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Title:
Should dietary guidelines recommend low red meat intake?
Authors:
Leroy, Frédéric; Cofnas, Nathan
Abstract:
Mainstream dietary recommendations now commonly advise people to minimize the intake of red meat for health and environmental reasons. Most recently, a major report issued by the EAT-Lancet Commission recommended a planetary reference diet mostly based on plants and with no or very low (14 g/d) consumption of red meat. We argue that claims about the health dangers of red meat are not only improbable in the light of our evolutionary history, they are far from being supported by robust scientific evidence.
Published:
September 5, 2019
Title:
Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Authors:
Stekovic, Slaven; Hofer, Sebastian J.; Tripolt, Norbert; Aon, Miguel A.; Royer, Philipp; Pein, Lukas; Stadler, Julia T.; Pendl, Tobias; Prietl, Barbara; Url, Jasmin; Schroeder, Sabrina; Tadic, Jelena; Eisenberg, Tobias; Magnes, Christoph; Stumpe, Michael; Zuegner, Elmar; Bordag, Natalie; Riedl, Regina; Schmidt, Albrecht; Kolesnik, Ewald; Verheyen, Nicolas; Springer, Anna; Madl, Tobias; Sinner, Frank; de Cabo, Rafael; Kroemer, Guido; Obermayer-Pietsch, Barbara; Dengjel, Jom; Sourij, Harald; Pieber, Thomas R.; Madeo, Frank
Abstract:
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased beta-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
Published:
September 3, 2019
Title:
The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose
Authors:
Defenouillère, Quentin; Verraes, Agathe; Laussel, Clotilde; Friedrich, Anne; Schacherer, Joseph; Léon, Sébastien
Abstract:
Resisting a metabolic poison Once imported into cells and phosphorylated, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, leading to the proposal of using 2DG as a cancer treatment. Using yeast as a model, Defenouillère et al. investigated how cells become resistant to 2DG. Exposure to 2DG activated several signaling pathways that resulted in the increased expression of the gene encoding the phosphatase Dog2. In contrast, glucose availability transcriptionally repressed DOG2 expression. When overexpressed, a human homolog of Dog2 conferred 2DG resistance to human cells, suggesting that cancer cells with increased abundance of this phosphatase could escape the toxic effects of 2DG. Anti-cancer strategies that target the glycolytic metabolism of tumors have been proposed. The glucose analog 2-deoxyglucose (2DG) is imported into cells and, after phosphorylation, becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. Using yeast as a model, we performed an unbiased mass spectrometry–based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms to 2DG. We found that two phosphatases that target 2DG-6-phosphate were induced upon exposure to 2DG and participated in 2DG detoxification. Dog1 and Dog2 are HAD (haloacid dehalogenase)–like phosphatases, which are evolutionarily conserved. 2DG induced Dog2 by activating several signaling pathways, such as the stress response pathway mediated by the p38 MAPK ortholog Hog1, the unfolded protein response (UPR) triggered by 2DG-induced ER stress, and the cell wall integrity (CWI) pathway mediated by the MAPK Slt2. Loss of the UPR or CWI pathways led to 2DG hypersensitivity. In contrast, mutants impaired in the glucose-mediated repression of genes were 2DG resistant because glucose availability transcriptionally repressed DOG2 by inhibiting signaling mediated by the AMPK ortholog Snf1. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed that DOG2 overexpression was a common strategy underlying 2DG resistance. The human Dog2 homolog HDHD1 displayed phosphatase activity toward 2DG-6-phosphate in vitro and its overexpression conferred 2DG resistance in HeLa cells, suggesting that this 2DG phosphatase could interfere with 2DG-based chemotherapies. These results show that HAD-like phosphatases are evolutionarily conserved regulators of 2DG resistance. An evolutionarily conserved family of phosphatases enables cells to resist the toxic metabolic effects of 2-deoxyglucose. An evolutionarily conserved family of phosphatases enables cells to resist the toxic metabolic effects of 2-deoxyglucose.
Published:
September 3, 2019
Title:
Dietary habits of the cave bear from the Late Pleistocene in the northeast of the Iberian Peninsula
Authors:
Ramírez-Pedraza, Iván; Pappa, Spyridoula; Blasco, Ruth; Arilla, Maite; Rosell Ardèvol, Jordi; Millán, Ferran; Maroto, Julià; Soler, Joaquim; Soler, Narcis; Rivals, Florent
Abstract:
The aim of this study is to understand the feeding habits of the cave bear, Ursus spelaeus by investigating the dental microwear patterns of 106 molars from six Late Pleistocene caves in Catalonia (Spain): Ermitons Cave, Arbreda Cave, Mollet Cave, Llenes Cave, Toll Cave, and Teixoneres Cave. Dental microwear patterns of U. spelaeus were compared with a reference collection of extant ursid species. The results show an omnivorous and carnivorous diet in all sites analyzed with both intra- and inter-site pattern variability. Unlike previous studies, here dental microwear identified more carnivorous habits for the herbivorous cave bear during the days/weeks before death. More varied and higher energy items would help to cope with the hibernation period. The variability between the samples could be due to the characteristic climatic shifts of the Late Pleistocene and to the corresponding differences in the availability of resources.
Published:
September 1, 2019
Title:
Hounds follow those who feed them: What can the ethnographic record of hunter-gatherers reveal about early human-canid partnerships?
Authors:
Lupo, Karen D.
Abstract:
The establishment of early human-canid partnerships involving the use of dogs in hauling and/or hunting is often nominated as a process that underwrote technological, economic and demographic changes in prehistoric human populations. Inferences about the uses of prehistoric canids are bolstered by reference to ethnographic analogues. Archeologists, however, lack an inferential framework encompassing a systematic analysis of the ethnographic record that identifies the circumstances that support and constrain the use of canids. This paper presents comparative analyses of hunter-gatherer ethnographic records that show the importance of provisioning in supporting dogs engaged in energetically demanding activities. Canid thermoregulation in concert with work load intensity require significant investments provisioning dogs that can greatly inflate the subsistence efforts of hunter-gatherers. These data suggest that anthropogenic food refuse could not have established or supported an indigenous working dog population. Prehistoric human-dog interactions in colder biomes that involved the use of dogs working in haulage and/or hunting could only be supported after intentional provisioning regimes emerged and were incorporated into hunter-gatherer subsistence systems. The importance of human provisioning in the use of working dogs has implications for understanding the circumstances that supported the formation of early human-canid working relationships and the domestication process.
Published:
September 1, 2019
Title:
The use of bones as retouchers at Unit III of Teixoneres Cave (MIS 3; Moià, Barcelona, Spain)
Authors:
Mateo Lomba, Paula; Rivals, Florent; Blasco, Ruth; Rosell Ardèvol, Jordi
Abstract:
Prehistoric human groups organize their subsistence strategies according to environmental parameters and socio-cultural variables. Functional analysis of artefacts allows researchers to recognize different activities and the characteristics of their utilization and to formulate hypotheses about the duration and the way that sites were occupied. Bones used as tools for the manufacture and maintenance of lithic artefacts have been recognized in multiple archaeological contexts. The Middle Palaeolithic site of the Teixoneres Cave (Moià, Barcelona, Spain) has yielded a small collection of bone fragments which were used as retouchers. The stratigraphic sequence is characterised by an alternation in the hominid and carnivore occupations. The sublevel IIIb (MIS 3) is the unit showing the highest anthropic intensity with lithic tools, human-induced damage on faunal specimens and, specifically, bone retouchers. In this study these bone artefacts have been studied according to the main standardized taphonomical and technological methods. Additionally, experimental protocols with bones used for retouching or re-sharpening quartz and flint flakes were conducted, which showed the different use traces produced on the bone surface. The analysis of the data indicates that these archaeological bone retouchers were obtained and discarded in situ, without any configuration of the blank. Before their abandonment, bone re-touchers were used to occasionally retouch and re-sharpen the lithic implements, especially the local quartz artefacts. This paper aims to explore new types of lithic raw material in experiments with bone retouchers and add data to the multidisciplinary study of the site.
Published:
August 30, 2019
Title:
Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives
Authors:
Abdi, Esmat; Latifi‐Navid, Saeid; Zahri, Saber; Yazdanbod, Abbas; Pourfarzi, Farhad
Abstract:
Recent decades have seen an alarming increase in the incidence of cardia gastric adenocarcinoma (CGA) while noncardia gastric adenocarcinoma (NCGA) has decreased. In 2012, 260 000 CGA cases (age‐standardised rate (ASR); 3.3/100 000) and 691 000 NCGA cases (ASR; 8.8/100 000) were reported worldwide. Compared with women, men had greater rates for both the subsites, especially for CGA. Recently, four molecular subtypes of GC have been proposed by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG); however, these classifications do not take into account predisposing germline variants and their possible interaction with somatic alterations in carcinogenesis. The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known. It is thought that CGA is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. Therefore, understanding the risk and the role of predisposing factors in etiology of CGA can inform clinical practice and counseling for risk reduction. In this paper, we showed that GC family history, lifestyle, demographics, gastroesophageal reflux disease, Helicobacter pylori infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions may underlie susceptibility to CGA. However, several genome‐wide association studies (GWASs) should be conducted to identify novel high‐penetrance genes and pathways as well as causal germline variants predisposing to CGA. They must include different ethnic groups, especially from high‐incidence countries for CGA, because some risk loci are ancestry‐specific. In parallel, statistical methods can be developed to identify cancer predisposition genes (CPGs) from tumor sequencing data. It is also necessary to find novel long noncoding RNAs related to the risk of CGA. Taken altogether, new cancer risk prediction models, including all genetic and nongenetic factors influencing risk, should be developed to facilitate risk assessment, disease prevention, and early diagnosis and intervention of CGA in the future., The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known and is doubted. It is thought that cardia gastric adenocarcinoma (CGA) is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. In this paper, we would like to ascertain the possible role of GC family history, lifestyle, demographics, gastroesophageal reflux disease, Helicobacter pylori infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions in susceptibility to CGA.
Published:
August 25, 2019
Title:
Characteristics of Selected Antioxidative and Bioactive Compounds in Meat and Animal Origin Products.
Authors:
B, Kulczyński; A, Sidor; A, Gramza-Michałowska
Abstract:
Europe PMC is an archive of life sciences journal literature., Characteristics of Selected Antioxidative and Bioactive Compounds in Meat and Animal Origin Products.
Published:
August 22, 2019
Title:
Dietary Fructose and the Metabolic Syndrome
Authors:
Taskinen, Marja-Riitta; Packard, Chris J.; Borén, Jan
Abstract:
Abstract: Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.
Published:
August 22, 2019
Title:
Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer
Authors:
Di Mitri, Diletta; Mirenda, Michela; Vasilevska, Jelena; Calcinotto, Arianna; Delaleu, Nicolas; Revandkar, Ajinkya; Gil, Veronica; Boysen, Gunther; Losa, Marco; Mosole, Simone; Pasquini, Emiliano; D’Antuono, Rocco; Masetti, Michela; Zagato, Elena; Chiorino, Giovanna; Ostano, Paola; Rinaldi, Andrea; Gnetti, Letizia; Graupera, Mariona; Martins Figueiredo Fonseca, Ana Raquel; Pereira Mestre, Ricardo; Waugh, David; Barry, Simon; De Bono, Johann; Alimonti, Andrea
Abstract:
Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that Pten-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc−/−; Trp53pc−/− mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, PTEN-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of TNFR1. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.
Published:
August 20, 2019
Title:
Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases
Authors:
Moldogazieva, Nurbubu T.; Mokhosoev, Innokenty M.; Mel’nikova, Tatiana I.; Porozov, Yuri B.; Terentiev, Alexander A.
Abstract:
Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging. Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF- κ B, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivatives such as glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), and 4-hydroxy-2-nonenal (HNE) giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.
Published:
August 14, 2019
Title:
Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts
Authors:
Mitsui, Yosuke; Tomonobu, Nahoko; Watanabe, Masami; Kinoshita, Rie; Sumardika, I Wayan; Youyi, Chen; Murata, Hitoshi; Yamamoto, Ken-ichi; Sadahira, Takuya; Rodrigo, Acosta Gonzalez Herik; Takamatsu, Hitoshi; Araki, Kota; Yamauchi, Akira; Yamamura, Masahiro; Fujiwara, Hideyo; Inoue, Yusuke; Futami, Junichiro; Saito, Ken; Iioka, Hidekazu; Kondo, Eisaku; Nishibori, Masahiro; Toyooka, Shinichi; Yamamoto, Yasuhiko; Nasu, Yasutomo; Sakaguchi, Masakiyo
Abstract:
Published:
August 8, 2019
Title:
The Role of the Anabolic Properties of Plant- versus Animal-Based Protein Sources in Supporting Muscle Mass Maintenance: A Critical Review
Authors:
Berrazaga, Insaf; Micard, Valérie; Gueugneau, Marine; Walrand, Stéphane
Abstract:
Plant-sourced proteins offer environmental and health benefits, and research increasingly includes them in study formulas. However, plant-based proteins have less of an anabolic effect than animal proteins due to their lower digestibility, lower essential amino acid content (especially leucine), and deficiency in other essential amino acids, such as sulfur amino acids or lysine. Thus, plant amino acids are directed toward oxidation rather than used for muscle protein synthesis. In this review, we evaluate the ability of plant- versus animal-based proteins to help maintain skeletal muscle mass in healthy and especially older people and examine different nutritional strategies for improving the anabolic properties of plant-based proteins. Among these strategies, increasing protein intake has led to a positive acute postprandial muscle protein synthesis response and even positive long-term improvement in lean mass. Increasing the quality of protein intake by improving amino acid composition could also compensate for the lower anabolic potential of plant-based proteins. We evaluated and discussed four nutritional strategies for improving the amino acid composition of plant-based proteins: fortifying plant-based proteins with specific essential amino acids, selective breeding, blending several plant protein sources, and blending plant with animal-based protein sources. These nutritional approaches need to be profoundly examined in older individuals in order to optimize protein intake for this population who require a high-quality food protein intake to mitigate age-related muscle loss.
Published:
August 7, 2019
Title:
Geological and soil maps of the Palaeo-Agulhas Plain for the Last Glacial Maximum
Authors:
Cawthra, Hayley C.; Cowling, Richard M.; Andò, Sergio; Marean, Curtis W.
Abstract:
The South African Cape South Coast is bordered by one of the broadest continental shelves in Africa. The Agulhas Bank, inshore shelf and presently exposed coastal plain make up the Palaeo-Agulhas Plain (PAP), though our area of study extends beyond this limit and as far inland as the first mountain belt. Quaternary sea levels have been significantly lower than at present for ∼90% of the Pleistocene, exposing a terrestrial ecosystem on what is now the submerged shelf. The presently drowned component makes up 94% of the total area of the PAP. Past work has hypothesised a contrast in character of this submerged landscape when compared to the subaerial environment. Here, we assimilate newly-acquired geophysical and geological datasets to produce geological- and soil maps from the Last Glacial Maximum on a scale of 1:750,000, covering an area of ∼55,000 km. Three broad geomorphic zones are defined, including the Western section from Cape Agulhas to Cape Infanta, the Central section from Cape Infanta to Knysna and the Eastern section extending eastward of Knysna. We demonstrate that Mesozoic sedimentary deposits crop out near the surface on this current-swept shelf and soils derived from siltstone and shale bedrock are prominent when the coast is up to 64 km distant from the modern shoreline at its maximum point. Beyond this, weathered limestone dominates the substrate sequences on the Agulhas Bank. We show that the submerged landscape was a unique terrestrial environment and that there is no exact modern-day analogue in the region other than a small (∼70 km2) area located at the edge of the Agulhas Plain near Cape Agulhas, and map major contrasts in the geological, topographic and edaphic nature of the landscape from the onshore to the offshore. The expansion of this plain is coupled with exaggerated floodplains, meandering shallowly incised rivers and wetlands. The submerged shelf is dominated by fertile soils compared to the dissected onshore belt, and extensive calcareous dunefields extending up to 10 km inland from their associated palaeoshorelines covered much of the emergent shelf. Sedimentary bedforms may have obstructed or slowed drainage as suggested by leached palaeosols and carbonate mixing observed in petrographic thin sections and grain mounts. The data show a low-relief “plains” landscape, which contrasts strongly to the topographically complex contemporary coastal foreland.
Published:
August 6, 2019
Title:
Metastasis as a systemic disease: molecular insights and clinical implications
Authors:
Alečković, Maša; McAllister, Sandra S.; Polyak, Kornelia
Abstract:
Metastasis is a complex systemic disease that develops as a result of interactions between tumor cells and their local and distant microenvironments. Local and systemic immune-related changes play especially critical roles in limiting or enabling the development of metastatic disease. Although anti-tumor immune responses likely eliminate most early primary and metastatic lesions, factors secreted by cancer or stromal cells in the primary tumor can mobilize and activate cells in distant organs in a way that promotes the outgrowth of disseminated cancer cells into macrometastatic lesions. Therefore, the prevention, detection, and effective treatment of metastatic disease require a deeper understanding of the systemic effects of primary tumors as well as predisposing hereditary and acquired host factors including chronic inflammatory conditions. The success of immunotherapy in a subset of cancer patients is an example of how modulating the microenvironment and tumor-immune cell interactions can be exploited for the effective eradiation of even advanced-stage tumors. Here, we highlight emerging insights and clinical implications of cancer as a systemic disease.
Published:
August 1, 2019
Title:
Seasonal and habitat effects on the nutritional properties of savanna vegetation: Potential implications for early hominin dietary ecology
Authors:
Paine, Oliver C. C.; Koppa, Abigale; Henry, Amanda G.; Leichliter, Jennifer N.; Codron, Daryl; Codron, Jacqueline; Lambert, Joanna E.; Sponheimer, Matt
Abstract:
The African savannas that many early hominins occupied likely experienced stark seasonality and contained mosaic habitats (i.e., combinations of woodlands, wetlands, grasslands, etc.). Most would agree that the bulk of dietary calories obtained by taxa such as Australopithecus and Paranthropus came from the consumption of vegetation growing across these landscapes. It is also likely that many early hominins were selective feeders that consumed particular plants/plant parts (e.g., leaves, fruit, storage organs) depending on the habitat and season within which they were foraging. Thus, improving our understanding of how the nutritional properties of potential hominin plant foods growing in modern African savanna ecosystems respond to season and vary by habitat will improve our ability to model early hominin dietary behavior. Here, we present nutritional analyses (crude protein and acid detergent fiber) of plants growing in eastern and southern African savanna habitats across both wet and dry seasons. We find that many assumptions about savanna vegetation are warranted. For instance, plants growing in our woodland habitats have higher average protein/fiber ratios than those growing in our wetland and grassland transects. However, we find that the effects of season and habitat are complex, an example being the unexpectedly higher protein levels we observe in the grasses and sedges growing in our Amboseli wetlands during the dry season. Also, we find significant differences between the vegetation growing in our eastern and southern African field sites, particularly among plants using the C4 photosynthetic pathway. This may have implications for the differences we see between the stable carbon isotope compositions and dental microwear patterns of eastern and southern African Paranthropus species, despite their shared, highly derived craniodental anatomy.
Published:
August 1, 2019
Title:
The androgen receptor regulates a druggable translational regulon in advanced prostate cancer
Authors:
Liu, Yuzhen; Horn, Jessie L.; Banda, Kalyan; Goodman, Asha Z.; Lim, Yiting; Jana, Sujata; Arora, Sonali; Germanos, Alexandre A.; Wen, Lexiaochuan; Hardin, William R.; Yang, Yu C.; Coleman, Ilsa M.; Tharakan, Robin G.; Cai, Elise Y.; Uo, Takuma; Pillai, Smitha P. S.; Corey, Eva; Morrissey, Colm; Chen, Yu; Carver, Brett S.; Plymate, Stephen R.; Beronja, Slobodan; Nelson, Peter S.; Hsieh, Andrew C.
Abstract:
Driving out translation to treat cancer The androgen receptor is a well-known driver of prostate cancer and a common therapeutic target in this disease. Now, Liu et al. have identified an unexpected link between the androgen receptor and regulation of mRNA translation. The authors determined that the androgen receptor has a suppressive effect on protein synthesis, whereas the loss of this receptor is associated with increased initiation of translation, facilitating tumor cell proliferation. This observation helps explain the rapid growth of late-stage androgen receptor–deficient prostate cancer and provides a therapeutic opportunity through inhibition of a translation initiation complex, which the authors demonstrate in mouse models. The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer. The androgen receptor (AR) regulates mRNA-specific translation through 4EBP1, which is a druggable vulnerability in AR-deficient prostate cancer. The androgen receptor (AR) regulates mRNA-specific translation through 4EBP1, which is a druggable vulnerability in AR-deficient prostate cancer.
Published:
July 31, 2019
Title:
Country-wide medical records infer increased allergy risk of gastric acid inhibition
Authors:
Jordakieva, Galateja; Kundi, Michael; Untersmayr, Eva; Pali-Schöll, Isabella; Reichardt, Berthold; Jensen-Jarolim, Erika
Abstract:
Gastric acid inhibitors promote experimental allergy in animals, and have been linked to allergy risk in observational human studies. Here the authors show in a country-wide medical record analysis that allergy development risk is doubled in gastric acid inhibitor users, and is higher in women and in older age.
Published:
July 30, 2019
Title:
Glycation of macrophages induces expression of pro-inflammatory cytokines and reduces phagocytic efficiency
Authors:
Bezold, Veronika; Rosenstock, Philip; Scheffler, Jonas; Geyer, Henriette; Horstkorte, Rüdiger; Bork, Kaya
Abstract:
Glycation and the accumulation of advanced glycation end products (AGEs) are known to occur during normal aging but also in the progression of several diseases, such as diabetes. Diabetes type II and aging both lead to impaired wound healing. It has been demonstrated that macrophages play an important role in impaired wound healing, however, the underlying causes remain unknown. Elevated blood glucose levels as well as elevated methylglyoxal (MGO) levels in diabetic patients result in glycation and increase of AGEs. We used MGO to investigate the influence of glycation and AGEs on macrophages. We could show that glycation, but not treatment with AGE-modified serum proteins, increased expression of pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-8 but also affected IL-10 and TNF-α expression, resulting in increased inflammation. At the same time, glycation reduced phagocytic efficiency and led to impaired clearance rates of invading microbes and cellular debris. Our data suggest that glycation contributes to changes of macrophage activity and cytokine expression and therefore could support the understanding of disturbed wound healing during aging and diabetes.
Published:
July 29, 2019
Title:
Alveolar macrophages generate a noncanonical NRF2-driven transcriptional response to Mycobacterium tuberculosis in vivo
Authors:
Rothchild, Alissa C.; Olson, Gregory S.; Nemeth, Johannes; Amon, Lynn M.; Mai, Dat; Gold, Elizabeth S.; Diercks, Alan H.; Aderem, Alan
Abstract:
Interfering with macrophage activation One of the many reasons for Mycobacterium tuberculosis (M.tb.) persistence is that the bacterium blocks activation of M.tb.-specific immune responses. Here, using a mouse model of tuberculosis, Rothchild et al. demonstrate that M.tb.-infected alveolar macrophages in the lung show an impaired ability to drive antibacterial responses. These M.tb.-infected macrophages up-regulate an antioxidant transcription signature that is driven by the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2). By infecting mice engineered to lack NRF2 in myeloid cells with M.tb., they show that loss of NRF2 in myeloid cells lowered bacterial burdens. Their studies have brought to the fore the importance of NRF2 in regulating early interactions between M.tb. and host immune cells. Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (M.tb.) infection. Thus, the AM response to infection is the first of many steps leading to initiation of the adaptive immune response required for efficient control of infection. A hallmark of M.tb. infection is the slow initiation of the adaptive response, yet the mechanisms responsible for this are largely unknown. To study the initial AM response to infection, we developed a system to identify, sort, and analyze M.tb.-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, M.tb.-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment but not bacterial virulence. Computational approaches including pathway analysis and transcription factor motif enrichment analysis identify NRF2 as a master regulator of the response. Using knockout mouse models, we demonstrate that NRF2 drives expression of the cell-protective signature in AMs and impairs the control of early bacterial growth. AMs up-regulate a substantial pro-inflammatory response to M.tb. infection only 10 days after infection, yet comparisons with bystander AMs from the same infected animals demonstrate that M.tb.-infected AMs generate a less robust inflammatory response than the uninfected cells around them. Our findings demonstrate that the initial macrophage response to M.tb. in the lung is far less inflammatory than has previously been described by in vitro systems and may impede the overall host response to infection. Induction of an NRF2-dependent cell-protective signature impairs alveolar macrophages from controlling M.tb. infection in vivo. Induction of an NRF2-dependent cell-protective signature impairs alveolar macrophages from controlling M.tb. infection in vivo.
Published:
July 26, 2019
Title:
Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases
Authors:
Yeo, In Jun; Lee, Chong-Kil; Han, Sang-Bae; Yun, Jaesuk; Hong, Jin Tae
Abstract:
Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases.
Published:
July 26, 2019
Title:
Is vegetarianism healthy for children?
Authors:
Cofnas, Nathan
Abstract:
According to the Academy of Nutrition and Dietetics' influential position statement on vegetarianism, meat and seafood can be replaced with milk, soy/legumes, and eggs without any negative effects in children. The United States Department of Agriculture endorses a similar view. The present paper argues that the Academy of Nutrition and Dietetics ignores or gives short shrift to direct and indirect evidence that vegetarianism may be associated with serious risks for brain and body development in fetuses and children. Regular supplementation with iron, zinc, and B12 will not mitigate all of these risks. Consequently, we cannot say decisively that vegetarianism or veganism is safe for children.
Published:
July 20, 2019
Title:
How to design a single-cell RNA-sequencing experiment: pitfalls, challenges and perspectives
Authors:
Dal Molin, Alessandra; Di Camillo, Barbara
Abstract:
The sequencing of the transcriptome of single cells, or single-cell RNA-sequencing, has now become the dominant technology for the identification of novel cell types in heterogeneous cell populations or for the study of stochastic gene expression. In recent years, various experimental methods and computational tools for analysing single-cell RNA-sequencing data have been proposed. However, most of them are tailored to different experimental designs or biological questions, and in many cases, their performance has not been benchmarked yet, thus increasing the difficulty for a researcher to choose the optimal single-cell transcriptome sequencing (scRNA-seq) experiment and analysis workflow. In this review, we aim to provide an overview of the current available experimental and computational methods developed to handle single-cell RNA-sequencing data and, based on their peculiarities, we suggest possible analysis frameworks depending on specific experimental designs. Together, we propose an evaluation of challenges and open questions and future perspectives in the field. In particular, we go through the different steps of scRNA-seq experimental protocols such as cell isolation, messenger RNA capture, reverse transcription, amplification and use of quantitative standards such as spike-ins and Unique Molecular Identifiers (UMIs). We then analyse the current methodological challenges related to preprocessing, alignment, quantification, normalization, batch effect correction and methods to control for confounding effects.
Published:
July 19, 2019
Title:
Reply to "Utility of Unrefined Carbohydrates in Type 2 Diabetes. Comment on Reversing Type 2 Diabetes: A Narrative Review of the Evidence, Nutrients, 2019, 11, 766"
Authors:
Hallberg, Sarah J.; Gershuni, Victoria M.; Hazbun, Tamara L.; Athinarayanan, Shaminie J.
Abstract:
We appreciate the interest and comments from Joshi et al [...].
Published:
July 18, 2019
Title:
Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology
Authors:
Ketelhuth, Daniel F J; Lutgens, Esther; Bäck, Magnus; Binder, Christoph J; Van den Bossche, Jan; Daniel, Carolin; Dumitriu, Ingrid E; Hoefer, Imo; Libby, Peter; O’Neill, Luke; Weber, Christian; Evans, Paul C
Abstract:
Published:
July 15, 2019
Title:
Dietary Care for ADPKD Patients: Current Status and Future Directions
Authors:
Carriazo, Sol; Perez-Gomez, Maria Vanessa; Cordido, Adrian; García-González, Miguel Angel; Sanz, Ana Belen; Ortiz, Alberto; Sanchez-Niño, Maria Dolores
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy, and tolvaptan is the only therapy available. However, tolvaptan slows but does not stop disease progression, is marred by polyuria, and most patients worldwide lack access. This and recent preclinical research findings on the glucose-dependency of cyst-lining cells have renewed interest in the dietary management of ADPKD. We now review the current dietary recommendations for ADPKD patients according to clinical guidelines, the evidence base for those, and the potential impact of preclinical studies addressing the impact of diet on ADPKD progression. The clinical efficacy of tolvaptan has put the focus on water intake and solute ingestion as modifiable factors that may impact tolvaptan tolerance and ADPKD progression. By contrast, dietary modifications suggested to ADPKD patients, such as avoiding caffeine, are not well supported and their impact is unknown. Recent studies have identified a chronic shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis (Warburg effect) as a contributor to cyst growth, rendering cyst cells exquisitely sensitive to glucose availability. Therefore, low calorie or ketogenic diets have delayed preclinical ADPKD progression. Additional preclinical data warn of potential negative impact of excess dietary phosphate or oxalate in ADPKD progression.
Published:
July 12, 2019
Title:
Diets and Disorders: Can Foods or Fasting Be Considered Psychopharmacologic Therapies?
Authors:
Palmer, Christopher M.
Abstract:
Most agree that a “healthy diet” confers health benefits, but defining “healthy” foods and specific benefits is increasingly confusing. This ASCP Corner article considers the evidence base for dietary interventions purported to have psychopharmacologic properties.
Published:
July 9, 2019
Title:
Glucagon Receptor Signaling and Glucagon Resistance
Authors:
Janah, Lina; Kjeldsen, Sasha; Galsgaard, Katrine D.; Winther-Sørensen, Marie; Stojanovska, Elena; Pedersen, Jens; Knop, Filip K.; Holst, Jens J.; Wewer Albrechtsen, Nicolai J.
Abstract:
Hundred years after the discovery of glucagon, its biology remains enigmatic. Accurate measurement of glucagon has been essential for uncovering its pathological hypersecretion that underlies various metabolic diseases including not only diabetes and liver diseases but also cancers (glucagonomas). The suggested key role of glucagon in the development of diabetes has been termed the bihormonal hypothesis. However, studying tissue-specific knockout of the glucagon receptor has revealed that the physiological role of glucagon may extend beyond blood-glucose regulation. Decades ago, animal and human studies reported an important role of glucagon in amino acid metabolism through ureagenesis. Using modern technologies such as metabolomic profiling, knowledge about the effects of glucagon on amino acid metabolism has been expanded and the mechanisms involved further delineated. Glucagon receptor antagonists have indirectly put focus on glucagon’s potential role in lipid metabolism, as individuals treated with these antagonists showed dyslipidemia and increased hepatic fat. One emerging field in glucagon biology now seems to include the concept of hepatic glucagon resistance. Here, we discuss the roles of glucagon in glucose homeostasis, amino acid metabolism, and lipid metabolism and present speculations on the molecular pathways causing and associating with postulated hepatic glucagon resistance.
Published:
July 5, 2019
Title:
Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth
Authors:
Agarwal, Ekta; Altman, Brian J.; Seo, Jae Ho; Ghosh, Jagadish C.; Kossenkov, Andrew V.; Tang, Hsin-Yao; Krishn, Shiv Ram; Languino, Lucia R.; Gabrilovich, Dmitry I.; Speicher, David W.; Dang, Chi V.; Altieri, Dario C.
Abstract:
The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo. We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic.
Published:
July 5, 2019
Title:
UCSD scientists find possible link between eating fast-food and Type 2 diabetes
Authors:
Abstract:
Researchers at the UCSD School of Medicine found a possible correlation between eating a high-calorie fast-food breakfast, and "leaky gut syndrome," which could be a factor in developing Type 2 diabetes .
Published:
July 3, 2019
Title:
Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health
Authors:
Monteagudo-Mera, Andrea; Rastall, Robert A.; Gibson, Glenn R.; Charalampopoulos, Dimitris; Chatzifragkou, Afroditi
Abstract:
Adhesion ability to the host is a classical selection criterion for potential probiotic bacteria that could result in a transient colonisation that would help to promote immunomodulatory effects, as well as stimulate gut barrier and metabolic functions. In addition, probiotic bacteria have a potential protective role against enteropathogens through different mechanisms including production of antimicrobial compounds, reduction of pathogenic bacterial adhesion and competition for host cell binding sites. The competitive exclusion by probiotic bacteria has a beneficial effect not only on the gut but also in the urogenital tract and oral cavity. On the other hand, prebiotics may also act as barriers to pathogens and toxins by preventing their adhesion to epithelial receptors. In vitro studies with different intestinal cell lines have been widely used along the last decades to assess the adherence ability of probiotic bacteria and pathogen antagonism. However, extrapolation of these results to in vivo conditions still remains unclear, leading to the need of optimisation of more complex in vitro approaches that include interaction with the resident microbiota to address the current limitations. The aim of this mini review is to provide a comprehensive overview on the potential effect of the adhesive properties of probiotics and prebiotics on the host by focusing on the most recent findings related with adhesion and immunomodulatory and antipathogenic effect on human health.
Published:
July 2, 2019
Title:
Host mitochondria influence gut microbiome diversity: A role for ROS
Authors:
Yardeni, Tal; Tanes, Ceylan E.; Bittinger, Kyle; Mattei, Lisa M.; Schaefer, Patrick M.; Singh, Larry N.; Wu, Gary D.; Murdock, Deborah G.; Wallace, Douglas C.
Abstract:
Inheriting microbiome variation In mice, the bacterial species that persist within the gut microbiome are maternally inherited. However, maternally inherited variations in mitochondrial DNA (mtDNA) sequence also correlate with gut microbiome diversity, as well as the production of reactive oxygen species (ROS). In mice with mtDNA variants associated with increased production of ROS, Yardeni et al. found reduced gut microbiome species diversity. When pups were cross-fostered to unlink inheritance of mtDNA and gut microbiota, after weening, the gut microbiome species were reflective of inherited mtDNA variation. Both pharmacological and genetic reduction of mitochondrial ROS abundance increased microbiome diversity. These data suggest that microbiome diversity is genetically encoded, and further imply that antioxidants may improve the efficacy of cancer immunotherapy, which is sensitive to microbiome composition. Changes in the gut microbiota and the mitochondrial genome are both linked with the development of disease. To investigate why, we examined the gut microbiota of mice harboring various mutations in genes that alter mitochondrial function. These studies revealed that mitochondrial genetic variations altered the composition of the gut microbiota community. In cross-fostering studies, we found that although the initial microbiota community of newborn mice was that obtained from the nursing mother, the microbiota community progressed toward that characteristic of the microbiome of unfostered pups of the same genotype within 2 months. Analysis of the mitochondrial DNA variants associated with altered gut microbiota suggested that microbiome species diversity correlated with host reactive oxygen species (ROS) production. To determine whether the abundance of ROS could alter the gut microbiota, mice were aged, treated with N-acetylcysteine, or engineered to express the ROS scavenger catalase specifically within the mitochondria. All three conditions altered the microbiota from that initially established. Thus, these data suggest that the mitochondrial genotype modulates both ROS production and the species diversity of the gut microbiome, implying that the connection between the gut microbiome and common disease phenotypes might be due to underlying changes in mitochondrial function. Inherited genetic variations in mitochondrial function shape the gut microbiota species diversity. Inherited genetic variations in mitochondrial function shape the gut microbiota species diversity.
Published:
July 2, 2019
Title:
Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology
Authors:
Nayar, Saba; Campos, Joana; Smith, Charlotte G.; Iannizzotto, Valentina; Gardner, David H.; Mourcin, Frédéric; Roulois, David; Turner, Jason; Sylvestre, Marvin; Asam, Saba; Glaysher, Bridget; Bowman, Simon J.; Fearon, Douglas T.; Filer, Andrew; Tarte, Karin; Luther, Sanjiv A.; Fisher, Benjamin A.; Buckley, Christopher D.; Coles, Mark C.; Barone, Francesca
Abstract:
Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases.
Published:
July 2, 2019
Title:
Are there marrow cavities in Pleistocene elephant limb bones, and was marrow available to early humans? New CT scan results from the site of Castel di Guido (Italy)
Authors:
Boschian, Giovanni; Caramella, Davide; Saccà, Daniela; Barkai, Ran
Abstract:
CT-scan analyses were carried out on limb bones of straight-tusked elephants (Palaeoloxodon antiquus)from the Middle Pleistocene site of Castel di Guido (Italy), where bifaces made of elephant bone were found in association with lithics and a large number of intentionally modified bone remains of elephants and other taxa. CT-scans show that marrow cavities are present within the limb bones of this taxon. Though rather small compared to the size of the bones, these cavities suggest that bone raw material procurement may not have been the unique goal of intentional elephant bone fracturing, and the marrow may also have been extracted for consumption.
Published:
July 1, 2019
Title:
Are there marrow cavities in Pleistocene elephant limb bones, and was marrow available to early humans? New CT scan results from the site of Castel di Guido (Italy)
Authors:
Boschian, Giovanni; Caramella, Davide; Saccà, Daniela; Barkai, Ran
Abstract:
CT-scan analyses were carried out on limb bones of straight-tusked elephants (Palaeoloxodon antiquus) from the Middle Pleistocene site of Castel di Guido (Italy), where bifaces made of elephant bone were found in association with lithics and a large number of intentionally modified bone remains of elephants and other taxa. CT-scans show that marrow cavities are present within the limb bones of this taxon. Though rather small compared to the size of the bones, these cavities suggest that bone raw material procurement may not have been the unique goal of intentional elephant bone fracturing, and the marrow may also have been extracted for consumption.
Published:
July 1, 2019
Title:
Comparative Analyses of Chromatin Landscape in White Adipose Tissue Suggest Humans May Have Less Beigeing Potential than Other Primates
Authors:
Swain-Lenz, Devjanee; Berrio, Alejandro; Safi, Alexias; Crawford, Gregory E; Wray, Gregory A
Abstract:
Humans carry a much larger percentage of body fat than other primates. Despite the central role of adipose tissue in metabolism, little is known about the evolution of white adipose tissue in primates. Phenotypic divergence is often caused by genetic divergence in cis-regulatory regions. We examined the cis-regulatory landscape of fat during human origins by performing comparative analyses of chromatin accessibility in human and chimpanzee adipose tissue using rhesus macaque as an outgroup. We find that many regions that have decreased accessibility in humans are enriched for promoter and enhancer sequences, are depleted for signatures of negative selection, are located near genes involved with lipid metabolism, and contain a short sequence motif involved in the beigeing of fat, the process in which lipid-storing white adipocytes are transdifferentiated into thermogenic beige adipocytes. The collective closing of many putative regulatory regions associated with beigeing of fat suggests a mechanism that increases body fat in humans.
Published:
July 1, 2019
Title:
Cyclooxygenase 2 augments osteoblastic but suppresses chondrocytic differentiation of CD90+ skeletal stem cells in fracture sites
Authors:
Wasnik, Samiksha; Lakhan, Ram; Baylink, David J.; Rundle, Charles H.; Xu, Yi; Zhang, Jintao; Qin, Xuezhong; Lau, Kin-Hing William; Carreon, Edmundo E.; Tang, Xiaolei
Abstract:
Cyclooxygenase 2 (COX-2) is essential for normal tissue repair. Although COX-2 is known to enhance the differentiation of mesenchymal stem cells (MSCs), how COX-2 regulates MSC differentiation into different tissue-specific progenitors to promote tissue repair remains unknown. Because it has been shown that COX-2 is critical for normal bone repair and local COX-2 overexpression in fracture sites accelerates fracture repair, this study aimed to determine the MSC subsets that are targeted by COX-2. We showed that CD90+ mouse skeletal stem cells (mSSCs; i.e., CD45−Tie2−AlphaV+ MSCs) were selectively recruited by macrophage/monocyte chemoattractant protein 1 into fracture sites following local COX-2 overexpression. In addition, local COX-2 overexpression augmented osteoblast differentiation and suppressed chondrocyte differentiation in CD90+ mSSCs, which depended on canonical WNT signaling. CD90 depletion data demonstrated that local COX-2 overexpression targeted CD90+ mSSCs to accelerate fracture repair. In conclusion, CD90+ mSSCs are promising targets for the acceleration of bone repair. This study identifies that cyclooxygenase 2 targets CD90+ skeletal stem cells in fracture sites to accelerate fracture repair. This study identifies that cyclooxygenase 2 targets CD90+ skeletal stem cells in fracture sites to accelerate fracture repair.
Published:
July 1, 2019
Title:
Late Middle Stone Age Behavior and Environments at Chaminade I (Karonga, Malawi)
Authors:
Nightingale, Sheila; Schilt, Flora; Thompson, Jessica; Wright, David; Mercader, Julio; Moss, P.; Clarke, Siobhan; Peter Itambu, Makarius; Gomani-Chindebvu, Elizabeth; Welling, Menno
Abstract:
The African Middle Stone Age (MSA, typical range ~ 320–30 ka) has been the subject of intense research interest in recent decades as a culture-chronological Unit associated with the emergence and dispersal of our species. Recent results of this work have shown that sites designated as “MSA” contain common approaches to lithic reduction, but that within this rubric, there is much diversity in overall assemblage characteristics and the timing of their appearance across the continent. As researchers recover more data from more sites, especially from undersampled geographic regions, this more complex picture of the MSA reveals technological and other behavioral diversity in early modern human populations that may inform about the ultimate success of our species. Here we add to this growing database by describing the environmental context and characteristics of two concentrations of stone artifacts from the late MSA (~ 43–21 ka) open-air locality of Chaminade-I (CHA-I), near the town of Karonga in northern Malawi. The CHA-I lithic artifacts show a flexible approach to stone tool production and use that is common to assemblages in Karonga but distinctive from MSA sites reported elsewhere. Radial and minimally reduced cores typify an unelaborated lithic assemblage, in which raw material choice is driven by toolstone clast size and shape rather than preferential use or treatment of specific materials, as found in MSA assemblages in the East African Rift, South Africa, and the North African coast. Lithic reduction at CHA-I took place within a woody, riparian context embedded within a more open woodland landscape. Most artifacts occurred in near-channel sandy deposits dated to ~ 41 ka, and were buried under alluvial fan deposits that began aggrading by at least ~ 21 ka and continued beyond ~ 5.5 ka within a grassy, open landscape. The site’s late MSA age and lack of elaboration in lithic technology challenges straightforward ideas of increasing complexity in human technological behavior over time and provides important insight into the diversity of MSA technologies and the environmental conditions in which they existed.
Published:
July 1, 2019
Title:
Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy
Authors:
Pauletti, Alberto; Terrone, Gaetano; Shekh-Ahmad, Tawfeeq; Salamone, Alessia; Ravizza, Teresa; Rizzi, Massimo; Pastore, Anna; Pascente, Rosaria; Liang, Li-Ping; Villa, Bianca R.; Balosso, Silvia; Abramov, Andrey Y.; van Vliet, Erwin A.; Del Giudice, Ennio; Aronica, Eleonora; Patel, Manisha; Walker, Matthew C.; Vezzani, Annamaria
Abstract:
Epilepsy therapy is based on antiseizure drugs that treat the symptom, seizures, rather than the disease and are ineffective in up to 30% of patients. There are no treatments for modifying the disease-preventing seizure onset, reducing severity or improving prognosis. Among the potential molecular targets for attaining these unmet therapeutic needs, we focused on oxidative stress since it is a pathophysiological process commonly occurring in experimental epileptogenesis and observed in human epilepsy. Using a rat model of acquired epilepsy induced by electrical status epilepticus, we show that oxidative stress occurs in both neurons and astrocytes during epileptogenesis, as assessed by measuring biochemical and histological markers. This evidence was validated in the hippocampus of humans who died following status epilepticus. Oxidative stress was reduced in animals undergoing epileptogenesis by a transient treatment with N-acetylcysteine and sulforaphane, which act to increase glutathione levels through complementary mechanisms. These antioxidant drugs are already used in humans for other therapeutic indications. This drug combination transiently administered for 2 weeks during epileptogenesis inhibited oxidative stress more efficiently than either drug alone. The drug combination significantly delayed the onset of epilepsy, blocked disease progression between 2 and 5 months post-status epilepticus and drastically reduced the frequency of spontaneous seizures measured at 5 months without modifying the average seizure duration or the incidence of epilepsy in animals. Treatment also decreased hippocampal neuron loss and rescued cognitive deficits. Oxidative stress during epileptogenesis was associated with de novo brain and blood generation of high mobility group box 1 (HMGB1), a neuroinflammatory molecule implicated in seizure mechanisms. Drug-induced reduction of oxidative stress prevented HMGB1 generation, thus highlighting a potential novel mechanism contributing to therapeutic effects. Our data show that targeting oxidative stress with clinically used drugs for a limited time window starting early after injury significantly improves long-term disease outcomes. This intervention may be considered for patients exposed to potential epileptogenic insults.
Published:
July 1, 2019
Title:
Gut microbiota dysbiosis increases the risk of visceral gout in goslings through translocation of gut-derived lipopolysaccharide
Authors:
Xi, Yumeng; Yan, Junshu; Li, Mingyang; Ying, Shijia; Shi, Zhendan
Abstract:
We investigated the gut-kidney interaction in goslings with gout and tried to decipher the probable mechanisms through which gut dysbiosis leads to the progression of renal injury and inflammation. A total of 15 goslings (Anser cygnoides), with typical visceral gout symptoms, were screened and compared with 15 healthy goslings. We determined the signatures of the microbiome in the cecum chyme of goslings in the 2 groups by 16S sequencing, and analyzed the changes in intestinal permeability, levels of serum lipopolysaccharide (LPS), and the induced inflammatory response of Toll-like receptors (TLRs). We found the existence of gut dysbiosis in goslings with gout as a result of interactions among the multitude of bacteria present in the gut, and the proliferation of a specific pathogenic genus, Proteobacteria, played a decisive role in this process. Moreover, the permeability increased not only in the intestinal epithelium but also in the renal endothelium, providing possibilities for gut-derived LPS to enter the blood circulation and damage the kidneys. The systemic LPS concentration was increased in the gout group and exhibited a positive correlation with the degree of renal injury. In addition, we also found that inflammatory disorders concurrently existed in the gut and kidney of goslings with gout, and the LPS/TLR4/MyD88 (Myeloid differentiation primary response gene 88) inflammatory signaling was activated. These results indicate that the loss of intestinal barrier as a result of gut dysbiosis causes the translocation of gut-derived LPS, which can play an important role in the development of gout in goslings through interference with kidney functions.
Published:
June 27, 2019
Title:
Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins
Authors:
Jaballah-Gabteni, Amira; Tounsi, Haifa; Kabbage, Maria; Hamdi, Yosr; Elouej, Sahar; Ben Ayed, Ines; Medhioub, Mouna; Mahmoudi, Moufida; Dallali, Hamza; Yaiche, Hamza; Ben Jemii, Nadia; Maaloul, Afifa; Mezghani, Najla; Abdelhak, Sonia; Hamzaoui, Lamine; Azzouz, Mousaddak; Boubaker, Samir
Abstract:
Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family.
Published:
June 27, 2019
Title:
Precision Nutrition and the Microbiome Part II: Potential Opportunities and Pathways to Commercialisation
Authors:
Mills, Susan; Lane, Jonathan A.; Smith, Graeme J.; Grimaldi, Keith A.; Ross, R. Paul; Stanton, Catherine
Abstract:
Modulation of the human gut microbiota through probiotics, prebiotics and dietary fibre are recognised strategies to improve health and prevent disease. Yet we are only beginning to understand the impact of these interventions on the gut microbiota and the physiological consequences for the human host, thus forging the way towards evidence-based scientific validation. However, in many studies a percentage of participants can be defined as 'non-responders' and scientists are beginning to unravel what differentiates these from 'responders;' and it is now clear that an individual's baseline microbiota can influence an individual's response. Thus, microbiome composition can potentially serve as a biomarker to predict responsiveness to interventions, diets and dietary components enabling greater opportunities for its use towards disease prevention and health promotion. In Part I of this two-part review, we reviewed the current state of the science in terms of the gut microbiota and the role of diet and dietary components in shaping it and subsequent consequences for human health. In Part II, we examine the efficacy of gut-microbiota modulating therapies at different life stages and their potential to aid in the management of undernutrition and overnutrition. Given the significance of an individual's gut microbiota, we investigate the feasibility of microbiome testing and we discuss guidelines for evaluating the scientific validity of evidence for providing personalised microbiome-based dietary advice. Overall, this review highlights the potential value of the microbiome to prevent disease and maintain or promote health and in doing so, paves the pathway towards commercialisation.
Published:
June 27, 2019
Title:
Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy
Authors:
Momin, Noor; Mehta, Naveen K.; Bennett, Nitasha R.; Ma, Leyuan; Palmeri, Joseph R.; Chinn, Magnolia M.; Lutz, Emi A.; Kang, Byong; Irvine, Darrell J.; Spranger, Stefani; Wittrup, K. Dane
Abstract:
Keeping it local Cancer immunotherapy has greatly advanced in recent years, with a variety of promising approaches. Unfortunately, many patients still do not respond to the available therapeutics. Cytokine-based treatments have been proposed in the past but have not caught on because of the severe adverse effects associated with systemic cytokine exposure. To address this problem, Momin et al. fused antitumor cytokines to the collagen-binding protein lumican. Intratumoral injection of the resulting fusion proteins in mouse models of cancer effectively potentiated the effects of other immunotherapies and stimulated systemic antitumor immunity without detectable toxicity. The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and markedly reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the BrafV600E/Ptenfl/fl genetically engineered melanoma model. Curative abscopal effects on noncytokine-injected tumors were also observed as a result of a protective and systemic CD8+ T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies. Collagen-localized cytokines potentiate disparate systemic cancer immunotherapies while minimizing toxicity in many tumor models. Collagen-localized cytokines potentiate disparate systemic cancer immunotherapies while minimizing toxicity in many tumor models.
Published:
June 26, 2019
Title:
Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer
Authors:
Zhao, Ning; Peacock, Stephanie O.; Lo, Chen Hao; Heidman, Laine M.; Rice, Meghan A.; Fahrenholtz, Cale D.; Greene, Ann M.; Magani, Fiorella; Copello, Valeria A.; Martinez, Maria Julia; Zhang, Yushan; Daaka, Yehia; Lynch, Conor C.; Burnstein, Kerry L.
Abstract:
Solving cancer’s (vaso)pressing problem Castration-resistant prostate cancer is a lethal late-stage form of prostate cancer, where the tumor can grow independently and no longer requires external stimulation of the androgen receptor. Zhao et al. found that the arginine vasopressin receptor 1a, which is normally associated with maintenance of blood pressure and fluid balance, can help activate signaling pathways involved in the development of castration resistance in prostate cancer. An antagonist of this receptor, relcovaptan, which can be safely used in humans, showed promising activity in mice modeling different stages of prostate cancer, suggesting this drug’s potential for repurposing if its effects are confirmed in clinical studies. Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7. AR-V7 lacks a ligand-binding domain and is linked to poor prognosis. We previously showed that VAV3 enhances AR-V7 activity to drive CRPC progression. Gene expression profiling after depletion of either VAV3 or AR-V7 in CRPC cells revealed arginine vasopressin receptor 1a (AVPR1A) as the most commonly down-regulated gene, indicating that this G protein–coupled receptor may be critical for CRPC. Analysis of publicly available human PC datasets showed that AVPR1A has a higher copy number and increased amounts of mRNA in advanced PC. Depletion of AVPR1A in CRPC cells resulted in decreased cell proliferation and reduced cyclin A. In contrast, androgen-dependent PC, AR-negative PC, or nontumorigenic prostate epithelial cells, which have undetectable AVPR1A mRNA, were minimally affected by AVPR1A depletion. Ectopic expression of AVPR1A in androgen-dependent PC cells conferred castration resistance in vitro and in vivo. Furthermore, treatment of CRPC cells with the AVPR1A ligand, arginine vasopressin (AVP), activated ERK and CREB, known promoters of PC progression. A clinically safe and selective AVPR1A antagonist, relcovaptan, prevented CRPC emergence and decreased CRPC orthotopic and bone metastatic growth in mouse models. Based on these preclinical findings, repurposing AVPR1A antagonists is a promising therapeutic approach for CRPC. Antagonism of arginine vasopressin receptor 1a inhibits growth of emergent, established, and bone metastatic castration-resistant prostate cancer. Antagonism of arginine vasopressin receptor 1a inhibits growth of emergent, established, and bone metastatic castration-resistant prostate cancer.
Published:
June 26, 2019
Title:
Cardiac disease is linked to adiposity in male gorillas (Gorilla gorilla gorilla)
Authors:
Dennis, Pam; Raghanti, Mary Ann; Meindl, Richard; Less, Elena; Henthorn, Eric; Devlin, William; Murray, Suzan; Meehan, Thomas; Kutinsky, Ilana; Murphy, Hayley
Abstract:
Cardiac disease is a major cause of morbidity and mortality for adult gorillas. Previous research indicates a sex-based difference with predominantly males demonstrating evidence of left ventricular hypertrophy. To evaluate these findings, we analyzed serum markers with cardiac measures in a large sample of gorillas. The study sample included 44 male and 25 female gorillas housed at American Association of Zoo and Aquariums (AZA)-accredited zoos. Serum samples were collected from fasted gorillas during routine veterinary health exams and analyzed to measure leptin, adiponectin, IGF-1, insulin, ferritin, glucose, triglycerides, and cholesterol. Cardiac ultrasonography via transthoracic echocardiogram was performed simultaneously. Three echocardiographic parameters were chosen to assess cardiac disease according to parameters established for captive lowland gorillas: left ventricular internal diameter, inter-ventricular septum thickness, and left ventricular posterior wall thickness. Our data revealed that high leptin, low adiponectin, and lowered cholesterol were significantly and positively correlated with measures of heart thickness and age in males but not in females. Lowered cholesterol in this population would be categorized as elevated in humans. High leptin and low adiponectin are indicative of increased adiposity and suggests a potential parallel with human obesity and cardiovascular disease in males. Interestingly, while females exhibited increased adiposity with age, they did not progress to cardiac disease.
Published:
June 26, 2019
Title:
TAMs target MLKL
Authors:
Foley, John F.
Abstract:
TAM family kinases promote necroptosis by stimulating the phosphorylation and oligomerization of the pseudokinase MLKL. TAM family kinases promote necroptosis by stimulating the phosphorylation and oligomerization of the pseudokinase MLKL. TAM family kinases promote necroptosis by stimulating the phosphorylation and oligomerization of the pseudokinase MLKL.
Published:
June 25, 2019
Title:
PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function
Authors:
Bianchini, Mariaelvy; Duchêne, Johan; Santovito, Donato; Schloss, Maximilian J.; Evrard, Maximilien; Winkels, Holger; Aslani, Maria; Mohanta, Sarajo K.; Horckmans, Michael; Blanchet, Xavier; Lacy, Michael; Hundelshausen, Philipp von; Atzler, Dorothee; Habenicht, Andreas; Gerdes, Norbert; Pelisek, Jaroslav; Ng, Lai Guan; Steffens, Sabine; Weber, Christian; Megens, Remco T. A.
Abstract:
Nonclassical Monocyte Marker Nonclassical monocytes (NCMs) are a subset of monocytes that act as sentinels in the skin endothelium and lung microvasculature. The origin of NCMs is not well understood, and Bianchini et al. now identify the immune checkpoint molecule PD-L1 as a marker that can track NCMs. Using two-photon microscopy, PD-L1+ NCMs could be tracked within the bone marrow, and contact with endosteal vessels was required for conversion from classical monocytes to NCMs. Under inflammatory conditions, PD-L1+ NCMs were found in tertiary lymphoid organs (TLOs), and expression of PD-L1 by NCMs regulated T cell survival in TLOs. Together, these findings reveal PD-L1 as a valuable tool for studying the origin and functions of NCMs. The role of nonclassical monocytes (NCMs) in health and disease is emerging, but their location and function within tissues remain poorly explored. Imaging of NCMs has been limited by the lack of an established single NCM marker. Here, we characterize the immune checkpoint molecule PD-L1 (CD274) as an unequivocal marker for tracking NCMs in circulation and pinpoint their compartmentalized distribution in tissues by two-photon microscopy. Visualization of PD-L1+ NCMs in relation to bone marrow vasculature reveals that conversion of classical monocytes into NCMs requires contact with endosteal vessels. Furthermore, PD-L1+ NCMs are present in tertiary lymphoid organs (TLOs) under inflammatory conditions in both mice and humans, and NCMs exhibit a PD-L1–dependent immunomodulatory function that promotes T cell apoptosis within TLOs. Our findings establish an unambiguous tool for the investigation of NCMs and shed light on their origin and function. PD-L1+Ly6Clo monocytes derive from Ly6Chi monocytes in bone marrow and control T cell survival in tertiary lymphoid organs. PD-L1+Ly6Clo monocytes derive from Ly6Chi monocytes in bone marrow and control T cell survival in tertiary lymphoid organs.
Published:
June 21, 2019
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