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Protein subcellular localization is tightly controlled and intimately linked to protein function in health and disease. Capturing the spatial proteome — that is, the localizations of proteins and their dynamics at the subcellular level — is therefore essential for a complete understanding of cell biology. Owing to substantial advances in microscopy, mass spectrometry and machine learning applications for data analysis, the field is now mature for proteome-wide investigations of spatial cellular regulation. Studies of the human proteome have begun to reveal a complex architecture, including single-cell variations, dynamic protein translocations, changing interaction networks and proteins localizing to multiple compartments. Furthermore, several studies have successfully harnessed the power of comparative spatial proteomics as a discovery tool to unravel disease mechanisms. We are at the beginning of an era in which spatial proteomics finally integrates with cell biology and medical research, thereby paving the way for unbiased systems-level insights into cellular processes. Here, we discuss current methods for spatial proteomics using imaging or mass spectrometry and specifically highlight global comparative applications. The aim of this Review is to survey the state of the field and also to encourage more cell biologists to apply spatial proteomics approaches.Spatial proteomics improves our understanding of protein function by revealing the subcellular localizations of proteins and their movement between compartments. This Review discusses spatial proteomics approaches, their successful application in cell biology and ways to improve integration of spatial proteomics data.

The ability to use common computational thermodynamic and kinetic tools to study the microstructure evolution in Inconel 625 (IN625) manufactured using the additive manufacturing (AM) technique of laser powder-bed fusion is evaluated. Solidification simulations indicate that laser melting and re-melting during printing produce highly segregated interdendritic regions. Precipitation simulations for different degrees of segregation show that the larger the segregation, i.e., the richer the interdendritic regions are in Nb and Mo, the faster the δ-phase (Ni3Nb) precipitation. This is in accordance with the accelerated δ precipitation observed experimentally during post-build heat treatments of AM IN625 compared to wrought IN625. The δ-phase may be undesirable since it can lead to detrimental effects on the mechanical properties. The results are presented in the form of a TTT diagram and agreement between the simulated diagram and the experimental TTT diagram demonstrate how these computational tools can be used to guide and optimize post-build treatments of AM materials.

Disease outbreaks are limiting factors for an ethical and economically sustainable aquaculture industry. The first point of contact between a pathogen and a host occurs in the mucus, which covers the epithelial surfaces of the skin, gills and gastrointestinal tract. Increased knowledge on host-pathogen interactions at these primary barriers may contribute to development of disease prevention strategies. The mucus layer is built of highly glycosylated mucins, and mucin glycosylation differs between these epithelial sites. We have previously shown that A. salmonicida binds to Atlantic salmon mucins. Here we demonstrate binding of four additional bacteria, A. hydrophila, V. harveyi, M. viscosa and Y. ruckeri, to mucins from Atlantic salmon and Arctic char. No specific binding could be observed for V. salmonicida to any of the mucin groups. Mucin binding avidity was highest for A. hydrophila and A. salmonicida, followed by V. harveyi, M. viscosa and Y. ruckeri in decreasing order. Four of the pathogens showed highest binding to either gills or intestinal mucins, whereas none of the pathogens had preference for binding to skin mucins. Fluid velocity enhanced binding of intestinal mucins to A. hydrophila and A. salmonicida at 1.5 and 2 cm/s, whereas a velocity of 2 cm/s for skin mucins increased binding of A. salmonicida and decreased binding of A. hydrophila. Binding avidity, specificity and the effect of fluid velocity on binding thus differ between salmonid pathogens and with mucin origin. The results are in line with a model where the short skin mucin glycans contribute to contact with pathogens whereas pathogen binding to mucins with complex glycans aid the removal of pathogens from internal epithelial surfaces.

Stripe (yellow) rust is one of the most destructive diseases in wheat production. More than 80 stripe rust resistance (Yr) genes have been officially named, however Yr26 gene has lost resistance to CYR34 (V26) since 2011. In this study, we evaluated resistance of 692 elite wheat cultivars from China to stripe rust in adult plant stage and resistance to CYR32, CYR33, and CYR34 Pst races in seedling stags. Yr26 was deduced in 692 cultivars by WE173 and WE33 molecular marks. The result showed that 45 (7%) entries had all-stage resistance, 79 (11%) entries had adult-plant resistance, and 568 (82%) entries were susceptible to one or more stripe rust races. Besides, 48 (81%) entries in over-summering region were resistant to CYR34, 4 (10%) in over-wintering region, 121 (20%) in spring epidemic region. And 43 entries across China were detected to have Yr26 gene.

In this survey, we review the field of human shoulder functional kinematic representations. The central question of this review is to evaluate whether the current approaches in shoulder kinematics can meet the high-reliability computational challenge. This challenge is posed by applications such as robot-assisted rehabilitation. Currently, the role of kinematic representations in such applications has been mostly overlooked. Therefore, we have systematically searched and summarised the existing literature on shoulder kinematics. The shoulder is an important functional joint, and its large range of motion (ROM) poses several mathematical and practical challenges. Frequently, in kinematic analysis, the role of the shoulder articulation is approximated to a ball-and-socket joint. Following the high-reliability computational challenge, our review challenges this inappropriate use of reductionism. Therefore, we propose that this challenge could be met by kinematic representations, that are redundant, that use an active interpretation and that emphasise on functional understanding.

Brain autopsy and biomarker studies indicate that the pathology of Alzheimer’s disease (AD) is initiated at least 10–20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden ( n =1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of β-amyloid (Aβ42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aβ40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% ( N =46) had CSF Aβ42 levels below 530 pg ml −1 . These individuals displayed significantly higher CSF concentrations of t-tau ( P <0.001), p-tau (181) ( P <0.001), neurogranin ( P =0.009) and FABP3 ( P =0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aβ. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.

Crop species have been deeply affected by the domestication process, and there have been many efforts to identify selection signatures at the genome level. This knowledge will help geneticists to better understand the evolution of organisms, and at the same time, help breeders to implement successful breeding strategies. Here, we focused on domestication in the Mesoamerican gene pool of by sequencing 49 gene fragments from a sample of 45 wild and domesticated accessions, and as controls, two accessions each of the closely related species and . An excess of nonsynonymous mutations within the domesticated germplasm was found. Our data suggest that the cost of domestication alone cannot explain fully this finding. Indeed, the significantly higher frequency of polymorphisms in the coding regions observed only in the domesticated plants (compared to noncoding regions), the fact that these mutations were mostly nonsynonymous and appear to be recently derived mutations, and the investigations into the functions of their relative genes (responses to biotic and abiotic stresses), support a scenario that involves new functional mutations selected for adaptation during domestication. Moreover, consistent with this hypothesis, selection analysis and the possibility to compare data obtained for the same genes in different studies of varying sizes, data types, and methodologies allowed us to identify four genes that were strongly selected during domestication. Each selection candidate is involved in plant resistance/tolerance to abiotic stresses, such as heat, drought, and salinity. Overall, our study suggests that domestication acted to increase functional diversity at target loci, which probably controlled traits related to expansion and adaptation to new agro-ecological growing conditions.

Measuring day length is critical for timing annual changes in physiology and behavior in many species. Recently, rapid changes in several photoperiodically-controlled genes following exposure to a single long day have been described. Components of this 'first day release' model have so far only been tested in highly domesticated species: quail, sheep, goats and rodents. Because artificial selection accompanying domestication acts on genes related to photoperiodicity, we must also study this phenomenon in wild organisms for it to be accepted as universal. In a songbird, the great tit (Parus major), we tested whether a) these genes are involved in photoperiodic time measurement (PTM) in a wild species, and b) whether predictable species and population differences in expression patterns exist. Using quantitative RT-PCR, we compared gene expression after a single long day in male great tits from Sweden (57°42'N) with that from a German (47°43'N) population. Hypothalamic gene expression key for PTM changed only in the northern population, and occurred earlier after dawn during the single long day than demonstrated in quail; however, gonadotropins (secretion and synthesis) were stimulated in both populations, albeit with different timing. Our data are the first to show acute changes in gene expression in response to photostimulation in any wild species not selected for study of photoperiodism. The pronounced differences in gene expression in response to a single long day between two populations raise exciting new questions about potential environmental selection on photoperiodic cue sensitivity.

It is often claimed both that forgiveness is elective and that forgiveness is something that we do for reasons. However, there is a tension between these two central claims about the nature of forgiveness. If forgiving is something one does for reasons, then, at least sometimes, those reasons may generate a requirement to forgive or withhold forgiveness. While not strictly inconsistent with electivity, the idea of required forgiveness strikes some as antithetical to the spirit of the concept. They argue that forgiveness is essentially elective. In this paper, I dispute these arguments. I argue that the intuitive plausibility of the position diminishes upon reflection and that the best arguments fail to explain why reasons to forgive, unlike most other reasons for action, cannot generate requirements.

Aims/hypothesis We compared the ability of genetic (established type 2 diabetes, fasting glucose, 2 h glucose and obesity variants) and modifiable lifestyle (diet, physical activity, smoking, alcohol and education) risk factors to predict incident type 2 diabetes and obesity in a population-based prospective cohort of 3,444 Swedish adults studied sequentially at baseline and 10 years later. Methods Multivariable logistic regression analyses were used to assess the predictive ability of genetic and lifestyle risk factors on incident obesity and type 2 diabetes by calculating the AUC. Results The predictive accuracy of lifestyle risk factors was similar to that yielded by genetic information for incident type 2 diabetes (AUC 75% and 74%, respectively) and obesity (AUC 68% and 73%, respectively) in models adjusted for age, age 2 and sex. The addition of genetic information to the lifestyle model significantly improved the prediction of type 2 diabetes (AUC 80%; p  = 0.0003) and obesity (AUC 79%; p  < 0.0001) and resulted in a net reclassification improvement of 58% for type 2 diabetes and 64% for obesity. Conclusions/interpretation These findings illustrate that lifestyle and genetic information separately provide a similarly high degree of long-range predictive accuracy for obesity and type 2 diabetes.