Explore the vast range of titles available.

GDNF receptor alpha-like is a brainstem-restricted receptor for growth and differentiation factor 15, regulating appetite and body weight in non-homeostatic conditions by activating the emergency circuit response to disease and toxin stresses. Brainstem receptor regulates body mass loss Growth and differentiation factor 15 (GDF15) acts on feeding centres in the brain to cause anorexia, leading to loss of both lean and fat mass and eventually cachexia. GDF15 levels rise in response to tissue stress and injury, and higher levels are associated with weight loss in numerous chronic human diseases, including cancer. Bernard Allan and colleagues now show that glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) is a GDF15 receptor in the brainstem. The structure of GDF15 and its interaction with GFRAL together with biochemical experiments and analysis of Gfral knockout mice demonstrate that regulation of body weight by GFRAL is independent of previously characterized pathways. Unlike hormones from gut and adipose tissue that activate receptors mostly in the hypothalamus, GDF15 increases in response to tissue damage and activates GFRAL-expressing neurons in the brainstem. Gfral knockout mice overate under stressed conditions and were resistant to chemotherapy-induced anorexia and weight loss. These findings provide therapeutic opportunities for disorders with altered energy demands. Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure 1 , 2 . In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand 3 . Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions 4 , 5 , 6 , but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions 7 . GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases 8 , 9 . By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.

Birth at term comprises a period with heterogeneous neonatal outcomes that tend to be worse for infants born earlier. However, few studies have analyzed this period, in which each day can make a difference. Therefore, we aim to assess neonatal mortality (NM) according to gestational age (GA) at birth measured in days in term liveborn infants born in 2012–2017 in São Paulo, the largest city in Latin America. This population-based cohort study assessed term liveborn infants followed until the end of the neonatal period. We analyzed 7 models for NM according to GA in days: crude NM adjusted for maternal and prenatal variables, NM additionally adjusted for type of birth and type of hospital, and adjusted NM stratified by type of birth (cesarean and vaginal) and by type of hospital (public and private). We included 440,119 live infants born at 259–293 days of gestation. The median GA at birth was 274 days. In all models, NM was higher for infants born early term, decreasing in infants born full term and rising again in infants born late term. In the unadjusted model, hazard ratios of NM changed daily, decreasing from 3.34 to 1.00 on day 278 and increasing again thereafter. In the stratified analysis according to type of hospital, being born in a public hospital was associated with a reduced risk of NM for infants born at 278–283 days of pregnancy. There was a decrease in GA related to obstetric interventions, especially cesarean sections, which increased NM. The loss of days of pregnancy was larger in private hospitals. Increasing the granularity of GA to days is feasible and has the potential to drive public policies. To the best of our knowledge, this is the first Brazilian study on GA in days using a national live births database.

Nature 550, 255–259 (2017); doi:10.1038/nature24042 Owing to an error during the production process, in Fig. 2c of this Letter, all four groups of mice were incorrectly labelled as ‘WT’ (wild type), but the two groups on the left (filled and open blue boxes) should have been labelled ‘WT’, whereas the two groups on the right (filled and open yellow boxes) should have been labelled ‘KO’ (knockout), as in the key for Fig. 2b. The original Letter has been corrected online.

Lifting tasks, among manual material handling activities, are those mainly associated with low back pain. In recent years, several instrumental-based tools were developed to quantitatively assess the biomechanical risk during lifting activities. In this study, parameters related to balance and extracted from the Centre of Pressure (CoP) data series are studied in fatiguing frequency-dependent lifting activities to: i) explore the possibility of classifying people with LBP and asymptomatic people during the execution of task; ii) examine the assessment of the risk levels associated with repetitive lifting activities, iii) enhance current understanding of postural control strategies during lifting tasks. Data were recorded from 14 asymptomatic participants and 7 participants with low back pain. The participants performed lifting tasks in three different lifting conditions (with increasing lifting frequency and risk levels) and kinetic and surface electromyography (sEMG) data were acquired. Kinetic data were used to calculated the CoP and parameters extracted from the latter show a discriminant capacity for the groups and the risk levels. Furthermore, sEMG parameters show a trend compatible with myoelectric manifestations of muscular fatigue. Correlation results between sEMG and CoP velocity parameters revealed a positive correlation between amplitude sEMG parameters and CoP velocity in both groups and a negative correlation between frequency sEMG parameters and CoP velocity. The current findings suggest that it is possible to quantitatively assess the risk level when monitoring fatiguing lifting tasks by using CoP parameters as well as identify different motor strategies between people with and without LBP.

This book examines the various ways in which age affects the process and the product of foreign language learning in a school setting. It presents studies that cover a wide range of topics, from phonetics to learning strategies. It will be of interest to students and researchers working in SLA research, language planning and language teaching.

Post-weaning diarrhea (PWD) is an often disease affecting piglets. It is caused mainly by enterotoxigenic Escherichia coli (ETEC) colonization in pig gut. Antibiotics has been used to prevent, combat and control PWD and its negative impact on the productivity of pig breeding sector. Nonetheless, antibiotics due to their wide antibacterial spectrum also can reach beneficial gut bacteria, such as Lactobacillus . Lately, essential oils (EOs) have emerged as a potential alternative to using antibiotics in animal breeding because of their effect on bacterial growth. Commonly, citrus EOs are by-products of food industry and the availability of these EOs in the worldwide market is huge. Thus, six commercials citrus EOs were evaluated on ETEC strains, as model of pathogenic bacteria, and on Lactobacillus species, as models of beneficial bacteria. In overall, citrus EOs exhibited a selective antibacterial activity with higher effect on pathogenic bacteria (ETECs) than beneficial bacteria ( Lactobacillus) . Brazilian orange terpenes (BOT) oil presented the highest selective performance and caused higher disturbances on the normal growth kinetic of ETEC than on Lactobacillus rhamnosus . The action was dose-dependent on the maximal culture density ( A ) and the lag phase duration (λ) of the ETEC. The highest sub-inhibitory concentration (0.925 mg/mL) extended the λ duration to ETEC eight times (14.6 h) and reduced A in 55.9%. For L. rhamnosus , the λ duration was only extended 1.6 times. Despite the fact that limonene was detected as the major compound, the selective antibacterial activity of the citrus EOs could not be exclusively attributed to limonene since the presence of minor compounds could be implicated in conferring this feature.

Extracellular vesicles (EVs) are emerging as novel theranostic tools. Limitations related to clinical uses are leading to a new research area on design and manufacture of artificial EVs. Several strategies have been reported in order to produce artificial EVs, but there has not yet been a clear criterion by which to differentiate these novel biomaterials. In this paper, we suggest for the first time a systematic classification of the terms used to build up the artificial EV landscape, based on the preparation method. This could be useful to guide the derivation to clinical trial routes and to clarify the literature. According to our classification, we have reviewed the main strategies reported to date for their preparation, including key points such as: cargo loading, surface targeting strategies, purification steps, generation of membrane fragments for the construction of biomimetic materials, preparation of synthetic membranes inspired in EV composition and subsequent surface decoration.

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease.

Legume nodules have two types of hemoglobins: symbiotic or leghemoglobins (Lbs) and nonsymbiotic or phytoglobins (Glbs). The latter are categorized into three phylogenetic classes differing in heme coordination and O2 affinity. This review is focused on the roles of Lbs and Glbs in the symbiosis of rhizobia with crop legumes and the model legumes for indeterminate (Medicago truncatula) and determinate (Lotus japonicus) nodulation. Only two hemoglobin functions are well established in nodules: Lbs deliver O2 to the bacteroids and act as O2 buffers, preventing nitrogenase inactivation; and Glb1-1 modulates nitric oxide concentration during symbiosis, from the early stage, avoiding the plant’s defense response, to nodule senescence. Here, we critically examine early and recent results, update and correct the information on Lbs and Glbs with the latest genome versions, provide novel expression data and identify targets for future research. Crucial unresolved questions include the expression of multiple Lbs in nodules, their presence in the nuclei and in uninfected nodule cells, and, intriguingly, their expression in nonsymbiotic tissues. RNA-sequencing data analysis shows that Lbs are expressed as early as a few hours after inoculation and that their mRNAs are also detectable in roots and pods, which clearly suggests that these heme proteins play additional roles unrelated to nitrogen fixation. Likewise, issues awaiting investigation are the functions of other Glbs in nodules, the spatiotemporal expression profiles of Lbs and Glbs at the mRNA and protein levels, and the molecular mechanisms underlying their regulation during nodule development and in response to stress and hormones.