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Title:
The effect of lipedema on health-related quality of life and psychological status: a narrative review of the literature
Authors:
Alwardat, Nuha; Di Renzo, Laura; Alwardat, Mohammad; Romano, Lorenzo; De Santis, Gemma Lou; Gualtieri, Paola; Carrano, Elena; Nocerino, Petronilla; De Lorenzo, Antonino
Abstract:
Published:
May 6, 2019
Title:
Contributing to characterise wild predator behaviour: consumption pattern, spatial distribution and bone damage on ungulate carcasses consumed by red fox (Vulpes vulpes)
Authors:
Arilla, Maite; Rosell Ardèvol, Jordi; Blasco, Ruth
Abstract:
Neo-taphonomic studies of carnivores are commonly used to explain the formation processes of Pleistocene faunal assemblages. However, these works have been developed mostly with large carnivores—e.g. hyenas. On the contrary, small and medium-sized carnivores have been scarcely studied in spite of their presence in most of the archaeological sites. Here, we present a study trying to characterise the wild predator behaviour from a taphonomic perspective, describing consumption patterns on 23 small-sized ungulate carcasses eaten by red foxes (Vulpes vulpes) during a 2-year period in the Spanish Pyrenees. The aim of this work, therefore, is to characterise taphonomically this predator and to obtain data to distinguish them from other most common carnivores. For that, a combination of observational data from photo/video-trap and taphonomic analyses was compiled, allowing us to control variables like seasonality and time of consumption, as well as the spatial dispersion of skeletal remains. The initial interest by foxes lies in the disassembly of the anatomical elements and their transport to secluded places giving rise to dispersion of bones. Regarding to seasonality, bone modification increases at the end of winter/spring time, and proportionally, the time of consumption decreases. When the carcass is complete, viscera seem to be an important resource, followed by meat covering femur and humerus. This phenomenon causes significant damage on axial bones (mainly fractures and tooth marks), and to a lesser extent, on pelvis and proximal stylopodials.
Published:
May 5, 2019
Title:
Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors
Authors:
Spallanzani, Raul German; Zemmour, David; Xiao, Tianli; Jayewickreme, Teshika; Li, Chaoran; Bryce, Paul J.; Benoist, Christophe; Mathis, Diane
Abstract:
Stromal sources of IL-33 in fat depots White adipose tissue (WAT) is home to Tregs and group 2 innate lymphoid cells (ILC2s) that help keep inflammation under check. Two studies in this week’s issue probe WAT in search of cells producing the alarmin cytokine IL-33 that regulates Tregs and ILC2s. Spallanzani et al. used single-cell RNA sequencing to characterize visceral WAT stromal cells and defined five distinct subtypes, with subtypes 1 to 3 producing IL-33 and subtypes 4 and 5 resembling adipocyte precursors. Mahlakõiv et al. identified adipose stem and progenitor cells as a source of IL-33 in all WAT depots and mesothelial cells as an additional source of IL-33 in visceral WAT. These studies improve our understanding of WAT stromal cell diversity and how the stromal cell landscape responds to physiological or pathological variations. See the related Research Article by Mahlakõiv et al. Regulatory T cells (Tregs) are key brakes on the visceral adipose tissue (VAT) inflammation that regulates local and systemic metabolic tenor. Breakdown of this regulation promotes type 2 diabetes. The cytokine IL-33 expands and sustains the unique Treg population residing within VAT. Here, relying on single-cell RNA sequencing, we identified the major IL-33 producers in VAT to be particular mesenchymal stromal cell subtypes, related to but distinct from adipocyte progenitor cells. We explored modulation of the VAT stromal cell landscape with physiologic variables such as age and sex, as well as its remodeling in pathogenic states like obesity. Last, we uncovered a VAT Treg:stromal cell negative regulatory loop that keeps the potent effect of IL-33 under rein. Adipose tissue Tregs dynamically dialogue with stromal cells via the ST2:IL-33 axis in homeostasis and disease. Adipose tissue Tregs dynamically dialogue with stromal cells via the ST2:IL-33 axis in homeostasis and disease.
Published:
May 3, 2019
Title:
Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33
Authors:
Mahlakõiv, T.; Flamar, A.-L.; Johnston, L. K.; Moriyama, S.; Putzel, G. G.; Bryce, P. J.; Artis, D.
Abstract:
Stromal sources of IL-33 in fat depots White adipose tissue (WAT) is home to Tregs and group 2 innate lymphoid cells (ILC2s) that help keep inflammation under check. Two studies in this week’s issue probe WAT in search of cells producing the alarmin cytokine interleukin-33 (IL-33) that regulates Tregs and ILC2s. Spallanzani et al. used single-cell RNA sequencing to characterize visceral WAT stromal cells and defined five distinct subtypes, with subtypes 1 to 3 producing IL-33 and subtypes 4 and 5 resembling adipocyte precursors. Mahlakõiv et al. identified adipose stem and progenitor cells as a source of IL-33 in all WAT depots and mesothelial cells as an additional source of IL-33 in visceral WAT. These studies improve our understanding of WAT stromal cell diversity and how the stromal cell landscape responds to physiological or pathological variations. See related Research Article by Spallanzani et al. Obesity is driven by chronic low-grade inflammation resulting from dysregulated immune cell accumulation and function in white adipose tissue (WAT). Interleukin-33 (IL-33) is a key cytokine that controls innate and adaptive immune cell activity and immune homeostasis in WAT, although the sources of IL-33 have remained controversial. Here, we show that WAT-resident mesenchyme-derived stromal cells are the dominant producers of IL-33. Adipose stem and progenitor cells (ASPCs) produced IL-33 in all WAT depots, whereas mesothelial cells served as an additional source of IL-33 in visceral WAT. ASPC-derived IL-33 promoted a regulatory circuit that maintained an immune tone in WAT via the induction of group 2 innate lymphoid cell–derived type 2 cytokines and maintenance of eosinophils, whereas mesothelial IL-33 also acted as an alarmin by inducing peritoneal immune response upon infection. Together, these data reveal a previously unrecognized regulatory network between tissue-resident progenitor cells and innate lymphoid cells that maintains immune homeostasis in adipose tissue. Tissue-resident stromal cells control innate lymphoid cell–dependent immune homeostasis in adipose tissue. Tissue-resident stromal cells control innate lymphoid cell–dependent immune homeostasis in adipose tissue.
Published:
May 3, 2019
Title:
Association of Delirium Response and Safety of Pharmacological Interventions for the Management and Prevention of Delirium: A Network Meta-analysis
Authors:
Wu, Yi-Cheng; Tseng, Ping-Tao; Tu, Yu-Kang; Hsu, Chung-Yao; Liang, Chih-Sung; Yeh, Ta-Chuan; Chen, Tien-Yu; Chu, Che-Sheng; Matsuoka, Yutaka J.; Stubbs, Brendon; Carvalho, Andre F.; Wada, Saho; Lin, Pao-Yen; Chen, Yen-Wen; Su, Kuan-Pin
Abstract:
OBJECTIVE To evaluate evidence regarding pharmacological interventions for delirium treatment and prevention. DATA SOURCES PubMed, Embase, ProQuest, ScienceDirect, Cochrane Central, Web of Science, ClinicalKey, and ClinicalTrials.gov from inception to May 17, 2018. STUDY SELECTION Randomized clinical trials (RCTs) examining pharmacological interventions for delirium treatment and prevention. DATA EXTRACTION AND SYNTHESIS To extract data according to a predetermined list of interests, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were applied, and all meta-analytic procedures were conducted using a random-effects model. MAIN OUTCOMES AND MEASURES The primary outcomes were treatment response in patients with delirium and the incidence of delirium in patients at risk of delirium. RESULTS A total of 58 RCTs were included, in which 20 RCTs with 1435 participants (mean age, 63.5 years; 65.1% male) compared the outcomes of treatment and 38 RCTs with 8168 participants (mean age, 70.2 years; 53.4% male) examined the prevention of delirium. A network meta-analysis demonstrated that haloperidol plus lorazepam provided the best response rate for delirium treatment (odds ratio [OR], 28.13; 95% CI, 2.38-333.08) compared with placebo/control. For delirium prevention, the ramelteon, olanzapine, risperidone, and dexmedetomidine hydrochloride groups had significantly lower delirium occurrence rates than placebo/control (OR, 0.07; 95% CI, 0.01-0.66 for ramelteon; OR, 0.25; 95% CI, 0.09-0.69 for olanzapine; OR, 0.27; 95% CI, 0.07-0.99 for risperidone; and OR, 0.50; 95% CI, 0.31-0.80 for dexmedetomidine hydrochloride). None of the pharmacological treatments were significantly associated with a higher risk of all-cause mortality compared with placebo/control. CONCLUSIONS AND RELEVANCE This network meta-analysis demonstrated that haloperidol plus lorazepam might be the best treatment and ramelteon the best preventive medicine for delirium. None of the pharmacological interventions for treatment or prophylaxis increased the all-cause mortality.
Published:
May 1, 2019
Title:
Comparative Effectiveness of Adjunctive Psychotropic Medications in Patients With Schizophrenia
Authors:
Stroup, T. Scott; Gerhard, Tobias; Crystal, Stephen; Huang, Cecilia; Tan, Zhiqiang; Wall, Melanie M.; Mathai, Chacku; Olfson, Mark
Abstract:
OBJECTIVE To study the comparative real-world effectiveness of adjunctive psychotropic treatments for patients with schizophrenia. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study used US national Medicaid data from January 1, 2001, to December 31, 2010, to examine the outcomes of initiating treatment with an antidepressant, a benzodiazepine, a mood stabilizer, or another antipsychotic among adult outpatients (aged 18-64 years) diagnosed with schizophrenia who were stably treated with a single antipsychotic. Data analysis was performed from January 1, 2017, to June 30, 2018. Multinomial logistic regression models were used to estimate propensity scores to balance covariates across the 4 medication groups. Weighted Cox proportional hazards regression models were used to compare treatment outcomes during 365 days on an intention-to-treat basis. MAIN OUTCOMES AND MEASURES Risk of hospitalization for a mental disorder (primary), emergency department (ED) visits for a mental disorder, and all-cause mortality. RESULTS The study cohort included 81 921 adult outpatients diagnosed with schizophrenia (mean [SD] age, 40.7 [12.4] years; 37 515 women [45.8%]) who were stably treated with a single antipsychotic and then initiated use of an antidepressant (n = 31 117), a benzodiazepine (n = 11 941), a mood stabilizer (n = 12 849), or another antipsychotic (n = 26 014) (reference treatment). Compared with initiating use of another antipsychotic, initiating use of an antidepressant was associated with a lower risk (hazard ratio [HR], 0.84; 95% CI, 0.80-0.88) of psychiatric hospitalization, whereas initiating use of a benzodiazepine was associated with a higher risk (HR, 1.08; 95% CI, 1.02-1.15); the risk associated with initiating use of a mood stabilizer (HR, 0.98; 95% CI, 0.94-1.03) was not significantly different from initiating use of another antipsychotic. A similar pattern of associations was observed in psychiatric ED visits for initiating use of an antidepressant (HR, 0.92; 95% CI, 0.88-0.96), a benzodiazepine (HR, 1.12; 95% CI, 1.07-1.19), and a mood stabilizer (HR, 0.99; 95% CI, 0.94-1.04). Initiating use of a mood stabilizer was associated with an increased risk of mortality (HR, 1.31; 95% CI, 1.04-1.66). CONCLUSIONS AND RELEVANCE In the treatment of schizophrenia, initiating adjunctive treatment with an antidepressant was associated with reduced risk of psychiatric hospitalization and ED visits compared with initiating use of alternative psychotropic medications. Associations of benzodiazepines and mood stabilizers with poorer outcomes warrant clinical caution and further investigation.
Published:
May 1, 2019
Title:
Glycine decarboxylase regulates the maintenance and induction of pluripotency via metabolic control
Authors:
Kang, Phil Jun; Zheng, Jie; Lee, Gilju; Son, Daryeon; Kim, In Yong; Song, Gwonhwa; Park, Gyuman; You, Seungkwon
Abstract:
Reprogramming of ‘adult’ differentiated somatic cells to ‘embryonic’ pluripotent stem cells accompanied by increased rate of glycolysis. Conversely, glycolysis triggers accumulation of advanced glycation end products (AGEs), a potential causative factor in aging, by promoting methylglyoxal production. Therefore, it is reasonable that pluripotent stem cells (PSCs) would specifically regulate glycolysis to maintain their embryonic features. In this study, we focused on glycine decarboxylase (GLDC), a key enzyme in the glycine cleavage system that regulates glycolysis and methylglyoxal production in cancer. GLDC was exclusively expressed in PSCs, and inhibition of this enzyme induced alterations of metabolome and AGE accumulation, thereby suppressing the embryonic pluripotent state. Surprisingly, the level of accumulated AGEs in somatic cells gradually decreased during reprogramming, ultimately disappearing in iPSCs. In addition, ectopic expression of GLDC or treatment with the AGE inhibitor LR-90 promoted reprogramming. Together, these findings suggest that GLDC-mediated regulation of glycolysis and controlling AGE accumulation is related to maintenance and induction of pluripotency.
Published:
May 1, 2019
Title:
High Plasma sRAGE (Soluble Receptor for Advanced Glycation End Products) Is Associated With Slower Carotid Intima-Media Thickness Progression and Lower Risk for First-Time Coronary Events and Mortality
Authors:
Grauen Larsen Helena; Marinkovic Goran; Nilsson Peter M.; Nilsson Jan; Engström Gunnar; Melander Olle; Orho-Melander Marju; Schiopu Alexandru
Abstract:
Objective—RAGE (receptor for advanced glycation end products) and EMMPRIN (extracellular matrix metalloproteinase inducer) are immune receptors for proinflammatory mediators. These receptors can also be found in a soluble form in the circulation. Soluble RAGE (sRAGE) has shown atheroprotective properties in animal studies, possibly by acting as a decoy receptor for its ligands. Whether sEMMPRIN (soluble EMMPRIN) has similar roles is unknown. We hypothesized that sRAGE and sEMMPRIN might be associated with vascular disease progression, incident coronary events, and mortality.Approach and Results—We measured baseline sRAGE and sEMMPRIN in 4612 cardiovascular disease-free individuals from the population-based Malmö Diet and Cancer cohort. Measurements of intima-media thickness in the common carotid artery were performed at inclusion and after a median of 16.5 years. sRAGE was negatively correlated with carotid intima-media thickness progression, independently of traditional cardiovascular risk factors, kidney function, and hsCRP (high sensitive C-reactive protein). Additionally, sRAGE was associated with decreased risk for major adverse coronary events (hazard ratio=0.90 [0.82–0.97]; P=0.009) and mortality (hazard ratio=0.93 [0.88–0.99]; P=0.011) during a follow-up period of 21 years. The relationship with mortality was independent of all considered potential confounders. We found no correlations between EMMPRIN, intima-media thickness progression, or prognosis.Conclusions—Individuals with high levels of circulating sRAGE have a slower rate of carotid artery disease progression and a better prognosis. Although its predictive value was too weak to promote sRAGE as a useful clinical biomarker in the population, the findings support further research into the potential anti-inflammatory and atheroprotective properties of this soluble receptor.
Published:
May 1, 2019
Title:
Very human bears: Wild brown bear neo-taphonomic signature and its equifinality problems in archaeological contexts
Authors:
Rosell Ardèvol, Jordi; Blasco, Ruth; Arilla, Maite; Fernández-Jalvo, Yolanda
Abstract:
Different agents can lead to similar damage patterns, and different causes can result in the same type of modification. This phenomenon was defined by Lyman (1987) as a problem of equifinality, with which the researcher warned about the risks of making direct systematic correlations. The fact that a specific type of damage cannot be linked to a single actor, behaviour or ecological context is primarily applicable to damage associated with the direct consumption of carcasses. Some carnivores show physical and dental characteristics that could lead to bone modifications potentially like those generated by humans. For example, bears have a bunodont dentition and plantigrade locomotion –the latter allows them to frequently release and use their claws as “hands”. Here, we present the neo-taphonomical study of 17 ungulate carcasses eaten by wild brown bears (Ursus arctos arctos) in the Spanish Pyrenees. Our observations express this equifinal problem due to the similarities between tooth marks and peeling generated by both bears and humans. This fact is especially significant, given that peeling and the combination of this damage with visible tooth marks were primarily associated with the feeding activities of humans and chimpanzees (Pan troglodytes) and only anecdotally with other taphonomic agents, such as spotted hyenas. With this research, we try to show some equifinal phenomena that could occur in Pleistocene faunal assemblages as well, where the presence of both hominids and bears is documented.
Published:
May 1, 2019
Title:
Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients
Authors:
Nielsen Roni; Møller Niels; Gormsen Lars C.; Tolbod Lars Poulsen; Hansson Nils Henrik; Sorensen Jens; Harms Hendrik Johannes; Frøkiær Jørgen; Eiskjaer Hans; Jespersen Nichlas Riise; Mellemkjaer Søren; Lassen Thomas Ravn; Pryds Kasper; Bøtker Hans Erik; Wiggers Henrik
Abstract:
Background:Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers.Methods:Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography.Results:3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM (P<0.001). CO rose by 2.0±0.2 L/min (P<0.001) because of an increase in stroke volume of 20±2 mL (P<0.001) and heart rate of 7±2 beats per minute (bpm) (P<0.001). Left ventricular ejection fraction increased 8±1% (P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM (P
Published:
April 30, 2019
Title:
Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation
Authors:
Koval, Olha M.; Nguyen, Emily K.; Santhana, Velarchana; Fidler, Trevor P.; Sebag, Sara C.; Rasmussen, Tyler P.; Mittauer, Dylan J.; Strack, Stefan; Goswami, Prabhat C.; Abel, E. Dale; Grumbach, Isabella M.
Abstract:
The mitochondrial Ca2+ uniporter enables ATP production to match energy demands during the cell cycle. The mitochondrial Ca2+ uniporter enables ATP production to match energy demands during the cell cycle.
Published:
April 30, 2019
Title:
NF-κB signaling dynamics is controlled by a dose-sensing autoregulatory loop
Authors:
DeFelice, Mialy M.; Clark, Helen R.; Hughey, Jacob J.; Maayan, Inbal; Kudo, Takamasa; Gutschow, Miriam V.; Covert, Markus W.; Regot, Sergi
Abstract:
Keeping a check on the infection response The innate immune system responds to various cytokines and other “danger signals” that occur during infection. These must be properly identified and responded to; however, too much stimulation of the immune system can have debilitating consequences and cause autoimmune disease. Using live-cell biosensors and optogenetics, DeFelice et al. identified a regulatory feedback loop in one such immune signaling system mediated by cytokine receptors through the protein NF-κB. They found that the protein IRAK1 acted as a sensor of the amount of cytokine stimulation such that a high amount of stimulus elicited IRAK1-dependent inhibition of NF-κB activity, whereas low amounts of stimuli elicited oscillatory patterns of activity. The findings place IRAK1 at the central controls of the overall immune response to infection and may explain why mutations in IRAK1 are associated with rheumatoid arthritis. Over the last decade, multiple studies have shown that signaling proteins activated in different temporal patterns, such as oscillatory, transient, and sustained, can result in distinct gene expression patterns or cell fates. However, the molecular events that ensure appropriate stimulus- and dose-dependent dynamics are not often understood and are difficult to investigate. Here, we used single-cell analysis to dissect the mechanisms underlying the stimulus- and dose-encoding patterns in the innate immune signaling network. We found that Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling dynamics relied on a dose-dependent, autoinhibitory loop that rendered cells refractory to further stimulation. Using inducible gene expression and optogenetics to perturb the network at different levels, we identified IL-1R–associated kinase 1 (IRAK1) as the dose-sensing node responsible for limiting signal flow during the innate immune response. Although the kinase activity of IRAK1 was not required for signal propagation, it played a critical role in inhibiting the nucleocytoplasmic oscillations of the transcription factor NF-κB. Thus, protein activities that may be “dispensable” from a topological perspective can nevertheless be essential in shaping the dynamic response to the external environment. The kinase IRAK1 senses the cytokine load to prevent overstimulation of the immune system. The kinase IRAK1 senses the cytokine load to prevent overstimulation of the immune system.
Published:
April 30, 2019
Title:
Evidence and mechanisms for statin-induced cognitive decline
Authors:
Tan, Brendan; Rosenfeldt, Franklin; Ou, Ruchong; Stough, Con
Abstract:
INTRODUCTION: Statin drugs have become the most highly prescribed drugs for cardiovascular disease. However, there is disagreement as to the existence of adverse effects of statin administration on cognitive function. Therefore, it is important to better understand the effects of statins on cognition and possible mechanisms of these effects. Areas covered: We analyzed relevant studies of the relationship between cognitive performance and statin and usage. We included articles published between 2018 and 1992. We identified three randomized trials, one observational study and 66 case reports that provided credible evidence of statin-induced cognitive impairment. We also identified seven randomized trials and two observational studies reporting no significant evidence of statin-induced cognitive impairment. Expert opinion: We found methodological differences that may have contributed to the divergence of these results. Evaluation of all these studies indicated that statin-associated cognitive decline is a real entity. Likely mechanisms to explain the adverse effects include 1. Reduction of synthesis of coenzyme Q10 with consequent increasing oxidative stress and reduction of cerebral energy production; 2. Depletion of central nervous system myelin by inhibition of cholesterol synthesis. We conclude that statin-induced cognitive decline does exist, needs to be better recognized and requires more studies of prevention and treatment.
Published:
April 27, 2019
Title:
Evolution of digestive enzymes and dietary diversification in birds
Authors:
Chen, Yan-Hong; Zhao, Huabin
Abstract:
As the most species-rich class of tetrapod vertebrates, Aves possesses diverse feeding habits, with multiple origins of insectivory, carnivory, frugivory, nectarivory, granivory and omnivory. Since digestive enzymes mediate and limit energy and nutrient uptake, we hypothesized that genes encoding digestive enzymes have undergone adaptive evolution in birds. To test this general hypothesis, we identified 16 digestive enzyme genes (including seven carbohydrase genes (hepatic amy, pancreatic amy, salivary amy, agl, g6pc, gaa and gck), three lipase genes (cyp7a1, lipf and pnlip), two protease genes (ctrc and pgc), two lysozyme genes (lyz and lyg) and two chitinase genes (chia and chit1)) from the available genomes of 48 bird species. Among these 16 genes, three (salivary amy, lipf and chit1) were not found in all 48 avian genomes, which was further supported by our synteny analysis. Of the remaining 13 genes, eight were single-copy and five (chia, gaa, lyz, lyg and pgc) were multi-copy. Moreover, the multi-copy genes gaa, lyg and pgc were predicted to exhibit functional divergence among copies. Positively selected sites were detected in all of the analyzed digestive enzyme genes, except agl, g6pc, gaa and gck, suggesting that different diets may have favored differences in catalytic capacities of these enzymes. Furthermore, the analysis also revealed that the pancreatic amylase gene and one of the lipase genes (cyp7a1) have higher ω (the ratio of nonsynonymous to the synonymous substitution rates) values in species consuming a larger amount of seeds and meat, respectively, indicating an intense selection. In addition, the gck carbohydrase gene in species consuming a smaller amount of seeds, fruits or nectar, and a lipase gene (pnlip) in species consuming less meat were found to be under relaxed selection. Thus, gene loss, gene duplication, functional divergence, positive selection and relaxed selection have collectively shaped the evolution of digestive enzymes in birds, and the evolutionary flexibility of these enzymes may have facilitated their dietary diversification.
Published:
April 25, 2019
Title:
Evolution of digestive enzymes and dietary diversification in birds
Authors:
Chen, Yan-Hong; Zhao, Huabin
Abstract:
As the most species-rich class of tetrapod vertebrates, Aves possesses diverse feeding habits, with multiple origins of insectivory, carnivory, frugivory, nectarivory, granivory and omnivory. Since digestive enzymes mediate and limit energy and nutrient uptake, we hypothesized that genes encoding digestive enzymes have undergone adaptive evolution in birds. To test this general hypothesis, we identified 16 digestive enzyme genes (including seven carbohydrase genes (hepatic amy, pancreatic amy, salivary amy, agl, g6pc, gaa and gck), three lipase genes (cyp7a1, lipf and pnlip), two protease genes (ctrc and pgc), two lysozyme genes (lyz and lyg) and two chitinase genes (chia and chit1)) from the available genomes of 48 bird species. Among these 16 genes, three (salivary amy, lipf and chit1) were not found in all 48 avian genomes, which was further supported by our synteny analysis. Of the remaining 13 genes, eight were single-copy and five (chia, gaa, lyz, lyg and pgc) were multi-copy. Moreover, the multi-copy genes gaa, lyg and pgc were predicted to exhibit functional divergence among copies. Positively selected sites were detected in all of the analyzed digestive enzyme genes, except agl, g6pc, gaa and gck, suggesting that different diets may have favored differences in catalytic capacities of these enzymes. Furthermore, the analysis also revealed that the pancreatic amylase gene and one of the lipase genes (cyp7a1) have higher ω (the ratio of nonsynonymous to the synonymous substitution rates) values in species consuming a larger amount of seeds and meat, respectively, indicating an intense selection. In addition, the gck carbohydrase gene in species consuming a smaller amount of seeds, fruits or nectar, and a lipase gene (pnlip) in species consuming less meat were found to be under relaxed selection. Thus, gene loss, gene duplication, functional divergence, positive selection and relaxed selection have collectively shaped the evolution of digestive enzymes in birds, and the evolutionary flexibility of these enzymes may have facilitated their dietary diversification.
Published:
April 25, 2019
Title:
Precision Nutrition and the Microbiome, Part I: Current State of the Science
Authors:
Mills, Susan; Stanton, Catherine; Lane, Jonathan A.; Smith, Graeme J.; Ross, R. Paul
Abstract:
The gut microbiota is a highly complex community which evolves and adapts to its host over a lifetime. It has been described as a virtual organ owing to the myriad of functions it performs, including the production of bioactive metabolites, regulation of immunity, energy homeostasis and protection against pathogens. These activities are dependent on the quantity and quality of the microbiota alongside its metabolic potential, which are dictated by a number of factors, including diet and host genetics. In this regard, the gut microbiome is malleable and varies significantly from host to host. These two features render the gut microbiome a candidate 'organ' for the possibility of precision microbiomics - the use of the gut microbiome as a biomarker to predict responsiveness to specific dietary constituents to generate precision diets and interventions for optimal health. With this in mind, this two-part review investigates the current state of the science in terms of the influence of diet and specific dietary components on the gut microbiota and subsequent consequences for health status, along with opportunities to modulate the microbiota for improved health and the potential of the microbiome as a biomarker to predict responsiveness to dietary components. In particular, in Part I, we examine the development of the microbiota from birth and its role in health. We investigate the consequences of poor-quality diet in relation to infection and inflammation and discuss diet-derived microbial metabolites which negatively impact health. We look at the role of diet in shaping the microbiome and the influence of specific dietary components, namely protein, fat and carbohydrates, on gut microbiota composition.
Published:
April 24, 2019
Title:
Skull shape and the demands of feeding: a biomechanical study of peccaries (Mammalia, Cetartiodactyla)
Authors:
Hendges, Carla D.; Patterson, Bruce D.; Caceres, Nilton C.; Gasparini, German M.; Ross, Callum F.
Abstract:
A primary requirement of the mammalian skull is to exert forces on different foods and to resist the forces imposed on it during feeding. Skull shape patterns within and among mammals are generally well known, but the biomechanical relevance of this variation remains limited for some groups. By integrating geometric morphometric and biomechanical analyses, we test the hypothesis that skull shape in peccaries reflects biomechanical attributes to generate and dissipate powerful forces, presumably in response to tough foods. We obtained skull shape and size from 213 specimens of the three living peccary species and estimated bite force, bite stress at molars, bending and shear stress on the mandibular corpus, and condylar stress. We found larger estimated bite forces, greater resistance to bending loads, and lower stress emerging from the larger muscle attachment areas and shorter and deeper mandibular corpora for both Pecari tajacu and Tayassu pecari relative to Parachoerus wagneri. Peccaries (P. tajacu and T. pecari) with more powerful biomechanical attributes feed mainly on tougher foods (e.g., palm fruits). These results support the hypothesis that species eating tough foods tend to have a feeding morphology mechanically adapted to stronger bites and greater biting resistance, which must be closely reflected in their craniomandibular shape.
Published:
April 24, 2019
Title:
Biocatalytic Reversal of Advanced Glycation End Product Modification
Authors:
Kim, Nam Y; Goddard, Tyler N; Sohn, Seungjung; Spiegel, David A; Crawford, Jason
Abstract:
Advanced glycation end products (AGEs) are a heterogeneous group of molecules that emerge from the condensation of sugars and proteins via the Maillard reaction. Despite a significant number of studies showing strong associations between AGEs and the pathologies of aging-related illnesses, it has been a challenge to establish AGEs as causal agents primarily due to the lack of tools in reversing AGE modifications at the molecular level. Here, we show that MnmC, an enzyme involved in a bacterial tRNAmodification pathway, is capable of reversing the AGEs carboxyethyllysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, sitedirected mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGEcontaining peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE). Our data demonstrate that MnmC variants are promising lead catalysts toward the development of AGEreversal tools and a better understanding of AGE biology.
Published:
April 23, 2019
Title:
MMSE changes during and after ECT in late-life depression: a prospective study
Authors:
Obbels, Jasmien; Vansteelandt, Kristof; Verwijk, Esmée; Dols, Annemieke; Bouckaert, Filip; Oudega, Mardien L.; Vandenbulcke, Mathieu; Stek, Max; Sienaert, Pascal
Abstract:
Abstract
Objective: There is an ongoing concern about the impact of electroconvulsive therapy (ECT) on cognition in late-life depression (LLD), especially when pre-treatment MMSE-scores (Mini-Mental state Examination) are low. Our aim was to examine the evolution of cognitive effects of ECT, using the MMSE in a large group of patients with LLD.
Methods: 109 patients aged 55 years and older with unipolar depression, referred for ECT were included. The MMSE was assessed before, weekly during, immediately, and six months after ECT.
Results: MMSE-scores improved significantly during the course of ECT and remained stable during the six months period after ending ECT in the total group. A low MMSE-score (<24) at baseline improved significantly during ECT, whereas a normal MMSE-score (≥24) at baseline did not change significantly. In both groups, MMSE-scores still increased slightly after discontinuing ECT.
Conclusion: ECT does not cause deleterious cognitive effects, as measured with the MMSE, during and until six months after ECT in patients with LLD. In the event of a baseline cognitive impairment, MMSE-scores tend to improve significantly during and six months after the ECT course. The presence of pretreatment cognitive impairment should not urge clinicians to withhold ECT in older patients with severe depression.
Published:
April 23, 2019
Title:
Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1
Authors:
Peng, Shiming; Xiao, Wen; Ju, Dapeng; Sun, Baofa; Hou, Nannan; Liu, Qianlan; Wang, Yanli; Zhao, Haijiao; Gao, Chunchun; Zhang, Song; Cao, Ran; Li, Pengfei; Huang, Huanwei; Ma, Yongfen; Wang, Yankai; Lai, Weiyi; Ma, Zhixiong; Zhang, Wei; Huang, Song; Wang, Hailin; Zhang, Zhiyuan; Zhao, Liping; Cai, Tao; Zhao, Yong-Liang; Wang, Fengchao; Nie, Yongzhan; Zhi, Gang; Yang, Yun-Gui; Zhang, Eric Erquan; Huang, Niu
Abstract:
The skinny on FTO Although the fat mass and obesity-associated gene FTO has been linked to genetic risk of obesity, the mRNA demethylase that it encodes has proven difficult to therapeutically target. From a screen of approved drugs, Peng et al. identified entacapone, a catechol-O-methyltransferase inhibitor used in the treatment of Parkinson’s disease, as an inhibitor of FTO. In vivo administration of entacapone improved body weight and glucose tolerance and increased adipose thermogenesis in mice, which the authors tied to decreased FTO-catalyzed m6A demethylation of FOXO1 mRNA. Further studies will need to confirm the repurposing potential of entacapone for obesity or metabolic disease in humans. Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis. Entacapone improves metabolic homeostasis in diet-induced obese mice through a direct effect on an FTO-FOXO1 regulatory axis. Entacapone improves metabolic homeostasis in diet-induced obese mice through a direct effect on an FTO-FOXO1 regulatory axis.
Published:
April 17, 2019
Title:
FGFR inhibitors get to nuclear PTEN
Authors:
Ferrarelli, Leslie K.
Abstract:
FGFR inhibitors block DNA repair coordinated by PTEN, enhancing radiotherapy in glioblastoma. FGFR inhibitors block DNA repair coordinated by PTEN, enhancing radiotherapy in glioblastoma. FGFR inhibitors block DNA repair coordinated by PTEN, enhancing radiotherapy in glioblastoma.
Published:
April 16, 2019
Title:
Functional assays for transcription mechanisms in high-throughput
Authors:
Qiu, Chenxi; Kaplan, Craig D.
Abstract:
Dramatic increases in the scale of programmed synthesis of nucleic acid libraries coupled with deep sequencing have powered advances in understanding nucleic acid and protein biology. Biological systems centering on nucleic acids or encoded proteins greatly benefit from such high-throughput studies, given that large DNA variant pools can be synthesized and DNA, or RNA products of transcription, can be easily analyzed by deep sequencing. Here we review the scope of various high-throughput functional assays for studies of nucleic acids and proteins in general, followed by discussion of how these types of study have yielded insights into the RNA Polymerase II (Pol II) active site as an example. We discuss methodological considerations in the design and execution of these experiments that should be valuable to studies in any system.
Published:
April 15, 2019
Title:
Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets
Authors:
Cassetta, Luca; Fragkogianni, Stamatina; Sims, Andrew H.; Swierczak, Agnieszka; Forrester, Lesley M.; Zhang, Hui; Soong, Daniel Y. H.; Cotechini, Tiziana; Anur, Pavana; Lin, Elaine Y.; Fidanza, Antonella; Lopez-Yrigoyen, Martha; Millar, Michael R.; Urman, Alexandra; Ai, Zhichao; Spellman, Paul T.; Hwang, E. Shelley; Dixon, J. Michael; Wiechmann, Lisa; Coussens, Lisa M.; Smith, Harriet O.; Pollard, Jeffrey W.
Abstract:
Summary The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.
Published:
April 15, 2019
Title:
MiR-644a Disrupts Oncogenic Transformation and Warburg Effect by Direct Modulation of Multiple Genes of Tumor-Promoting Pathways
Authors:
Ebron, Jey S.; Shankar, Eswar; Singh, Jagjit; Sikand, Kavleen; Weyman, Crystal M.; Gupta, Sanjay; Lindner, Daniel J.; Liu, Xiaoqi; Campbell, Moray J.; Shukla, Girish C.
Abstract:
Graphical Abstract 
Download figureOpen in new tabDownload powerpoint Castration-resistant prostate cancer (CRPC) is defined by tumor microenvironment heterogeneity affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), and aberrant activation of transcription factors including androgen receptor (AR) and c-Myc. Using in vitro, in vivo, and animal models, we find a direct correlation between miR-644a downregulation and dysregulation of essential cellular processes. MiR-644a downregulated expression of diverse tumor microenvironment drivers including c-Myc, AR coregulators, and antiapoptosis factors Bcl-xl and Bcl2. Moreover, miR-644a modulates epithelial–mesenchymal transition (EMT) by directly targeting EMT-promoting factors ZEB1, cdk6, and Snail. Finally, miR-644a expression suppresses the Warburg effect by direct targeting of c-Myc, Akt, IGF1R, and GAPDH expression. RNA sequencing analysis revealed an analogous downregulation of these factors in animal tumor xenografts. These data demonstrate miR-644a mediated fine-tuning of oncogenesis, stimulating pathways and resultant potentiation of enzalutamide therapy in CRPC patients. Significance: This study demonstrates that miR-644a therapeutically influences the CRPC tumor microenvironment by suppressing androgen signaling and additional genes involved in metabolism, proliferation, Warburg effect, and EMT, to potentiate the enzalutamide therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1844/F1.large.jpg.
Download figureOpen in new tabDownload powerpoint Castration-resistant prostate cancer (CRPC) is defined by tumor microenvironment heterogeneity affecting intrinsic cellular mechanisms including dysregulated androgen signaling, aerobic glycolysis (Warburg effect), and aberrant activation of transcription factors including androgen receptor (AR) and c-Myc. Using in vitro, in vivo, and animal models, we find a direct correlation between miR-644a downregulation and dysregulation of essential cellular processes. MiR-644a downregulated expression of diverse tumor microenvironment drivers including c-Myc, AR coregulators, and antiapoptosis factors Bcl-xl and Bcl2. Moreover, miR-644a modulates epithelial–mesenchymal transition (EMT) by directly targeting EMT-promoting factors ZEB1, cdk6, and Snail. Finally, miR-644a expression suppresses the Warburg effect by direct targeting of c-Myc, Akt, IGF1R, and GAPDH expression. RNA sequencing analysis revealed an analogous downregulation of these factors in animal tumor xenografts. These data demonstrate miR-644a mediated fine-tuning of oncogenesis, stimulating pathways and resultant potentiation of enzalutamide therapy in CRPC patients. Significance: This study demonstrates that miR-644a therapeutically influences the CRPC tumor microenvironment by suppressing androgen signaling and additional genes involved in metabolism, proliferation, Warburg effect, and EMT, to potentiate the enzalutamide therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1844/F1.large.jpg.Published:
April 15, 2019
Title:
Studying the mechanisms and targets of glycation and advanced glycation end-products in simple eukaryotic model systems
Authors:
Scheckhuber, Christian Q.
Abstract:
Biological systems are usually astonishingly complex. This complexity makes it often difficult if not impossible to study their inner workings. In order to address complex research questions more simply structured models (e.g., microorganisms, plants, non-vertebrate animals) are utilized. Findings from these studies can then be translated to more complex systems like mammals. This strategy facilitates the identification of relevant ‘leads’ that can be specifically addressed in the higher organism. In this review studies to elucidate the relevance, modes of action and molecular targets of reactive carbonyl species using simple model systems are discussed. These dicarbonyls are formed during metabolic activity in all organisms as toxic by-products that lead to the dysfunction of essential cellular components by a process termed glycation, resulting ultimately in the generation of advanced glycation end-products. Understanding how both dicarbonyls and advanced glycation end-products are formed, which environmental conditions influence their levels and what cellular pathways they affect is paramount to develop efficient strategies targeting diseases that are related to reactive carbonyl species, like diabetes, neurodegenerative disorders and cancer. This contribution presents important findings in the field of dicarbonyls and glycation from fungi, plants, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster.
Published:
April 15, 2019
Title:
The protective effects of exenatide against AGEs-induced articular matrix degradation in human primary chondrocytes
Authors:
Tong, Changgui; Liang, Haidong; Liu, Xuehui; Yuan, Bo; Xue, Boqiong; Tong, Zhihong; Yin, Peng
Abstract:
Osteoarthritis (OA) presents a major global health burden and is projected to become even more prevalent in coming decades. Therefore, it is of utmost importance to uncover novel therapies for the treatment and prevention of this disease. In the present study, we investigated the effects of exenatide, a specific glucagon-like peptide (GLP) agonist, on degradation of type II collagen and aggrecan, the two main components of the articular extracellular matrix, in human primary chondrocytes. Our results reveal that exenatide could ameliorate degradation of type II collagen and aggrecan by inhibiting expression of metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) induced by advanced glycation end-products. We also found that exenatide reduces oxidative stress and inhibits activation of nuclear factor-κB through the p38 cellular signaling pathway. Taken together, the findings of this study indicate that exenatide may have potential as a novel treatment for osteoarthritis.
Published:
April 15, 2019
Title:
Pilot study of a ketogenic diet in relapsing-remitting MS
Authors:
Brenton, J. Nicholas; Banwell, Brenda; Bergqvist, A.G. Christina; Lehner-Gulotta, Diana; Gampper, Lauren; Leytham, Emily; Coleman, Rachael; Goldman, Myla D.
Abstract:
Objective To assess the safety and tolerability of a modified Atkins diet (KDMAD), a type of ketogenic diet (KD), in subjects with relapsing MS while exploring potential benefits of KDs in MS. Methods Twenty subjects with relapsing MS enrolled into a 6-month, single-arm, open-label study of the KDMAD. Adherence to KDMAD was objectively monitored by daily urine ketone testing. Fatigue and depression scores and fasting adipokines were obtained at baseline and on diet. Brain MRI was obtained at baseline and 6 months. Intention to treat was used for primary data analysis, and a per-protocol approach was used for secondary analysis. Results No subject experienced worsening disease on diet. Nineteen subjects (95%) adhered to KDMAD for 3 months and 15 (75%) adhered for 6 months. Anthropometric improvements were noted on KDMAD, with reductions in body mass index and total fat mass (p < 0.0001). Fatigue (p = 0.002) and depression scores (p = 0.003) were improved. Serologic leptin was significantly lower at 3 months (p
Published:
April 12, 2019
Title:
Inhibition of HMGB1/RAGE-mediated endocytosis by HMGB1 antagonist box A, anti-HMGB1 antibodies, and cholinergic agonists suppresses inflammation
Authors:
Yang, Huan; Liu, Hui; Zeng, Qiong; Imperato, Gavin H.; Addorisio, Meghan E.; Li, Jianhua; He, Mingzhu; Cheng, Kai Fan; Al-Abed, Yousef; Harris, Helena E.; Chavan, Sangeeta S.; Andersson, Ulf; Tracey, Kevin J.
Abstract:
BackgroundExtracellular high mobility group box 1 protein (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization.MethodsEndocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student’s t test or one-way ANOVA followed by the least significant difference or Tukey’s tests.ResultsAnti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes.ConclusionThese results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.
Published:
April 11, 2019
Title:
Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention
Authors:
Gross, Elena C.; Klement, Rainer J.; Schoenen, Jean; D'Agostino, Dominic P.; Fischer, Dirk
Abstract:
An increasing amount of evidence suggests that migraines are a response to a cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity. The ketogenic diet (KD), a diet mimicking fasting that leads to the elevation of ketone bodies (KBs), is a therapeutic intervention targeting cerebral metabolism that has recently shown great promise in the prevention of migraines. KBs are an alternative fuel source for the brain, and are thus likely able to circumvent some of the abnormalities in glucose metabolism and transport found in migraines. Recent research has shown that KBs-D-β-hydroxybutyrate in particular-are more than metabolites. As signalling molecules, they have the potential to positively influence other pathways commonly believed to be part of migraine pathophysiology, namely: mitochondrial functioning, oxidative stress, cerebral excitability, inflammation and the gut microbiome. This review will describe the mechanisms by which the presence of KBs, D-BHB in particular, could influence those migraine pathophysiological mechanisms. To this end, common abnormalities in migraines are summarised with a particular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies. Experimental animal data will be discussed to elaborate on the potential therapeutic mechanisms of elevated KBs in migraine pathophysiology, with a particular focus on the actions of D-BHB. In complex diseases such as migraines, a therapy that can target multiple possible pathogenic pathways seems advantageous. Further research is needed to establish whether the absence/restriction of dietary carbohydrates, the presence of KBs, or both, are of primary importance for the migraine protective effects of the KD.
Published:
April 10, 2019
Title:
Targeted antibody and cytokine cancer immunotherapies through collagen affinity
Authors:
Ishihara, Jun; Ishihara, Ako; Sasaki, Koichi; Lee, Steve Seung-Young; Williford, John-Michael; Yasui, Mariko; Abe, Hiroyuki; Potin, Lambert; Hosseinchi, Peyman; Fukunaga, Kazuto; Raczy, Michal M.; Gray, Laura T.; Mansurov, Aslan; Katsumata, Kiyomitsu; Fukayama, Masashi; Kron, Stephen J.; Swartz, Melody A.; Hubbell, Jeffrey A.
Abstract:
Conjugated bliss Immunotherapies for cancer are becoming increasingly common due to their impressive ability to activate the patients’ own immune system to fight tumors. However, systemic approaches to immune system activation are not risk free, and immunotherapies are often associated with corresponding immune side effects, which can be severe. To address this problem, Ishihara et al. conjugated immune checkpoint inhibitors and the cytokine interleukin-2 to the collagen-binding domain from a blood protein, allowing them to bind to tumor stroma and exert their effects locally. The researchers tested this approach in multiple mouse models, demonstrating improved efficacy and safety compared to the unconjugated molecules. Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti–cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti–programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4 + αPD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD–IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD–IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise. An engineered cancer immunotherapy using a collagen-binding domain enhances efficacy and reduces adverse events. An engineered cancer immunotherapy using a collagen-binding domain enhances efficacy and reduces adverse events.
Published:
April 10, 2019
Title:
With macrophages, tumors won’t go hungry
Authors:
El-Kenawi, Asmaa
Abstract:
Metabolic cross-talk between macrophages and tumor cells results in cancer progression and therapeutic resistance. Metabolic cross-talk between macrophages and tumor cells results in cancer progression and therapeutic resistance. Metabolic cross-talk between macrophages and tumor cells results in cancer progression and therapeutic resistance.
Published:
April 10, 2019
Title:
Stalk of the town: the shaky science behind the 'global celery movement'
Authors:
Abstract:
Anthony William, who calls himself the Medical Medium, preaches the juice’s ‘healing powers’ as sales of the vegetable jump 400% – despite having no medical training
Published:
April 9, 2019
Title:
Fructose Promotes Leaky Gut, Endotoxemia, and Liver Fibrosis Through Ethanol-Inducible Cytochrome P450-2E1-Mediated Oxidative and Nitrative Stress
Authors:
Cho, Young-Eun; Kim, Do-Kyun; Seo, Wonhyo; Gao, Bin; Yoo, Seong-Ho; Song, Byoung-Joon
Abstract:
Fructose intake is known to induce obesity, insulin resistance, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the effects of fructose drinking on gut leakiness, endotoxemia, and NAFLD and study the underlying mechanisms in rats, mice, and T84 colon cells. Levels of ileum junctional proteins, oxidative stress markers, and apoptosis-related proteins in rodents, T84 colonic cells, and human ileums were determined by immunoblotting, immunoprecipitation, and immunofluorescence analyses. Fructose drinking caused microbiome change, leaky gut, and hepatic inflammation/fibrosis with increased levels of nitroxidative stress marker proteins cytochrome P450-2E1 (CYP2E1), inducible nitric oxide synthase, and nitrated proteins in small intestine and liver of rodents. Fructose drinking significantly elevated plasma bacterial endotoxin levels, likely resulting from decreased levels of intestinal tight junction (TJ) proteins (zonula occludens 1, occludin, claudin-1, and claudin-4), adherent junction (AJ) proteins (β-catenin and E-cadherin), and desmosome plakoglobin, along with α-tubulin, in wild-type rodents, but not in fructose-exposed Cyp2e1-null mice. Consistently, decreased intestinal TJ/AJ proteins and increased hepatic inflammation with fibrosis were observed in autopsied obese people compared to lean individuals. Furthermore, histological and biochemical analyses showed markedly elevated hepatic fibrosis marker proteins in fructose-exposed rats compared to controls. Immunoprecipitation followed by immunoblot analyses revealed that intestinal TJ proteins were nitrated and ubiquitinated, leading to their decreased levels in fructose-exposed rats. Conclusion: These results showed that fructose intake causes protein nitration of intestinal TJ and AJ proteins, resulting in increased gut leakiness, endotoxemia, and steatohepatitis with liver fibrosis, at least partly, through a CYP2E1-dependent manner.
Published:
April 8, 2019
Title:
Effect of a four-week ketogenic diet on exercise metabolism in CrossFit-trained athletes.
Authors:
Durkalec-Michalski, Krzysztof; Nowaczyk, Paulina M.; Siedzik, Katarzyna
Abstract:
BACKGROUND: The ketogenic diet is becoming a popular nutritional model among athletes. However, the relationship between its use and metabolism during exercise seems to have not been fully investigated. METHODS: The aim of the study was to assess the effects of a four-week ketogenic diet (KD) on fat and carbohydrate (CHO) utilization during an incremental cycling test (ICT) in CrossFit-trained female (n = 11) and male (n = 11) athletes. During the ICT (while consuming the customary diet and after the KD), oxygen uptake and carbon dioxide exhalation were registered, and CHO and fat utilization as well as energy expenditure were calculated. RESULTS: In males, the KD led to an increase in fat utilization (g.min(- 1).kgFFM(- 1) and % oxidation). It was particularly noticeable at exercise intensities up to 80% of VO2max. An increase in the area under the curve (AUC) was seen in males but not in females at up to
Published:
April 5, 2019
Title:
Microwear and isotopic analyses on cave bear remains from Toll Cave reveal both short-term and long-term dietary habits
Authors:
Ramírez-Pedraza, Iván; Tornero, Carlos; Pappa, Spyridoula; Talamo, Sahra; Salazar-García, Domingo; Blasco, Ruth; Rosell Ardèvol, Jordi; Rivals, Florent
Abstract:
Dietary habits of the extinct Ursus spelaeus have always been a controversial topic in paleontological studies. In this work, we investigate carbon and nitrogen values in the bone collagen and dental microwear of U. spelaeus specimens recovered in Level 4 from Toll Cave (Moià, Catalonia, NE Iberian Peninsula). These remains have been dated to > 49,000 14C BP. The ability of both proxies to provide data on the diet of U. spelaeus at different times in the life-history (isotopes: average diet of life; microwear: last days/weeks before death), allows us to generate high-resolution and complementary data. Our results show lower values (δ13C & δ15N) in cave bears than in strict herbivores (i.e. Cervus elaphus) recovered from the same level of Toll Cave. On the other hand, 12 lower molars (m1) were analysed through low-magnification microwear technique. The cave bears from Toll Cave show a microwear pattern like that of extant bears with omnivorous and carnivorous diets. These data are discussed in the framework of all available data in Europe and add new information about the plasticity of the dietary habits of this species at the southern latitudes of Europe during Late Pleistocene periods.
Published:
April 5, 2019
Title:
Embracing diversity in the 5-HT neuronal system
Authors:
Okaty, Benjamin W.; Commons, Kathryn G.; Dymecki, Susan M.
Abstract:
Neurons that synthesize and release 5-hydroxytryptamine (5-HT; serotonin) express a core set of genes that establish and maintain this neurotransmitter phenotype and distinguish these neurons from other brain cells. Beyond a shared 5-HTergic phenotype, these neurons display divergent cellular properties in relation to anatomy , morphology , hodology , electrophysiology and gene expression, including differential expression of molecules supporting co-t ransmission of additional neurotransmitters. This diversity suggests that functionally heterogeneous subtypes of 5-HT neurons exist, but linking subsets of these neurons to particular functions has been technically challenging. We discuss recent data from molecular genetic, genomic and functional methods that, when coupled with classical findings, yield a reframing of the 5-HT neuronal system as a conglomeration of diverse subsystems with potential to inspire novel, more targeted therapies for clinically distinct 5-HT-related disorders.
Published:
April 4, 2019
Title:
AGEs induce epithelial to mesenchymal transformation of human peritoneal mesothelial cells via upregulation of STAT3
Authors:
Zhang, Pei; Dai, Hong; Peng, Lei
Abstract:
Epithelial-mesenchymal transition (EMT) in peritoneum was induced during peritoneal dialysis (PD), which finally caused progressive fibrosis. However, the underlying mechanisms were not well elucidated. We established advanced glycation end-products (AGEs)-induced EMT model using primary human peritoneal mesothelial cells (HPMCs). The working concentration and time of AGEs were optimized. Then the expression and activation signal transducer and activator of transcription 3 (STAT3), a key factor of EMT in cancer, were detected. The regulation of STAT3 by miRNA was also explored. 50 μg/ml AGEs treatment for 24 h can successfully induce EMT in HPMCs. AGEs treatment upregulated and activated STAT3. miRNA-454, potentially targeting STAT3, was down-regulated in AGEs-treated HPMCs. Overexpression of miRNA-454 prevented AGEs- induced EMT in HPMCs. AGEs induce epithelial to mesenchymal transformation of Human peritoneal mesothelial cells via upregulation of STAT3.
Published:
April 1, 2019
Title:
Amygdala Activation and Connectivity to Emotional Processing Distinguishes Asymptomatic Patients With Bipolar Disorders and Unipolar Depression
Authors:
Korgaonkar, Mayuresh S.; Erlinger, May; Breukelaar, Isabella A.; Boyce, Philip; Hazell, Philip; Antees, Cassandra; Foster, Sheryl; Grieve, Stuart M.; Gomes, Lavier; Williams, Leanne M.; Harris, Anthony W. F.; Malhi, Gin S.
Abstract:
Background Mechanistically based neural markers, such as amygdala reactivity, offer one approach to addressing the challenges of differentiating bipolar and unipolar depressive disorders independently from mood state and acute symptoms. Although emotion-elicited amygdala reactivity has been found to distinguish patients with bipolar depression from patients with unipolar depression, it remains unknown whether this distinction is traitlike and present in the absence of an acutely depressed mood. We addressed this gap by investigating patients with bipolar disorder (BP) and unipolar major depressive disorder (MDD) in remission. Methods Supraliminal and subliminal processing of faces exhibiting threat, sad, happy, and neutral emotions during functional magnetic resonance imaging was completed by 73 participants (23 BP patients and 25 MDD patients matched for age and gender, number of depressive episodes and severity; 25 age- and gender-matched healthy control subjects). We compared groups for activation and connectivity for the amygdala. Results BP patients had lower left amygdala activation than MDD patients during supraliminal and subliminal threat, sad, and neutral emotion processing and for subliminal happy faces. BP patients also exhibited lower amygdala connectivity to the insula and hippocampus for threat and to medial orbitofrontal cortex for happy supraliminal and subliminal processing. BP patients also demonstrated greater amygdala-insula connectivity for sad supraliminal and subliminal face processing. Both patient groups were distinct from control subjects across several measures for activation and connectivity. Conclusions Independent of valence or level of emotional awareness, amygdala activation and connectivity during facial emotion processing can distinguish BP patients and MDD patients. These findings provide evidence that this neural substrate could be a potential trait marker to differentiate these two disorders largely independent of illness state.
Published:
April 1, 2019
Title:
CTBP1 depletion on prostate tumors deregulates miRNA/mRNA expression and impairs cancer progression in metabolic syndrome mice
Authors:
Dalton, Guillermo Nicolás; Massillo, Cintia; Scalise, Georgina Daniela; Duca, Rocío; Porretti, Juliana; Farré, Paula Lucia; Gardner, Kevin; Paez, Alejandra; Gueron, Geraldine; Luca, Paola De; Siervi, Adriana De
Abstract:
About 20% of prostate cancer (PCa) patients progress to metastatic disease. Metabolic syndrome (MeS) is a pathophysiological disorder that increases PCa risk and aggressiveness. C-terminal binding protein (CTBP1) is a transcriptional corepressor that is activated by high-fat diet (HFD). Previously, our group established a MeS/PCa mice model that identified CTBP1 as a novel link associating both diseases. Here, we integrated in vitro (prostate tumor cell lines) and in vivo (MeS/PCa NSG mice) models with molecular and cell biology techniques to investigate MeS/CTBP1 impact over PCa progression, particularly over cell adhesion, mRNA/miRNA expression and PCa spontaneous metastasis development. We found that CTBP1/MeS regulated expression of genes relevant to cell adhesion and PCa progression, such as cadherins, integrins, connexins, and miRNAs in PC3 xenografts. CTBP1 diminished PCa cell adhesion, membrane attachment to substrate and increased filopodia number by modulating gene expression to favor a mesenchymal phenotype. NSG mice fed with HFD and inoculated with CTBP1-depleted PC3 cells, showed a decreased number and size of lung metastases compared to control. Finally, CTBP1 and HFD reduce hsa-mir-30b-5p plasma levels in mice. This study uncovers for the first time the role of CTBP1/MeS in PCa progression and its molecular targets.
Published:
April 1, 2019
Title:
Can’t or Won’t? Immunometabolic Constraints on Dopaminergic Drive
Authors:
Treadway, Michael; Cooper, Jessica; Miller, Andrew
Abstract:
Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. To date, however, the broader implications of this communication between inflammation and mesolimbic DA have yet to be explored. Here, we suggest that the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can’t) versus preference (won’t) for reward. This theoretical framework can inform how the mesolimbic DA system responds to increased immunometabolic demands during chronic inflammation, ultimately contributing to motivational impairments in psychiatric and other medical disorders.
Published:
April 1, 2019
Title:
Cytochrome c Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer
Authors:
Kumar, Rahul; Bhat, Tariq A.; Walsh, Elise M.; Chaudhary, Ajay K.; O'Malley, Jordan; Rhim, Johng S.; Wang, Jianmin; Morrison, Carl D.; Attwood, Kristopher; Bshara, Wiam; Mohler, James L.; Yadav, Neelu; Chandra, Dhyan
Abstract:
Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity. SIGNIFICANCE: Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.
Published:
April 1, 2019
Title:
Effects of hyperthyroidism in the development of the appendicular skeleton and muscles of zebrafish, with notes on evolutionary developmental pathology (Evo-Devo-Path)
Authors:
Shkil, Fedor; Siomava, Natalia; Voronezhskaya, Elena; Diogo, Rui
Abstract:
The hypothalamus-pituitary-thyroid (HPT) axis plays a crucial role in the metabolism, homeostasis, somatic growth and development of teleostean fishes. Thyroid hormones regulate essential biological functions such as growth and development, regulation of stress, energy expenditure, tissue compound, and psychological processes. Teleost thyroid follicles produce the same thyroid hormones as in other vertebrates: thyroxin (T4) and triiodothyronine (T3), making the zebrafish a very useful model to study hypo- and hyperthyroidism in other vertebrate taxa, including humans. Here we investigate morphological changes in T3 hyperthyroid cases in the zebrafish to better understand malformations provoked by alterations of T3 levels. In particular, we describe musculoskeletal abnormalities during the development of the zebrafish appendicular skeleton and muscles, compare our observations with those recently done by us on the normal developmental of the zebrafish, and discuss these comparisons within the context of evolutionary developmental pathology (Evo-Devo-Path), including human pathologies.
Published:
April 1, 2019
Title:
LIMPRINT: Estimation of the Prevalence of Lymphoedema/Chronic Oedema in Acute Hospital in In-Patients
Authors:
Quéré, Isabelle; Palmier, Sylvie; Nøerregaard, Susan; Pastor, Jenica; Sykorova, Martina; Dring, Eleanor; Franks, Peter J.; Murray, Susie; Keeley, Vaughan; Bermark, Susan; Karlsmark, Tonny; Kyne, Norah; Colgan, Mary-Paula; Coulombe, Marie-Michelle; Mestre, Sandrine; Mercier, Gregoire; Moffatt, Christine J.
Abstract:
Background: To estimate the prevalence of lymphedema/chronic edema (CO) and wounds in acute hospital inpatients in five different countries., Methods and Results: A point-prevalence study was carried out during working day periods in six general hospitals in four countries (Denmark, France, United Kingdom, and Australia) and one hospital oncology inpatient unit in one other country (Ireland). The study used validated clinical tools for the assessment and collection of data. Data were collected by expert clinicians through interviews and physical examination of the patients present in the wards. A total of 1905 patients could be included and investigated among the 3041 total bed occupancy in the seven hospitals. Lymphedema/CO was present in 723 of them (38%). Main risk factors associated with CO were age, morbid obesity, and heart failure, as well as chair bound immobility and neurological deficiency. History of cellulitis was frequent in patients with CO and wounds (24.8%) and CO alone (14.1%) compared to the 1.5% prevalence in patients without CO., Conclusion: Lymphedema/CO is very frequent in patients hospitalized in hospital acute wards. It is strongly associated with obesity, venous insufficiency, and heart failure. Our results strongly suggest a hidden health care burden and cost linked to CO independently of chronic wounds.
Published:
April 1, 2019
Title:
Lymphedema Impact and Prevalence International Study: The Canadian Data
Authors:
Keast, David H.; Moffatt, Christine; Janmohammad, Ashrafunissa
Abstract:
Background: Chronic edema/lymphedema is defined as edema present for more than 3 months. It is underrecognized and undertreated. The International Lymphedema Framework developed an international study, Lymphedema Impact and Prevalence International (LIMPRINT), to estimate the prevalence and impact of chronic edema in heterogeneous populations. Canada participated in this study., Methods and Results: Participants were recruited from an outpatient chronic wound management clinic. At a study visit, the following tools were administered: The Core Tool, Demographics and Disability assessment (WHODAS 2.0), Quality-of-life assessment (LYMQOL + EQ-5D), Details of swelling, Wound assessment, and Cancer. Data were entered into an international database (Clindex), and country-specific data were analyzed. Sixty-eight subjects were enrolled. Fifty-seven percent were males and 43% females. More than 90% were older than 45 years. Only 7.35% had primary lymphedema. Most had lower extremity edema (65 of 68). Over half (47.06%) were morbidly obese with body mass index of >40. The most common underlying condition was venous disease. Only 8 of 68 had a history of cancer. While 72.06% had a history of cellulitis, only 10.2% had been hospitalized in the past year. 39.71% had an open wound. More than 75% had received multilayer bandaging, compression garments, wound dressings, and extensive counseling. Few had received manual lymphatic drainage, which is not funded. Disability was less than expected., Conclusion: Chronic edema/lymphedema is an underrecognized condition. These data and the wider LIMPRINT study are important tools to advocate for wider recognition and funding of treatment by health care systems.
Published:
April 1, 2019
Title:
Reversing Type 2 Diabetes: A Narrative Review of the Evidence
Authors:
Hallberg, Sarah J.; Gershuni, Victoria M.; Hazbun, Tamara L.; Athinarayanan, Shaminie J.
Abstract:
BACKGROUND: Type 2 diabetes (T2D) has long been identified as an incurable chronic disease based on traditional means of treatment. Research now exists that suggests reversal is possible through other means that have only recently been embraced in the guidelines. This narrative review examines the evidence for T2D reversal using each of the three methods, including advantages and limitations for each. METHODS: A literature search was performed, and a total of 99 original articles containing information pertaining to diabetes reversal or remission were included. RESULTS: Evidence exists that T2D reversal is achievable using bariatric surgery, low-calorie diets (LCD), or carbohydrate restriction (LC). Bariatric surgery has been recommended for the treatment of T2D since 2016 by an international diabetes consensus group. Both the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) now recommend a LC eating pattern and support the short-term use of LCD for weight loss. However, only T2D treatment, not reversal, is discussed in their guidelines. CONCLUSION: Given the state of evidence for T2D reversal, healthcare providers need to be educated on reversal options so they can actively engage in counseling patients who may desire this approach to their disease.
Published:
April 1, 2019
Title:
Healthy nutrition for Homo sapiens. How many solutions do you have?
Authors:
Clemens, Zsofia; Tóth, Csaba; Daniels, Natalie
Abstract:
Healthy nutrition for Homo sapiens. Scientific facts. Anthropological and clinical evidence. The Paleolithic diet which can be used in clinical practice without risks and side effects.
Published:
March 30, 2019
Title:
Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression
Authors:
Goossens, Pieter; Rodriguez-Vita, Juan; Etzerodt, Anders; Masse, Marion; Rastoin, Olivia; Gouirand, Victoire; Ulas, Thomas; Papantonopoulou, Olympia; Van Eck, Miranda; Auphan-Anezin, Nathalie; Bebien, Magali; Verthuy, Christophe; Vu Manh, Thien Phong; Turner, Martin; Dalod, Marc; Schultze, Joachim L.; Lawrence, Toby
Abstract:
Summary Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.
Published:
March 28, 2019
Title:
The early use of fire among Neanderthals from a zooarchaeological perspective
Authors:
Rosell Ardèvol, Jordi; Blasco, Ruth
Abstract:
Fire represented a real revolution in human lifestyles, transforming the way food was processed and leading to a new way of organising settlements and interacting socially. Yet, it is one of the most debated and controversial issues in the field of Palaeolithic archaeology. The scientific community generally proposes that the regular and controlled use of fire occurred from 400 to 300 ka onward, and that the archaeological signal became well established in sites younger than 100 ka. Thus, the chronological range between 400 and 300 ka is crucial to exploring how this phenomenon and the associated behavioural changes occurred. Here, we examine the zooarchaeological signature this process left on the faunal record, including procurement techniques and animal processing (e.g., roasting). The data are compared to information from sites without fire that are framed within the same chronological period. Our objective is to collect zooarchaeological data on the process of dependence on fire as a central element in the new human mode of adaptation.
Published:
March 28, 2019
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