consumed.This cohort study using a personalized predictive model enrolled 327 individuals without diabetes from October 11, 2016, to December 13, 2017, in Minnesota and Florida to be part of a study lasting 6 days. The study measured anthropometric variables, described the gut microbial composition, and assessed blood glucose levels every 5 minutes using a continuous glucose monitor. Participants logged their food and activity information for the duration of the study. A predictive model of individualized PPGRs to a diverse array of foods was trained and applied.Glycemic responses to food consumed over 6 days for each participant. The predictive model of personalized PPGRs considered individual features, including the microbiome, in addition to the features of the foods consumed.Postprandial response to the same foods varied across 327 individuals (mean [SD] age, 45 [12] years; 78.0% female). A model predicting each individual’s responses to food that considers several individual factors in addition to food features had better overall performance (R = 0.62) than current standard-of-care approaches using nutritional content alone (R = 0.34 for calories and R = 0.40 for carbohydrates) to control postprandial glycemic levels.Across the cohort of adults without diabetes who were examined, a personalized predictive model that considers unique features of the individual, such as clinical characteristics, physiological variables, and the microbiome, in addition to nutrient content was more predictive than current dietary approaches that focus only on the calorie or carbohydrate content of foods. Providing individuals with tools to manage their glycemic responses to food based on personalized predictions of their PPGRs may allow them to maintain their blood glucose levels within limits associated with good health.
Published:
February 8, 2019
Title:
James Rippe
Authors:
Abstract:
James M. Rippe (born June 26, 1947) is an American cardiologist. He is the founder and director of the Rippe Lifestyle Institute, located in Shrewsbury, Massachusetts. According to the New York Times, he received $10M in funding between 2010 and 2014 from the Corn Refiners Association to study health effects of high fructose corn syrup and published reports "disputing any special health consequences associated with the corn-based sweeter"; he also received a $41,000-a-month fee from the group which the Times said was for him "to serve as an outside expert whom it repeatedly asked to send commentary pieces to local newspapers and dispute any claims that consuming high-fructose corn syrup in foods was any more risky than sugar."[5][6] Rippe is the editor-in-chief of the American Journal of Lifestyle Medicine, as well as the co-editor-in-chief of the Journal of Intensive Care Medicine.[7] Dr. Rippe has published over 50 books, including Encyclopedia of Lifestyle Medicine and Health,[8] Lifestyle Medicine, Second Edition, [9] and Nutrition in Lifestyle Medicine[10]
Published:
February 7, 2019
Title:
Supplementary Material
Authors:
Werneburg, Ingmar; Esteve-Altava, Borja; Araújo Bruno, Joana; Ladeira, Marta; Diogo, Rui
Abstract:
Published:
February 6, 2019
Title:
Unique skull network complexity of Tyrannosaurus rex among land vertebrates
Authors:
Werneburg, Ingmar; Esteve-Altava, Borja; Araújo Bruno, Joana; Ladeira, Marta; Diogo, Rui
Abstract:
Like other diapsids, Tyrannosaurus rex has two openings in the temporal skull region. In addition, like in other dinosaurs, its snout and lower jaw show large cranial fenestrae. In T .rex, they are thought to decrease skull weight, because, unlike most other amniotes, the skull proportion is immense compared to the body. Understanding morphofunctional complexity of this impressive skull architecture requires a broad scale phylogenetic comparison with skull types different to that of dinosaurs with fundamentally diverging cranial regionalization. Extant fully terrestrial vertebrates (amniotes) provide the best opportunities in that regard, as their skull performance is known from life. We apply for the first time anatomical network analyses to study skull bone integration and modular constructions in tyrannosaur and compare it with five representatives of the major amniote groups in order to get an understanding of the general patterns of amniote skull modularity. Our results reveal that the tyrannosaur has the most modular skull organization among the amniotes included in our study, with an unexpected separation of the snout in upper and lower sub-modules and the presence of a lower adductor chamber module. Independent pathways of bone reduction in opossum and chicken resulted in different degrees of cranial complexity with chicken having a typical sauropsidian pattern. The akinetic skull of opossum, alligator, and leatherback turtle evolved in independent ways mirrored in different patterns of skull modularity. Kinetic forms also show great diversity in modularity. The complex tyrannosaur skull modularity likely represents a refined mosaic of phylogenetic and ecological factors with food processing being probably most important for shaping its skull architecture. Mode of food processing primarily shaped skull integration among amniotes, however, phylogenetic patterns of skull integration are low in our sampling. Our general conclusions on amniote skull integrity are obviously preliminary and should be tested in subsequent studies. As such, this study provides a framework for future research focusing on the evolution of modularity on lower taxonomic levels.
Published:
February 6, 2019
Title:
Origins of the Human Predatory Pattern: The Transition to Large-Animal Exploitation by Early Hominins
Authors:
Thompson, Jessica; Carvalho, Susana; Marean, Curtis; Alemseged, Zeresenay
Abstract:
The habitual consumption of large-animal resources (e.g., similar sized or larger than the consumer) separates human and nonhuman primate behavior. Flaked stone tool use, another important hominin behavior, is often portrayed as being functionally related to this by the necessity of a sharp edge for cutting animal tissue. However, most research on both issues emphasizes sites that postdate ca. 2.0 million years ago. This paper critically examines the theoretical significance of the earlier origins of these two behaviors, their proposed interrelationship, and the nature of the empirical record. We argue that concepts of meat-eating and tool use are too loosely defined: outside-bone nutrients (e.g., meat) and inside-bone nutrients (e.g., marrow and brains) have different macronutrient characteristics (protein vs. fat), mechanical requirements for access (cutting vs. percussion), search, handling and competitive costs, encounter rates, and net returns. Thus, they would have demanded distinct technological and behavioral solutions. We propose that the regular exploitation of large-animal resources—the “human predatory pattern”—began with an emphasis on percussion based scavenging of inside-bone nutrients, independent of the emergence of flaked stone tool use. This leads to a series of empirical test implications that differ from previous “meat-eating” origins scenarios.
Published:
February 5, 2019
Title:
Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism
Authors:
Serveaux-Dancer, Marine; Jabaudon, Matthieu; Creveaux, Isabelle; Belville, Corinne; Blondonnet, Raïko; Gross, Christelle; Constantin, Jean-Michel; Blanchon, Loïc; Sapin, Vincent
Abstract:
The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn's disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.
Published:
February 4, 2019
Title:
Origins of the Human Predatory Pattern: The Transition to Large-Animal Exploitation by Early Hominins
Authors:
Thompson, Jessica C.; Carvalho, Susana; Marean, Curtis W.; Alemseged, Zeresenay
Abstract:
The habitual consumption of large-animal resources (e.g., similar sized or larger than the consumer) separates human and nonhuman primate behavior. Flaked stone tool use, another important hominin behavior, is often portrayed as being functionally related to this by the necessity of a sharp edge for cutting animal tissue. However, most research on both issues emphasizes sites that postdate ca. 2.0 million years ago. This paper critically examines the theoretical significance of the earlier origins of these two behaviors, their proposed interrelationship, and the nature of the empirical record. We argue that concepts of meat-eating and tool use are too loosely defined: outside-bone nutrients (e.g., meat) and inside-bone nutrients (e.g., marrow and brains) have different macronutrient characteristics (protein vs. fat), mechanical requirements for access (cutting vs. percussion), search, handling and competitive costs, encounter rates, and net returns. Thus, they would have demanded distinct technological and behavioral solutions. We propose that the regular exploitation of large-animal resources—the “human predatory pattern”—began with an emphasis on percussion-based scavenging of inside-bone nutrients, independent of the emergence of flaked stone tool use. This leads to a series of empirical test implications that differ from previous “meat-eating” origins scenarios.
Published:
February 2, 2019
Title:
Anxiety, Depression, and Insomnia Among Adults With Opioid Dependence Treated With Extended-Release Naltrexone vs Buprenorphine-Naloxone: A Randomized Clinical Trial and Follow-up Study
Authors:
Latif, Zill-e-Huma; Šaltyte Benth, Jurate; Solli, Kristin Klemmetsby; Opheim, Arild; Kunoe, Nikolaj; Krajci, Peter; Sharma-Haase, Kamni; Tanum, Lars
Abstract:
OBJECTIVE To investigate whether XR-NTX unmasks or reinforces current comorbid symptoms of anxiety, depression, or insomnia compared with opioid agonist treatment. DESIGN, SETTING, AND PARTICIPANTS In this prospective randomized clinical trial, 159 men and women aged 18 to 60 years with opioid dependence were randomized to 12 weeks of treatment with either XR-NTX or combined buprenorphine-naloxone (BP-NLX) followed by a 9-month, open-label treatment study with participant choice of 1 of these 2 drugs. The study was conducted at outpatient addiction clinics in 5 urban hospitals in Norway, with the clinical trial performed from November 1, 2012, to October 23, 2015, and the follow-up study completed on July 23, 2016. All analyses were conducted using an intention-to-treat sample. INTERVENTIONS Extended-release naltrexone hydrochloride, 380 mg, administered as an injection every 4 weeks or flexible doses (4-24 mg; target dosage 16 mg/d) of daily oral combined BP-NLX. MAIN OUTCOMES AND MEASURES Every 4 weeks, symptoms of anxiety and depression were assessed using the 25-item Hopkins Symptom Checklist, and symptoms of insomnia were assessed using the Insomnia Severity Index. RESULTS In total, 159 participants were randomized to treatment with either XR-NTX (n = 80) or BP-NLX (n = 79), and 105 participants (66.0%) completed the trial. The treatment groups showed similar distributions of age (mean [SD], 36.4 [8.8] vs 35.7 [8.5] years), sex (61 [76.3%] women and 54 [68.4%] men), and duration of heroin use (mean [SD], 6.9 [5.8] vs 6.7 [5.2] years). For the clinical trial period, no overall differences were detected between treatment groups for anxiety (effect size [95% CI], −0.14 [−0.47 to 0.19]) or depression (effect size [95% CI], −0.12 [−0.45 to 0.21]) scores, but the insomnia score was significantly lower in the XR-NTX group (effect size [95% CI], −0.32 [−0.61 to −0.02]; P = .008). In the follow-up period, no overall differences could be detected in the effect size [95% CI] of scores for anxiety (0.04 [−0.34 to 0.42]), depression (−0.04 [−0.42 to 0.33]), or insomnia (0.04 [−0.33 to 0.42]) between participants continuing with and participants switching to XR-NTX. No significant sex differences between the 2 treatment groups were detected. CONCLUSIONS AND RELEVANCE Comorbid symptoms of anxiety, depression, or insomnia in abstinence-motivated persons with opioid dependence should not prevent switching from treatment with an opioid agonist to treatment with XR-NTX.
Published:
February 1, 2019
Title:
Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths: A Systematic Review and Meta-analysis of Longitudinal Population Studies
Authors:
Yates, Kathryn; Lång, Ulla; Cederlöf, Martin; Boland, Fiona; Taylor, Peter; Cannon, Mary; McNicholas, Fiona; DeVylder, Jordan; Kelleher, Ian
Abstract:
OBJECTIVE To provide a quantitative synthesis of the literature examining the longitudinal association between psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide deaths in the general population. DATA SOURCES We searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO from their inception until September 2017 for longitudinal population studies on psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. STUDY SELECTION Two authors searched for original articles that reported a prospective assessment of psychotic experiences and suicidal ideation, suicide attempts, or suicide death in general population samples, with at least 1 follow-up point. DATA EXTRACTION AND SYNTHESIS Two authors conducted independent data extraction. Authors of included studies were contacted for information where necessary. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. We calculated pooled odds ratios using a random-effects model. A secondary analysis assessed the mediating role of co-occurring psychopathology. Supplemental content MAIN OUTCOMES AND MEASURES Psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. RESULTS Of a total of 2540 studies retrieved, 10 met inclusion criteria. These 10 studies reported on 84 285 participants from 12 different samples and 23 countries. Follow-up periods ranged from 1 month to 27 years. Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78]). Risk was increased in excess of that explained by co-occurring psychopathology: suicidal ideation (adjusted OR, 1.59 [95% CI, 1.09-2.32]) and suicide attempt (adjusted OR, 2.68 [95% CI, 1.71-4.21]). CONCLUSIONS AND RELEVANCE Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior.
Published:
February 1, 2019
Title:
Comparative Expression of RAGE and SOX2 in Benign and Malignant Prostatic Lesions
Authors:
Aboushousha, Tarek; Lashen, Rana; Abdelnaser, Khadega; Helal, Noha; Moussa, Mona; Omran, Zeinab; Eldahshan, Samir; El Ganzoury, Hossam
Abstract:
Background: Prostate cancer (PCa) is a common health problem in elderly. RAGE (Receptor for advanced glycation end products) is overexpressed in multiple human cancers. SOX2 (Sex-determining region Y box 2) also functions as an oncoprotein and promotes cancer progression but the mechanisms involved remain largely unknown. Aim: The current study investigated the expression patterns of RAGE and SOX2 in benign and malignant prostate samples in correlation with the histopathological findings in order to evaluate their role as prognostic markers or therapeutic targets. Methods: Immunohistochemical staining for RAGE and SOX2 antibodies was applied on 87 prostatic biopsies [16 of prostatitis, 20 of benign prostatic hyperplasia (BPH) and 51 of PCa]. Results: Expression of RAGE and SOX2 (percentage of positive cells) was significantly higher in PCa lesions compared with prostatitis (p<0.01) and BPH (p<0.0001) and was also significantly higher in prostatitis compared with BPH lesions (p
Published:
February 1, 2019
Title:
Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action
Authors:
Kan, Wei-Chih; Hwang, Jean-Yu; Chuang, Lea-Yea; Guh, Jinn-Yuh; Ye, Yi-Ling; Yang, Yu-Lin; Huang, Jau-Shyang
Abstract:
Background Osthole has been widely reported to have pharmacological activities such as anti-cancer, anti-inflammation and anti-hyperlipidemic effects. Klotho was identified as an anti-senescence protein in a variety of tissues. Loss of klotho has been associated with chronic kidney disease. However, potential roles and molecular events for osthole and klotho in diabetic nephropathy remain unclear. Purpose In the current study, we undertook to study the effect of osthole on klotho expression in advanced glycation end products (AGE)-cultured human renal proximal tubular cells, and to investigate the molecular mechanisms of osthole and exogenous klotho against AGE-induced renal tubular hypertrophy. Methods Cell viability was elucidated by MTT assay. Protein expression was measured by Western blotting. mRNA level was analyzed by real-time PCR. Cellular hypertrophy growth was evaluated by hypertrophy index. Relative cell size was detected by flow cytometry. Results We found that raising the ambient AGE concentration causes a dose-dependent decrease in klotho synthesis. Osthole significantly increased AGE-inhibited klotho mRNA and protein expression. Osthole and exogenous klotho treatments significantly attenuated AGE-induced Janus kinase 2 (JAK2)-signal transducers and activators of transcription 1 (STAT1) and STAT3 activation. Moreover, protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 were augmented by osthole and exogenous klotho. The abilities of osthole and exogenous klotho to reverse AGE-induced cellular hypertrophy were verified by the observation that osthole and exogenous klotho inhibited p21Waf1/Cip1/collagen IV/RAGE expression, total protein content, and cell size. Conclusion Consequently, we found that osthole attenuated AGE-induced renal tubular hypertrophy via induction of klotho expression and suppression of the JAK2-STAT1/STAT3 signaling. These results also showed that klotho might be used as a unique molecular target for the treatment of diabetic nephropathy.
Published:
February 1, 2019
Title:
Factors Associated With Successful Medication Discontinuation After a Randomized Clinical Trial of Relapse Prevention in First-Episode Psychosis: A 10-Year Follow-up
Authors:
Hui, Christy L. M.; Honer, William G.; Lee, Edwin H. M.; Chang, W. C.; Chan, Sherry K. W.; Chen, Eric Y. H.
Abstract:
Published:
February 1, 2019
Title:
Hallucinations Beyond Voices: A Conceptual Review of the Phenomenology of Altered Perception in Psychosis
Authors:
Pienkos, Elizabeth; Giersch, Anne; Hansen, Marie; Humpston, Clara; McCarthy-Jones, Simon; Mishara, Aaron; Nelson, Barnaby; Park, Sohee; Raballo, Andrea; Sharma, Rajiv; Thomas, Neil; Rosen, Cherise
Abstract:
Published:
February 1, 2019
Title:
INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway
Authors:
Zhang, Boke; Du, Yan; He, Yiqing; Liu, Yiwen; Zhang, Guoliang; Yang, Cuixia; Gao, Feng
Abstract:
As a major component of the microenvironment of solid tumors, tumor-associated macrophages (TAMs) facilitate tumor progression. Intermediate-sized hyaluronan (INT-HA) fragments have an immunological function in cell differentiation; however, their role in promoting the polarization of non-activated macrophages to an M2-like TAM phenotype has not been characterized, and the underlying mechanisms remain unclear. Here, we used a miRNA microarray to find that some miRNAs (especially miR-935) were differentially regulated in INT-HA-induced M2-like macrophages. According to RT-qPCR and Western blot, there was an association between miR-935 and C/EBPβ, that control the polarization of macrophages. Moreover, we found that INT-HA induced an M2-like phenotype via the TLR4 receptor. In our study, there was a negative correlation between plasma HA and miR-935 in monocytes from the peripheral blood of patients with solid tumors. There was also a negative correlation between miR-935 and M2-like macrophage markers in monocytes. These findings suggest that HA fragments interact with TLR4 and educate macrophage polarization to an M2-like phenotype via miR-935. Therefore, this study provides new insight into the role of miR-935 in INT-HA-induced M2-like polarization, and suggests a potential therapeutic target for antitumor treatment.
Published:
February 1, 2019
bottom of page