Published Science

The intestinal and hepatobiliary tract exhibits host-specific commensal colonization. The resident microbiota has emerged as a key player in intestinal and hepatic diseases. Alcoholic and nonalcoholic fatty liver diseases (ALD/NAFLD), primary sclerosing cholangitis (PSC), liver cirrhosis, and some of their clinical complications, such as hepatic encephalopathy (HE), have been linked to a microbial signature, as also observed for severe liver inflammation in alcoholic hepatitis. In turn, the liver impacts, and communicates with, the microbiota through hepatic mediators, such as bile acids or inflammatory signals. Therefore, a liver–microbiome bidirectional crosstalk appears to be critical in health and various liver diseases and could be therapeutically targeted, such as by fecal microbiota transplantation.

BACKGROUND: Amino acid (AA) and acylcarnitine (AC) are important biomarkers of protein and fatty acid metabolism. Examining their levels in newborns may reveal multiple inherited metabolic diseases. However, they have rarely been assessed in very low birth weight (VLBW) neonates, low birth weight (LBW) neonates and rarely been compared with normal weight (NW) neonates. The aim of the study was to identify the AA and AC profiles in dried blood spot (DBS) specimens of LBW and VLBW neonates, then compare with NW neonates, and make a contribution to the determination of cutoff values of VLBW and LBW neonates. METHODS: Liquid Chromatography tandem mass spectrometry (LC/MS/MS) is an excellent tool for quantitatively detecting AA and AC profiles. This article verified the precision, accuracy, and linearity of the LC/MS/MS method in AA and AC detection, then analyzed AA and AC profiles in DBS of VLBW, LBW and NW neonates, and compared the difference of AA and AC in the three groups. RESULTS: The results showed that the LC/MS/MS method had wide linear range, satisfied precision and reproducibility in detecting AA and AC in DBS specimens; most AA and AC concentrations significantly correlated with birth weight in DBS samples (p

Despite the American public following recommendations to decrease absolute dietary fat intake and specifically decrease saturated fat intake, we have seen a dramatic rise over the past 40 years in the rates of non-communicable diseases associated with obesity and overweight, namely cardiovascular disease. The development of the diet-heart hypothesis in the mid twentieth century led to faulty but long-held beliefs that dietary intake of saturated fat led to heart disease. Saturated fat can lead to increased LDL cholesterol levels, and elevated plasma cholesterol levels have been shown to be a risk factor for cardiovascular disease; however, the correlative nature of their association does not assign causation.

It is currently assumed that Neandertals evolved gradually over at least 400,000 years in Europe. Neadertals disappeared from the fossil record in Western Europe (Spain, France) some 40,000 years ago (40 Kya). Anatomically modern humans (AMH) started to occupy parts of Europe 43,000 – 45,000 years ago, a few thousand years before the disappearance of the Neandertals although no contemporaneous or alternate occupations of the same sites have been discovered. The reason for the extinction of the Neandertals in Western Europe, and especially the question of whether AMH played an active role in their demise, is one of the most controversial issues in prehistoric research (Villa and Roebroeks, 2014), and “remains an enigma, even after more than 150 years of research” (Bradtmöller et al., 2012). Indeed, Smith (2013) identifies the debate as “one of the longest, most contentious in science.” This thesis aims to present and test a hypothesis that the megafaunal extinction that began some 50 Kya in Western Europe played a significant role in the extinction of the Neandertals. A natural decrease in plant food availability during the long and harsh MIS 3 winters in Western Europe lead to the conclusion that Neandertals relied to a significant extent on animal-sourced food, especially during winters. A physiological ceiling on their protein consumption, coupled with the limited availability of plant food, must have forced Neandertals to depend on the acquisition and consumption of a substantial amount of animal fat. This obligatory amount of fat could only be supplied by acquiring large animals which contain, relatively, a higher proportion of calories from fat than smaller animals and even more so during harsh winters. When large animals diminished, a chronic energetic stress developed which could have caused the extinction of the Neandertals. The identification of shortage of fat as an environmental stress that could significantly affect Neandertals’ survival relies on insights gained from The Obligatory Dietary Fat Bioenergetic Model (ODFBM). Bioenergetic models have been used since the early 1980s to explain human evolutionary phenomena, including the Neandertals’ extinction. The ODFBM model is unique in that it uses the three individual macronutrients as parameters in the model. The model relies on the well-accepted fact that humans are much more limited in the amount of protein that they can metabolize to energy in comparison with other carnivores. The model takes into account the energetic requirements of the studied human and the physiological ceiling on protein consumption to arrive at an obligatory ratio of non-protein caloric sources. Assuming that plant food was scarce during MIS 3 winters, the model determined the obligatory dietary fat ratio of Neandertals to be 75% to 85% of the calories. The last step in the model compares the obligatory dietary fat ratio with the ratio in available prey as it is represented in the archaeological record of the relevant regions. Larger animals have relatively higher fat content. I argue that Neandertals were dependent on calories gained from large animals, with the focus on fat as a major supplier of calories. It is therefore concluded that a diminution of large animals, in the face of such a high obligatory dietary fat requirement, had resulted in energetic stress due to the need to obtain the same amount of fat from a disproportionally higher number of smaller animals. Conversely, it could be that AMH’s lighter weight and longer legs made him better suited, energetically, to obtain and metabolize the required number of calories from smaller prey. The body of the thesis is devoted to validating the assumptions that were used in the model’s calculations. The reconstruction of the Neandertal diet begins with an analysis of general patterns in the human diet throughout the Paleolithic. In line with the requirements of the model, the main effort is aimed at determining whether a pattern of the plant-animal ratio can be discerned in the Paleolithic diet that caused humans to exceed the protein constraint and dictate an obligatory consumption of fat. Most of the attempts to discern a plant-animal ratio in past human diets have relied to a great extent on the ethnographic record. The ethnographic record of two of the most extensively researched hunter-gatherer (HG) groups, the Hadza and the San, is reviewed for suitability as an analog for the Paleolithic HG. The review finds that the plant-animal ratios of recent groups have been significantly affected by a reduction in the prevalence of megafauna and other large animals which dramatically altered the risk-reward ratio of hunting. Also, hunting of smaller animals and gathering were made more efficient by the replacement of stone tools with metal tools, the use of dogs, cooking utensils and other artifacts that were not available to Paleolithic humans. For example, the availability of iron arrow tips saves the time that acquiring, maintaining and replacing stone arrow tips would have required. This time saving could be used to track and hunt smaller animals which have a lower caloric return per hour than larger animals. Ecologically, the area in which these groups live has gone and is still going through a major faunal and vegetation disturbance which have started some 50 thousand years ago, late in the Pleistocene, as part of the Late Quaternary Megafauna Extinction and possibly even earlier. The result is that the Hadza, for example, no longer hunt elephants, rhinos, and hippos, the three largest animals that they used to hunt. The archaeological record can only be considered as a partial source of the plant-animal ratio in the Paleolithic diet since plant remains are preserved poorly compared to animal remains. The human body, however, should contain genetic and physiological information that may point to evolutionary adaptations to cope with a particular dietary pattern. A review of some such presumed adaptations, as well as paleontological and other types of archaeological information, has provided significant evidence for adaptation to a high degree of carnivory during most of human evolution. Signs of increasing plant consumption appear in Homo sapiens although its diet apparently remained highly carnivorous until well into the Upper Paleolithic (UP). The archaeological and genetic record indicates that a further increase in the share of plants in the diet took place during the UP and beyond. Such a description of the diet during human evolution provides further credence to the notion that the Neandertal diet was also highly carnivorous. A specific reconstruction of the Neandertal diet concludes that indeed they were top predators although plants were consumed regularly and possibly in higher proportion in more southern regions. Due to the protein ceiling, highly carnivorous diets entailed a dependency on the acquisition of a significant amount of fat. The archaeological and ethnographical records were reviewed for evidence of such a dependency. The review of the ethnographical record, this time for a pattern of behavior rather than quantitative ratios, showed a strong emphasis on fat acquisition as a major parameter in prey selection, to the extent that hunted animals with low fat content are sometimes abandoned. Several archaeological patterns of animal acquisition and exploitation were identified as emanating from the need to obtain fat. Targeting ‘prime adults,' preferential transportation of fatty parts, exploitation of marrow and bone grease, and preference of large animals were all identified as such patterns both in Neandertals and in other Homo species. Specifically, a strong association between animal size and fat content was established through a detailed analysis of a sizeable database of recent African animals. Lastly, three archaeological faunal databases covering Western Europe during MIS 3 were analyzed together with 13 individual multi-cultural sites to identify trends in large prey exploitation beginning 50 Kya. The analysis confirmed a significant reduction in the acquisition of the largest prey between 50 Kya to 40 Kya. This trend continued after the Neandertals’ extinction. In summary, application of the Obligatory Dietary Fat Bioenergetic Model to the case of the Neandertals’ extinction provided evidence that the demise of Neandertals was a result of energetic stress that developed in Western Europe beginning 50 Kya due to the diminishing of large animals.

It is currently assumed that Neandertals evolved gradually over at least 400,000 years in Europe. Neadertals disappeared from the fossil record in Western Europe (Spain, France) some 40,000 years ago (40 Kya). Anatomically modern humans (AMH) started to occupy parts of Europe 43,000 – 45,000 years ago, a few thousand years before the disappearance of the Neandertals although no contemporaneous or alternate occupations of the same sites have been discovered. The reason for the extinction of the Neandertals in Western Europe, and especially the question of whether AMH played an active role in their demise, is one of the most controversial issues in prehistoric research (Villa and Roebroeks, 2014), and “remains an enigma, even after more than 150 years of research” (Bradtmöller et al., 2012). Indeed, Smith (2013) identifies the debate as “one of the longest, most contentious in science.” This thesis aims to present and test a hypothesis that the megafaunal extinction that began some 50 Kya in Western Europe played a significant role in the extinction of the Neandertals. A natural decrease in plant food availability during the long and harsh MIS 3 winters in Western Europe lead to the conclusion that Neandertals relied to a significant extent on animal-sourced food, especially during winters. A physiological ceiling on their protein consumption, coupled with the limited availability of plant food, must have forced Neandertals to depend on the acquisition and consumption of a substantial amount of animal fat. This obligatory amount of fat could only be supplied by acquiring large animals which contain, relatively, a higher proportion of calories from fat than smaller animals and even more so during harsh winters. When large animals diminished, a chronic energetic stress developed which could have caused the extinction of the Neandertals. The identification of shortage of fat as an environmental stress that could significantly affect Neandertals’ survival relies on insights gained from The Obligatory Dietary Fat Bioenergetic Model (ODFBM). Bioenergetic models have been used since the early 1980s to explain human evolutionary phenomena, including the Neandertals’ extinction. The ODFBM model is unique in that it uses the three individual macronutrients as parameters in the model. The model relies on the well-accepted fact that humans are much more limited in the amount of protein that they can metabolize to energy in comparison with other carnivores. The model takes into account the energetic requirements of the studied human and the physiological ceiling on protein consumption to arrive at an obligatory ratio of non-protein caloric sources. Assuming that plant food was scarce during MIS 3 winters, the model determined the obligatory dietary fat ratio of Neandertals to be 75% to 85% of the calories. The last step in the model compares the obligatory dietary fat ratio with the ratio in available prey as it is represented in the archaeological record of the relevant regions. Larger animals have relatively higher fat content. I argue that Neandertals were dependent on calories gained from large animals, with the focus on fat as a major supplier of calories. It is therefore concluded that a diminution of large animals, in the face of such a high obligatory dietary fat requirement, had resulted in energetic stress due to the need to obtain the same amount of fat from a disproportionally higher number of smaller animals. Conversely, it could be that AMH’s lighter weight and longer legs made him better suited, energetically, to obtain and metabolize the required number of calories from smaller prey. The body of the thesis is devoted to validating the assumptions that were used in the model’s calculations. The reconstruction of the Neandertal diet begins with an analysis of general patterns in the human diet throughout the Paleolithic. In line with the requirements of the model, the main effort is aimed at determining whether a pattern of the plant-animal ratio can be discerned in the Paleolithic diet that caused humans to exceed the protein constraint and dictate an obligatory consumption of fat. Most of the attempts to discern a plant-animal ratio in past human diets have relied to a great extent on the ethnographic record. The ethnographic record of two of the most extensively researched hunter-gatherer (HG) groups, the Hadza and the San, is reviewed for suitability as an analog for the Paleolithic HG. The review finds that the plant-animal ratios of recent groups have been significantly affected by a reduction in the prevalence of megafauna and other large animals which dramatically altered the risk-reward ratio of hunting. Also, hunting of smaller animals and gathering were made more efficient by the replacement of stone tools with metal tools, the use of dogs, cooking utensils and other artifacts that were not available to Paleolithic humans. For example, the availability of iron arrow tips saves the time that acquiring, maintaining and replacing stone arrow tips would have required. This time saving could be used to track and hunt smaller animals which have a lower caloric return per hour than larger animals. Ecologically, the area in which these groups live has gone and is still going through a major faunal and vegetation disturbance which have started some 50 thousand years ago, late in the Pleistocene, as part of the Late Quaternary Megafauna Extinction and possibly even earlier. The result is that the Hadza, for example, no longer hunt elephants, rhinos, and hippos, the three largest animals that they used to hunt. The archaeological record can only be considered as a partial source of the plant-animal ratio in the Paleolithic diet since plant remains are preserved poorly compared to animal remains. The human body, however, should contain genetic and physiological information that may point to evolutionary adaptations to cope with a particular dietary pattern. A review of some such presumed adaptations, as well as paleontological and other types of archaeological information, has provided significant evidence for adaptation to a high degree of carnivory during most of human evolution. Signs of increasing plant consumption appear in Homo sapiens although its diet apparently remained highly carnivorous until well into the Upper Paleolithic (UP). The archaeological and genetic record indicates that a further increase in the share of plants in the diet took place during the UP and beyond. Such a description of the diet during human evolution provides further credence to the notion that the Neandertal diet was also highly carnivorous. A specific reconstruction of the Neandertal diet concludes that indeed they were top predators although plants were consumed regularly and possibly in higher proportion in more southern regions. Due to the protein ceiling, highly carnivorous diets entailed a dependency on the acquisition of a significant amount of fat. The archaeological and ethnographical records were reviewed for evidence of such a dependency. The review of the ethnographical record, this time for a pattern of behavior rather than quantitative ratios, showed a strong emphasis on fat acquisition as a major parameter in prey selection, to the extent that hunted animals with low fat content are sometimes abandoned. Several archaeological patterns of animal acquisition and exploitation were identified as emanating from the need to obtain fat. Targeting ‘prime adults,' preferential transportation of fatty parts, exploitation of marrow and bone grease, and preference of large animals were all identified as such patterns both in Neandertals and in other Homo species. Specifically, a strong association between animal size and fat content was established through a detailed analysis of a sizeable database of recent African animals. Lastly, three archaeological faunal databases covering Western Europe during MIS 3 were analyzed together with 13 individual multi-cultural sites to identify trends in large prey exploitation beginning 50 Kya. The analysis confirmed a significant reduction in the acquisition of the largest prey between 50 Kya to 40 Kya. This trend continued after the Neandertals’ extinction. In summary, application of the Obligatory Dietary Fat Bioenergetic Model to the case of the Neandertals’ extinction provided evidence that the demise of Neandertals was a result of energetic stress that developed in Western Europe beginning 50 Kya due to the diminishing of large animals.

TORC1 (target of rapamycin complex) integrates complex nutrient signals to generate and fine-tune a growth and metabolic response. Npr1 (nitrogen permease reactivator) is a downstream effector kinase of TORC1 that regulates the stability, activity, and trafficking of various nutrient permeases including the ammonium permeases Mep1, Mep2, and Mep3 and the general amino acid permease Gap1. Npr1 exerts its regulatory effects on Mep1 and Mep3 via Par32 (phosphorylated after rapamycin). Activation of Npr1 leads to phosphorylation of Par32, resulting in changes in its subcellular localization and function. Here we demonstrate that Par32 is a positive regulator of TORC1 activity. Loss of Par32 renders cells unable to recover from exposure to rapamycin and reverses the resistance to rapamycin of Δnpr1 cells. The sensitivity to rapamycin of cells lacking Par32 is dependent on Mep1 and Mep3 and the presence of ammonium, linking ammonium metabolism to TORC1 activity. Par32 function requires its conserved repeated glycine-rich motifs to be intact but, surprisingly, does not require its localization to the plasma membrane. In all, this work elucidates a novel mechanism by which Npr1 and Par32 exert regulatory feedback on TORC1.

Ya han pasado 30 años desde que Gans y Northcutt (1983) propusieron que la cabeza de los vertebrados es una novedad evolutiva, resultado de la aparición de la cresta neural y las pláco-das cefálicas. La cresta neural forma el cráneo y los tejidos conectivos asociados, mientras que las plácodas forman los órganos de los sentidos. Sin embargo, los músculos cefálicos, un componente crucial de la compleja cabeza de los vertebrados, no son formados ni por la cresta ni por las pláco-das. En este capítulo, se discutirá la evidencia que está surgiendo sobre la sorprendente relación entre la evolución de los músculos de la cabeza y el corazón cameral; ambos sistemas provienen de un mismo grupo de células progenitoras mesodérmicas incluídas en un campo cardiofaríngeo de los embriones de los vertebrados. Es importante notar que tanto el campo cardiofaríngeo como los músculos branquioméricos evolucionaron bastante antes que el origen de los Vertebrados, por lo que no se puede decir que los vertebrados tienen una nueva cabeza, ni un nuevo corazón. Introducción En un importante trabajo titulado "Neural crest and the origin of vertebrates: a new head", Gans y Northcutt propusieron en 1983 que los primeros vertebrados evolucionaron de inverte-brados principalmente por innovaciones en la cabeza. Estas innovaciones incluyen la musculari-zación del mesodermo ventrolateral (o hipómero), para formar los musculos branquioméricos y la emergencia de dos estructuras ectodérmicas novedosas: la cresta neural y las plácodas neuro-génicas. Las células de la cresta neural producen la mayor parte del cartílago, hueso, dentina y otros tejidos conectivos de la cabeza de los vertebrados, mientras que de las plácodas derivan las neuronas sensitivas escenciales para la formación de los complejos sistemas sensoriales de los vertebrados (Northcutt, 2005; Graham y Shimeld, 2013; Patthey et al., 2014). La Hipótesis de la Nueva Cabeza propone que estas innovaciones evolutivas estaban asociadas con el cambio de una alimentación filtradora pasiva a una predación activa. El aumento de las capacidades senso-riales y una faringe muscularizada permitirían la detección y captura de presas más eficiente, así como mayores tasas de intercambio de gases respiratorios, lo que acompañaría al estilo de vida predatorio. Esta importante transición en el comportamiento y en la ecología coincidió también con la aparición de un corazón con cámaras, que presumiblemente permitió el mayor crecimiento y metabolismo que demandaba la depredación activa. Sin embargo, la Hipótesis de la Nueva Ca-beza estaba principalmente relacionada con los derivados de la cresta neural y las plácodas, que

Machine learning is a formidable tool for pattern recognition in large datasets. We developed and expanded on these methods, applying machine learning pattern recognition to a problem in paleoanthropology and evolution. For decades, paleontologists have used the chimpanzee as a model for the chimpanzee-human last common ancestor (LCA) because they are our closest living primate relative. Using a large sample of extant and extinct primates, we tested the hypothesis that machine learning methods can accurately classify extant apes based on dental data. We then used this classification tool to observe the affinities between extant apes and Miocene hominoids. We assessed the discrimination accuracy of supervised learning algorithms when tasked with the classification of extant apes (n=175), using three types of data from the postcanine dentition: linear, 2-dimensional, and the morphological output of two genetic patterning mechanisms that are independent of body size: molar module component (MMC) and premolar-molar module (PMM) ratios. We next used the trained algorithms to classify a sample of fossil hominoids (n=95), treated as unknowns. Machine learning classifies extant apes with greater than 92% accuracy with linear and 2-dimensional dental measurements, and greater than 60% accuracy with the MMC and PMM ratios. Miocene hominoids are morphologically most similar in dental size and shape to extant chimpanzees. However, relative dental proportions of Miocene hominoids are more similar to extant gorillas and follow a strong trajectory through evolutionary time. Machine learning is a powerful tool that can discriminate between the dentitions of extant apes with high accuracy and quantitatively compare fossil and extant morphology. Beyond detailing applications of machine learning to vertebrate paleontology, our study highlights the impact of phenotypes of interest and the importance of comparative samples in paleontological studies.

This paper uses a dataset of heights calculated from the femurs of skeletal remains to explore the development of stature in England across the last two millennia. We find that heights increased during the Roman period and then steadily fell during the ‘Dark Ages’ in the early medieval period. At the turn of the first millennium heights grew rapidly, but after 1200 they started to decline coinciding with the agricultural depression, the Great Famine and the Black Death. Then they recovered to reach a plateau which they maintained for almost 300 years, before falling on the eve of industrialisation. The data show that average heights in England in the early nineteenth century were shorter than those in Roman times, and that average heights reported between 1400 and 1700 were similar to those of the twentieth century. The paper also discusses the association of heights across time with some potential determinants and correlates (real wages, inequality, food supply, climate change and expectation of life), showing that in the long run heights change with these variables, and that in certain periods, notably the thirteenth and fourteenth centuries, the associations are observable over the shorter run as well. We also examine potential biases surrounding the use of skeletal remains.

The emphasis on health ministry within the Seventh-day Adventist (SDA) movement led to the development of sanitariums in mid-nineteenth century America. These facilities, the most notable being in Battle Creek, Michigan, initiated the development of vegetarian foods, such as breakfast cereals and analogue meats. The SDA Church still operates a handful of food production facilities around the world. The first Battle Creek Sanitarium dietitian was co-founder of the American Dietetics Association which ultimately advocated a vegetarian diet. The SDA Church established hundreds of hospitals, colleges, and secondary schools and tens of thousands of churches around the world, all promoting a vegetarian diet. As part of the ‘health message,’ diet continues to be an important aspect of the church’s evangelistic efforts. In addition to promoting a vegetarian diet and abstinence from alcohol, the SDA church has also invested resources in demonstrating the health benefits of these practices through research. Much of that research has been conducted at Loma Linda University in southern California, where there have been three prospective cohort studies conducted over 50 years. The present study, Adventist Health Study-2, enrolled 96,194 Adventists throughout North America in 2003–2004 with funding from the National Institutes of Health. Adventist Health Studies have demonstrated that a vegetarian diet is associated with longer life and better health.

People living in the tundra are accustomed to a nomadic life. Their homes are ascetic, food is basic, and deer are their everything. They don't watch TV or use the Internet. However, their children do go to boarding schools, but not all parents are in favor of them. Find out more about life and education out on the tundra on RTDoc. More films about life in Russian tundra: https://rtd.rt.com/search/?q=tundra SUBSCRIBE TO RTD Channel to get documentaries firsthand! http://bit.ly/1MgFbVy FOLLOW US RTD WEBSITE: https://RTD.rt.com/ RTD ON TWITTER: http://twitter.com/RT_DOC RTD ON FACEBOOK: http://www.facebook.com/RTDocumentary RTD ON DAILYMOTION http://www.dailymotion.com/rt_doc RTD ON INSTAGRAM http://instagram.com/rtdocumentaries/ RTD LIVE https://rtd.rt.com/on-air/

The Past The Nenet tribe of Siberia. A beautiful group of people who live and survive on their land. Their culture is rich with knowledge and truth. One day I hope to learn from them in person.

The Nenets Tribe of the north find peace and healing through raw meat. Both the animals in nature and the ancestors of our race guide us to the natural path that is raw meat, a vital source of food and power for the body and for our minds. Do not feel confusing when a creature dies, its passing shall be honored, its body shall be used in whole and will give life to those who are willing to take it.

Many of us believe our ancestors lived much shorter lives than we do. Cutting-edge archaeology shows otherwise.

Mitochondrial gene expression in Saccharomyces cerevisiae is responsible for the production of highly hydrophobic subunits of the oxidative phosphorylation system. Membrane insertion occurs cotranslationally on membrane-bound mitochondrial ribosomes. Here, by employing a systematic mass spectrometry–based approach, we discovered the previously uncharacterized membrane protein Mrx15 that interacts via a soluble C-terminal domain with the large ribosomal subunit. Mrx15 contacts mitochondrial translation products during their synthesis and plays, together with the ribosome receptor Mba1, an overlapping role in cotranslational protein insertion. Taken together, our data reveal how these ribosome receptors organize membrane protein biogenesis in mitochondria.

A drug that slows cancer growth has been found to elevate the level of the hormone insulin. This insulin rise lessens the drug’s effectiveness, but a diet that lowers insulin can increase the benefits of the therapy in mice.

BACKGROUND: Type 2 diabetes mellitus has serious health consequences, including blindness, amputation, stroke, and dementia, and its annual global costs are more than US $800 billion. Although typically considered a progressive, nonreversible disease, some researchers and clinicians now argue that type 2 diabetes may be effectively treated with a carbohydrate-reduced diet. OBJECTIVE: Our objective was to evaluate the 1-year outcomes of the digitally delivered Low-Carb Program, a nutritionally focused, 10-session educational intervention for glycemic control and weight loss for adults with type 2 diabetes. The program reinforces carbohydrate restriction using behavioral techniques including goal setting, peer support, and behavioral self-monitoring. METHODS: The study used a quasi-experimental research design comprised of an open-label, single-arm, pre-post intervention using a sample of convenience. From adults with type 2 diabetes who had joined the program and had a complete baseline dataset, we randomly selected participants to be followed for 1 year (N=1000; mean age 56.1, SD 15.7 years; 59.30% (593/1000) women; mean glycated hemoglobin A1c (HbA1c) 7.8%, SD 2.1%; mean body weight 89.6 kg, SD 23.1 kg; taking mean 1.2, SD 1.01 diabetes medications). RESULTS: Of the 1000 study participants, 708 (70.80%) individuals reported outcomes at 12 months, 672 (67.20%) completed at least 40% of the lessons, and 528 (52.80%) completed all lessons of the program. Of the 743 participants with a starting HbA1c at or above the type 2 diabetes threshold of 6.5%, 195 (26.2%) reduced their HbA1c to below the threshold while taking no glucose-lowering medications or just metformin. Of the participants who were taking at least one hypoglycemic medication at baseline, 40.4% (289/714) reduced one or more of these medications. Almost half (46.40%, 464/1000) of all participants lost at least 5% of their body weight. Overall, glycemic control and weight loss improved, especially for participants who completed all 10 modules of the program. For example, participants with elevated baseline HbA1c (≥7.5%) who engaged with all 10 weekly modules reduced their HbA1c from 9.2% to 7.1% (P<.001) and lost an average of 6.9% of their body weight (P

Before bariatric surgery (BS), moderate weight loss, left hepatic lobe volume reduction, and micronutrient deficiency (MD) identification and correction are desirable.

The 2010 Dietary Guidelines for Americans (DGA) recommend nutrient needs be met by increasing fruit, vegetable, and whole-grain intake with the use of low-fat or fat-free dairy products and by reducing sodium, solid fats, and added sugars. However, the DGA, as a dietary pattern, have not been tested in an intervention trial.The aim of this study was to evaluate the impact of a DGA-based diet compared with a representative typical American diet (TAD) on glucose homeostasis and fasting lipids in individuals at risk of cardiometabolic disease.A randomized, double-blind, controlled 8-wk intervention was conducted in overweight and obese women selected according to indexes of insulin resistance or dyslipidemia. Women were randomly assigned to the DGA or TAD group (n = 28 DGA and 24 TAD). The TAD diet was based on average adult intake from the NHANES 2009–2010. The DGA and TAD diets had respective Healthy Eating Index scores of 98 and 62. All foods and beverages were provided during the intervention. Oral-glucose tolerance and fasting lipids were evaluated at 0, 2, and 8 wk of the intervention. Insulin resistance and sensitivity were estimated with the use of surrogates (e.g., homeostasis model assessment of insulin resistance).By design, volunteers maintained their weight during the intervention. Fasting insulin, glucose, triglycerides, oral-glucose tolerance, and indexes of insulin resistance were not affected by either of the diets. Systolic blood pressure decreased in the DGA group (∼−9 mm Hg; P < 0.05). Total and HDL cholesterol also decreased in both groups (P < 0.05). Exploratory analysis comparing volunteers entering the study with insulin resistance and dyslipidemia with those with only dyslipidemia did not show an effect of pre-existing conditions on glucose tolerance or fasting lipid outcomes.The consumption of a DGA dietary pattern for 8 wk without weight loss reduced systolic blood pressure. There were no differences between the DGA and TAD diets in fasting insulin, glucose, indexes of insulin resistance, or fasting lipids. This trial was registered at www.clinicaltrials.gov as NCT02298725.

The analysis of bone breakage is one of the most relevant issues of current taphonomic studies. Available experimental analogies aim at differentiating agencies in the production of fractured bones. Possible equifinality presented by different agents can hinder the characterisation of bone breakage at archaeological sites. Equally important is the potential distortion that bone-breaking processes introduce in bone surface modification (BSM) frequencies. This study presents an experimental approach to the problem of identifying signatures for anthropogenic bone breaking as a product of direct hammerstone percussion. This study also contributes to improving the existing analogical framework on processes related to bone breakage of medium-sized animals (80–200 kg), since most previous experimentation has focused on smaller (10–80 kg) and larger (200–800 kg) carcasses. It has been possible to verify the existence of non-random and non-intentional breakage patterns on long bones due to their shape and structural properties. Thus, this introduces the possibility of correctly identifying anthropogenic fracture patterns in the archaeological record. Additionally, it also opens up the possibility of finding different cultural patterns. It has frequently been argued that the frequency of bone surface modifications correlates with fragmentation intensity. However, this assertion remained untested until now. Here, we test the frequency and occurrence of percussion and cut marks in faunal assemblages according to the intensity of green bone fragmentation. The results also improve the current referential framework in reference to interpretation of notches produced by dynamic loading.

Timing of energy intake, a temporal dietary pattern, may enhance health. Eating a greater amount of energy earlier and a smaller amount of energy later in the day, a behavioral circadian rhythm, may assist with chronoenhancement. Chronoenhancement seeks to enhance entrainment (synchronization) of biological and behavioral circadian rhythms. In humans, research reports that eating a greater amount of energy early and a smaller amount of energy later in the day increases dietary induced thermogenesis, improves cardiometabolic outcomes, and enhances weight loss. However, little human research has examined if this eating pattern enhances regularity of biological circadian rhythm. In a randomized controlled 8-week pilot study, the influence of energy distribution timing on weight loss and regularity of sleep onset and wake times (marker for biological circadian rhythm) was examined. Within an hypocaloric, three-meal prescription, participants (n = 8) were assigned to either: 1) Morning: 50%, 30%, and 20% of kcal at breakfast, lunch, and dinner, respectively; or 2) Evening: 20%, 30%, and 50% of kcal at breakfast, lunch, and dinner, respectively. Percent weight loss and regularity of sleep onset and wake times were significantly (p 

MicroRNAs (miRNAs) are small, single-stranded, endogenous non-coding RNAs that repress the expression of target genes via post-transcriptional mechanisms. Due to their broad regulatory effects, the precisely regulated, spatial-specific and temporal-specific expression of miRNAs is fundamentally important to various biological processes including the immune homeostasis and normal function of both innate and adaptive immune response. Aberrance of miRNAs is implicated in the development of various human diseases, especially cancers. Increasing evidence has revealed a dysregulated expression pattern of miRNAs in autoimmune diseases, among which many play key roles in the pathogenesis. In this review we summarize these findings on miRNA dysregulation implicated in autoimmune diseases, focusing on four representative systemic autoimmune diseases, i.e. systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and dermatomyositis. The causes of the dysregulation of miRNA expression in autoimmune diseases may include genetic and epigenetic variants, and various environmental factors. Further understanding of miRNA dysregulation and its mechanisms during the development of different autoimmune diseases holds enormous potential to bring about novel therapeutic targets or strategies for these complex human disorders, as well as novel circulating or exosomal miRNA biomarkers.

We know that animals are harmed in plant production. Unfortunately, though, we know very little about the scale of the problem. This matters for two reasons. First, we can’t decide how many resources to devote to the problem without a better sense of its scope. Second, this information shortage throws a wrench in arguments for veganism, since it’s always possible that a diet that contains animal products is complicit in fewer deaths than a diet that avoids them. In this paper, then, we have two aims: first, we want to collect and analyze all the available information about animal death associated with plant agriculture; second, we try to show just how difficult it’s to come up with a plausible estimate of how many animals are killed by plant agriculture, and not just because of a lack of empirical information. Additionally, we show that there are significant philosophical questions associated with interpreting the available data—questions such that different answers generate dramatically different estimates of the scope of the problem. Finally, we document current trends in plant agriculture that cause little or no collateral harm to animals, trends which suggest that field animal deaths are a historically contingent problem that in future may be reduced or eliminated altogether.

Eggs from an intestinal parasite has been found in a burial radiocarbon dated to 5210-4840 cal BC in Motala, east-central Sweden. The two helminth eggs are identified as Trichuris trichiura (human whipworm). Control samples from the cemetery site were all negative and confirmed that there was no evident contamination of younger material. This discovery raises new questions concerning the early geographical spread and timing of parasitic diseases among hunter-gatherer societies in northern Europe, and in the temperate zone of the northern hemisphere. Whipworm infection (Trichuriasis) is perhaps the disease most associated with crowding and poor sanitation, and as it manifests itself in the youngest dated burial, it could be a contributing factor to the final abandonment of the Mesolithic settlement. Also, parasite eggs found in a soil sample from the Neolithic Alvastra pile dwelling could indicate the continued presence of the Trichuris parasite in east-central Sweden. Generally, parasite ecology can aid in reconstructing human behaviors that include aspects of sedentism, mobility, food preferences, hygiene and other social practices.

Transcription factor networks have evolved in order to control, coordinate, and separate, the functions of distinct network modules spatially and temporally. In this review we focus on the MYC network (also known as the MAX-MLX Network), a highly conserved super-family of related basic-helix-loop-helix-zipper (bHLHZ) proteins that functions to integrate extracellular and intracellular signals and modulate global gene expression. Importantly the MYC network has been shown to be deeply involved in a broad spectrum of human and other animal cancers. Here we summarize molecular and biological properties of the network modules with emphasis on functional interactions among network members. We suggest that these network interactions serve to modulate growth and metabolism at the transcriptional level in order to balance nutrient demand with supply, to maintain growth homeostasis, and to influence cell fate. Moreover, oncogenic activation of MYC and/or loss of a MYC antagonist, results in an imbalance in the activity of the network as a whole, leading to tumor initiation, progression and maintenance.

Skip to Next Section The extracellular space of solid tumors ranges from being well-nurtured to being completely ischemic and can serve as a source of intratumoral heterogeneity, determining the behavior and molecular profiles of malignant and stromal cells. Here, we discuss how the metabolic tumor microenvironment modulates the phenotypes of the immune cells that infiltrate tumors, with an emphasis on tumor-associated macrophages. These cells constitute a diverse population that has pro-tumoral and anti-inflammatory properties, and are likened to anti-inflammatory ‘M2’ macrophages. Recent findings show how different metabolic microenvironments specify an array of phenotypic changes in macrophages. In tumors, extracellular metabolite levels vary predictably according to proximity to the vasculature, and phenotypic changes in tumor-associated macrophages and in other immune cells are also predictable. We speculate that this ‘metabolic axis’ of macrophage polarization modulates – and is modulated by – the response to inflammatory cues, creating a wide variety of possible phenotypic states. Understanding how extracellular metabolites influence cell phenotypes allows us to predict how tumor-associated macrophages and other tumor cells might change, with the aim of harnessing this predictability for therapy. Overall, we describe an emerging picture in which chemokines, growth factors and the metabolic tumor microenvironment act together to determine the phenotypes of tumor-infiltrating immune cells.

BACKGROUND: The development of radioresistance is one of main causes for therapeutic failure of prostate cancer (PCa). The present study aims to investigate the function and the related mechanism by which HZ08 sensitizes radiotherapeutic efficiency to treat aggressive PCa cells. METHODS: PCa cells were pretreated with HZ08 (6,7-dimethoxy-1-(3,4-dimethoxy) benzyl-2-(N-n-octyl-N'-cyano) guanyl-1,2,3,4-tetrahydroisoquinoline) and followed by ionizing radiation (IR) treatment. Cytotoxicity in the treated cells was analyzed to assess the radiosensitization capacity of HZ08 by flow cytometry, MTT and colony survival assays. The cellular levels of reactive oxygen species (ROS) and oxygen consumption rates (OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. RelB binding to the NF-κB intronic enhancer region of the human SOD2 gene was determined using a ChIP assay. The levels of phosphorylation of PI3K, Akt and IKKα were quantified and further confirmed using a PI3K inhibitor. Finally, the synergistic effect of HZ08 on radiosensitization of PCa cells was validated using a mouse xenograft tumor model. RESULTS: HZ08 enhanced radiosensitivity of PCa cells through increasing ROS and declining mitochondrial respiration due to suppression of mitochondrial antioxidant enzyme MnSOD. Mechanistically, HZ08 appeared to inhibit PI3K/Akt/IKKα signaling axis, resulting in transcriptional repression of MnSOD expression by preventing RelB nuclear translocation. CONCLUSIONS: HZ08 can serve as a useful radiosensitizing agent to improve radiotherapy for treating aggressive PCa cells with high level of constitutive RelB. The present study suggests a promising approach for enhancing radiotherapeutic efficiency to treat advanced PCa by inhibiting antioxidant defense function.

Plants have always been a source of nourishment and healing for living things. Their dual task of producing nutrients and medicines has played a key role in the evolution of herbivore and omnivore organisms. The so-called secondary metabolites are molecules with well-defined functional roles. These compounds are produced to defend plants from abiotic and biotic stresses. The complexity of the molecular structures produced by plants is only equal to their versatility and chemical diversity, while the harmonic intertwining of biosynthetic and metabolic pathways offers a perfect picture of the adaptive plasticity of plants to changing environmental conditions. This book is divided into three parts designed to provide the reader with a general overview, a biochemical and a biotechnological approach to plant bioactive molecules. The first part analyses the concepts of chemical diversity, sustainability and functional role of bioactive molecules, by exploring the sites of synthesis and accumulation, the plant defence strategies and the use of bioactive molecules as food supplements and as a source for natural products to fight diseases. The first part ends with the study of chemotaxonomy. The second part is dedicated to plant biochemistry, with the detailed description of the main biosynthetic pathways leading to the synthesis of phenols and flavonoids, terpenes, oxylipins and nitrogen-containing substances. The third and final part describes plant biotechnology and production of bioactive molecules with industrial processes, both in vivo and in vitro. Special attention is paid to cell and tissue cultures, roots and shoots cultures, technological aspects describing bioreactors, biofermenters and photobioreactors. The book concludes with a chapter describing the genetic engineering strategies for the production of plant bioactive molecules, facing with ethical problems, risks and benefits of using recombinant DNA in genetically modified organisms (GMOs) and the use of molecular pharming, with a general discussion on food safety. You can buy the book at: http://www.cambridgescholars.com/plant-bioactive-molecules

Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called “glucotypes” that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.

Pectoral and pelvic lobe-fins transformed into fore- and hindlimbs during the Devonian period, enabling the water-to-land transition in tetrapods. In the timespan of ~60 million years, transitional forms evolved, spanning a wide range of morphologies. Here we traced the evolution of well-articulated appendicular skeletons across the fins-to-limbs transition, using a network-based approach and phylogenetic tools to quantify and compare topological features of skeletal anatomy of fins and limbs. We show that the topological arrangement of bones in the pectoral and pelvic appendages evolved in parallel during the fins-to-limbs transition, occupying overlapping regions of the morphospace, following a directional mode of evolution, and decreasing their disparity over time. We identify the presence of digits as the morphological novelty triggering significant topological changes that clearly discriminated limbs from fins. The origin of digits caused an evolutionary shift towards appendages that were less densely and heterogeneously connected, but more assortative and modular. Topological disparity likewise decreased for both appendages: for the pectoral appendage, until the origin of amniotes; for the pelvic appendage, until a time concomitant with the earliest-known tetrapod tracks. Finally, we tested and rejected the presence of a pectoral-pelvic similarity bottleneck for the network-anatomy of appendages at the origin of tetrapods. We interpret our findings in the context of a dynamic compromise between possibly different functional demands in pectoral and pelvic appendages during the water-to-land transition and a shared developmental program constraining the evolvability of limbs.

The authors describe the implementation of a 3-week dietary intervention in elite race walkers at the Australian Institute of Sport, with a focus on the resources and strategies needed to accomplish a complex study of this scale. Interventions involved: traditional guidelines of high carbohydrate (CHO) availability for all training sessions; a periodized CHO diet which integrated sessions with low and high CHO availability within the same total CHO intake; and a ketogenic low-CHO high-fat diet. Seven-day menus and recipes were constructed for a communal eating setting to meet nutritional goals as well as individualized food preferences and special needs. Menus also included nutrition support before, during, and after exercise. Daily monitoring, via observation and food checklists, showed that energy and macronutrient targets were achieved. Diets were matched for energy (∼14.8 MJ/d) and protein (∼2.1 g·kg-1·day-1) and achieved desired differences for fat and CHO, with high CHO availability and periodized CHO availability: CHO = 8.5 g·kg-1·day-1, 60% energy, fat = 20% of energy and low-CHO high-fat diet: 0.5 g·kg-1·day-1 CHO, fat = 78% energy. There were no differences in micronutrient intake or density between the high CHO availability and periodized CHO availability diets; however, the micronutrient density of the low-CHO high-fat diet was significantly lower. Daily food costs per athlete were similar for each diet (∼AU$ 27 ± 10). Successful implementation and monitoring of dietary interventions in sports nutrition research of the scale of the present study require meticulous planning and the expertise of chefs and sports dietitians. Different approaches to sports nutrition support raise practical challenges around cost, micronutrient density, accommodation of special needs, and sustainability.

Methionine-restricted diets (MRD) show an integrated series of beneficial health effects, including improving insulin sensitivity, limiting fat deposition, and decreasing oxidative stress, and inflammation responses. We aimed to explore the systemic responses to a MRD in mice fed with a high fat (HFD) and clarify the possible mechanism. Mice were fed with a control diet (0.86% methionine + 4% fat, CON), HFD (0.86% methionine + 20% fat), or MRD (0.17% methionine + 20% fat) for 22 consecutive weeks. HFD-fed mice showed widespread systemic metabolic disorders and thyroid dysfunction. A MRD significantly increased energy expenditure (e.g. fatty acid oxidation, glycolysis, and tricarboxylic acid cycle metabolism), regulated protein homeostasis, improved gut microbiota functions, prevented thyroid dysfunction, increased plasma thyroxine and triiodothyronine levels, decreased plasma thyroid stimulating hormone levels, increased type 2 deiodinase (DIO2) activity, and up-regulated mRNA and protein expression levels of DIO2 and thyroid hormone receptor α1 in the skeletal muscle. These results suggest that a MRD can improve the metabolic disorders induced by a HFD, and especially regulate energy and protein homeostasis likely through improved thyroid function. Thus, reducing methionine intake (e.g. through a vegan diet) may improve metabolic health in animals and humans.

The association of cabbage white butterflies (Pieris spec., Lepidoptera: Pieridae) with their glucosinolate-containing host plants represents a well-investigated example of the sequential evolution of plant defenses and insect herbivore counteradaptations. The defensive potential of glucosinolates, a group of amino acid-derived thioglucosides present in plants of the Brassicales order, arises mainly from their rapid breakdown upon tissue disruption resulting in formation of toxic isothiocyanates. Larvae of P. rapae are able to feed exclusively on glucosinolate-containing plants due to expression of a nitrile-specifier protein in their gut which redirects glucosinolate breakdown to the formation of nitriles. The release of equimolar amounts of cyanide upon further metabolism of the benzylglucosinolate-derived nitrile suggests that the larvae are also equipped with efficient means of cyanide detoxification such as β-cyanoalanine synthases or rhodaneses. While insect β-cyanoalanine synthases have recently been identified at the molecular level, no sequence information was available of characterized insect rhodaneses. Here, we identify and characterize two single-domain rhodaneses from P. rapae, PrTST1 and PrTST2. The enzymes differ in their kinetic properties, predicted subcellular localization and expression in P. rapae indicating different physiological roles. Phylogenetic analysis together with putative lepidopteran rhodanese sequences indicates an expansion of the rhodanese family in Pieridae.

BACKGROUND: Health-related effects of a vegetarian or vegan diet are known to support parameters positively affecting exercise performance in athletes, whereas knowledge about psyche and wellbeing is sparse. Therefore, the aim of the Nutrition and Running High Mileage (NURMI) Study (Step 2) was to compare Quality of Life (QOL) scores among endurance runners following a vegetarian or vegan diet against those who adhere to an omnivorous diet. METHODS: The study was conducted following a cross-sectional design. A total of 281 recreational runners (159 women, 122 men) completed the WHOQOL-BREF questionnaire consisting of the domains physical health, psychological wellbeing, social relationships and environment, which generates scores on a scale from 4 to 20. Data analysis was performed using ANOVA. RESULTS: It was found that 123 subjects followed an omnivorous diet and 158 adhered to a vegetarian/vegan diet. There were 173 runners who met the inclusion criteria ('NURMI-Runners'), among them 103 half-marathoners and 70 marathoners and ultramarathoners, as well as 108 10 km runners as control group. Overall QOL scores were high (~ 16.62 ± 1.91). Men had higher scores than women due to high scores in the physical health and psychological well-being dimensions. Adhering to an omnivorous diet affected environment scores for women and social relationships scores for men. A minor effect concerning race distance was observed in women, where half-marathoners had a higher environmental score than 10-km runners. A moderate diet×race distance interaction on environment scores was shown for men. CONCLUSIONS: The results revealed that endurance runners had a high QOL regardless of the race distance or diet choice. These findings support the notion that adhering to a vegetarian or vegan diet can be an appropriate and equal alternative to an omnivorous diet. TRIAL REGISTRATION: ISRCTN73074080 . Registered 12th June 2015, retrospectively registered.

Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture.Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.

It took 20 years to find his stomach. Now researchers know what was inside—in excruciating detail.

The composition of the gut microbiota can be influenced by dietary composition. In pregnancy, the maternal gut microbiome has associations with maternal and infant metabolic status. There is little known regarding the impact of a vegetarian diet in pregnancy on maternal gut microbiota. This study explored the gut microbiota profile in women who were vegetarian or omnivorous in early gestation. Women were selected from participants in the Study of PRobiotics IN Gestational diabetes (SPRING) randomised controlled trial. Nine women identified as vegetarians were matched to omnivorous women in a 1:2 ratio. Microbiota analyses were performed using 16S rRNA gene amplicon sequencing and analysed using the Quantitative Insights Into Microbial Ecology (QIIME) and Calypso software tools. There was no difference in alpha diversity, but beta diversity was slightly reduced in vegetarians. There were differences seen in the relative abundance of several genera in those on a vegetarian diet, specifically a reduction in Collinsella, Holdemania, and increases in the relative abundances of Roseburia and Lachnospiraceae. In this sub-analysis of gut microbiota from women in early pregnancy, a vegetarian as compared to omnivorous diet, was associated with a different gut microbiome, with features suggesting alterations in fermentation end products from a mixed acid fermentation towards more acetate/butyrate.

Lipoteichoic acid (LTA) and lipopolysaccharide (LPS) are bacterial lipids that stimulate pro-inflammatory cytokine production, thereby exacerbating sepsis pathophysiology. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates uptake of cholesterol by downregulating hepatic lipoprotein receptors, including low-density lipoprotein (LDL) receptor (LDLR) and possibly LDLR-related protein-1 (LRP1). PCSK9 also negatively regulates Gram-negative LPS uptake by hepatocytes, however this mechanism is not completely characterized and mechanisms of Gram-positive LTA uptake are unknown. Therefore, our objective was to elucidate the mechanisms through which PCSK9 regulates uptake of LTA and LPS by investigating the roles of lipoproteins and lipoprotein receptors. Here we show that plasma PCSK9 concentrations increase transiently over time in septic and non-septic critically ill patients, with highly similar profiles over 14 days. Using flow cytometry, we demonstrate that PCSK9 negatively regulates LDLR-mediated uptake of LTA and LPS by HepG2 hepatocytes through an LDL-dependent mechanism, whereas LRP1 and high-density lipoprotein do not contribute to this uptake pathway. Bacterial lipid uptake by hepatocytes was not associated with cytokine production or hepatocellular injury. In conclusion, our study characterizes an LDL-dependent and LDLR-mediated bacterial lipid uptake pathway regulated by PCSK9, and provides evidence in support of PCSK9 inhibition as a potential therapeutic strategy for sepsis.

The autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades. While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies. We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model. We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease. Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids. Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects. Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS.

The objective of this review is to highlight the evidence on the association between contextual characteristics of residential environments and type 2 diabetes, to provide an overview of the methodological challenges and to outline potential topics for future research in this field.

The gut microbiome is associated with many different aspects of human health, but which diseases and treatments have most associations and how much do they overlap?

Importance: Intermittent energy restriction is an alternative weight loss method that is becoming popular; however, to date, there are no long-term clinical trials of intermittent energy restriction in patients with type 2 diabetes. Objective: To compare the effects of intermittent energy restriction (2 days per week) with those of continuous energy restriction on glycemic control and weight loss in patients with type 2 diabetes during a 12-month period. Design, Setting, and Participants: Adult participants (N = 137) with type 2 diabetes were randomized 1:1 to parallel diet groups (intermittent energy restriction [n = 70] or continuous energy restriction [n = 67]) between April 7, 2015, and September 7, 2017, at the University of South Australia. Medications likely to cause hypoglycemia were reduced at baseline according to the medication management protocol. Interventions: An intermittent energy restriction diet (500-600 kcal/d) followed for 2 nonconsecutive days per week (participants followed their usual diet for the other 5 days) or a continuous energy restriction diet (1200-1500 kcal/d) followed for 7 days per week for 12 months. Main Outcomes and Measures: The primary outcome was change in hemoglobin A1c (HbA1c) level, with equivalence prespecified by a 90% CI margin of +/-0.5%. The secondary outcome was weight loss with equivalence set at +/-2.5 kg (+/-1.75 kg for fat mass loss and +/-0.75 kg for fat-free mass loss). All other outcomes were tested for superiority. Results: Of the 137 randomized participants (77 women and 60 men; mean [SD] age, 61.0 [9.1] years; mean [SD] body mass index, 36.0 [5.8] [calculated as weight in kilograms divided by height in meters squared]; and mean [SD] HbA1c level, 7.3% [1.3%]), 97 completed the trial. Intention-to-treat analysis showed similar reductions in mean (SEM) HbA1c level between the continuous and intermittent energy restriction groups (-0.5% [0.2%] vs -0.3% [0.1%]; P = .65), with a between-group difference of 0.2% (90% CI, -0.2% to 0.5%) meeting the criteria for equivalence. Mean (SEM) weight change was similar between the continuous and intermittent energy restriction groups (-5.0 [0.8] kg vs -6.8 [0.8] kg; P = .25), but the between-group difference did not meet the criteria for equivalence (-1.8 kg; 90% CI, -3.7 to 0.07 kg), nor did the between-group difference in fat mass (-1.3 kg; 90% CI, -2.8 to 0.2 kg) or fat-free mass (-0.5 kg; 90% CI, -1.4 to 0.4 kg). There were no significant differences between groups in final step count, fasting glucose levels, lipid levels, or total medication effect score at 12 months. Effects did not differ using completers analysis. Hypoglycemic or hyperglycemic events in the first 2 weeks of treatment were similar between the continuous and intermittent energy restriction groups (mean number [SEM] of events, 3.2 [0.7] vs 4.9 [1.4]; P = .28), affecting 35% of participants (16 of 46) using sulfonylureas and/or insulin. Conclusions and Relevance: Intermittent energy restriction is an effective alternative diet strategy for the reduction of HbA1c and is comparable with continuous energy restriction in patients with type 2 diabetes. Trial Registration: anzctr.org.au Identifier: ACTRN12615000383561.

Objective IBS is associated with an intestinal dysbiosis and faecal microbiota transplantation (FMT) has been hypothesised to have a positive effect in patients with IBS. We performed a randomised, double-blind placebo-controlled trial to investigate if FMT resulted in an altered gut microbiota and improvement in clinical outcome in patients with IBS. Design We performed this study in 52 adult patients with moderate-to-severe IBS. At the screening visit, clinical history and symptoms were assessed and faecal samples were collected. Patients were randomised to FMT or placebo capsules for 12 days and followed for 6 months. Study visits were performed at baseline, 1, 3 and 6 months, where patients were asked to register their symptoms using the IBS-severity scoring system (IBS-SSS) and IBS-specific quality of life (IBS-QoL). Prior to each visit, faecal samples were collected. Results A significant difference in improvement in IBS-SSS score was observed 3 months after treatment (p=0.012) favouring placebo. This was similar for IBS-QoL data after 3 months (p=0.003) favouring placebo. Patients receiving FMT capsules had an increase in faecal microbial biodiversity while placebos did not. Conclusion In this randomised double-blinded placebo-controlled study, we found that FMT changed gut microbiota in patients with IBS. But patients in the placebo group experienced greater symptom relief compared with the FMT group after 3 months. Altering the gut microbiota is not enough to obtain clinical improvement in IBS. However, different study designs and larger studies are required to examine the role of FMT in IBS. Trial registration number NCT02788071.