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Key Points The development of compensatory movement strategies is a reliable consequence of strokes that result in motor disabilities. Obvious forms of compensation for upper-limb disability after stroke include dominant reliance on the non-paretic upper limb and the use of trunk movements, in place of distal movements, to control the paretic upper limb. Converging evidence from animal and clinical studies of stroke indicate that reliance on the obvious forms of compensation described above can limit the recovery of more-normal movements and more-functional use of the paretic upper limb. Their potential to do so can be expected to vary with impairment severity. By contrast, the use of relatively subtle compensatory strategies to perform skilled motor tasks with the paretic upper limb can precede the recovery of more-normal movements on those tasks. The initial reliance on compensatory strategies that approximate normal movements may enable the task practice that is needed to support the recovery of those movements. Both the effects of motor rehabilitative training focused on the paretic limb and the development of compensatory movement strategies depend on learning-related neural plasticity mechanisms that can be facilitated by their interaction with early post-stroke neuroregenerative responses. As compensation starts early after stroke, its neural plasticity mechanisms are probably normally facilitated by this interaction. In rodent models of stroke, the neural plasticity involved in learning to compensate with the non-paretic upper limb can compete with the neural plasticity related to rehabilitative training of the paretic forelimb. This competitive plasticity is a putative mechanism by which compensatory strategies counter functional improvements in the paretic upper limb and exacerbate its disuse. Compensation is not currently receiving the prominent attention in animal models of stroke that is warranted by its reliable clinical manifestation and its potential to either promote or impede recovery. A better understanding of the neural mechanisms, and adaptive and maladaptive consequences, of behavioural compensation has a strong potential to lead to new treatments that optimize functional outcome after stroke. Stroke survivors often adapt to the loss of upper-limb function by adopting compensatory strategies. Jones discusses evidence that these compensatory strategies may influence the neural remodelling processes that occur after the initial stroke and can have mixed effects on functional outcome of the paretic limb. Stroke instigates a dynamic process of repair and remodelling of remaining neural circuits, and this process is shaped by behavioural experiences. The onset of motor disability simultaneously creates a powerful incentive to develop new, compensatory ways of performing daily activities. Compensatory movement strategies that are developed in response to motor impairments can be a dominant force in shaping post-stroke neural remodelling responses and can have mixed effects on functional outcome. The possibility of selectively harnessing the effects of compensatory behaviour on neural reorganization is still an insufficiently explored route for optimizing functional outcome after stroke.

\"Their peace was a fragile thing, but it had endured for seven years, mostly because the people of Darassus and the king of the Naor hordes believed his doom was foretold upon the edge of the great sword hung in the hall of champions. Unruly Naor clans might raid across the border, but the king himself would never lead his people to war so long as the blade remained in the hands of his enemies. But when squire Elenai's aging mentor uncovers evidence that the sword in their hall is a forgery she's forced to flee Darassus for her life, her only ally the reckless, disillusioned Kyrkenall the archer. Framed for murder and treason, pursued by the greatest heroes of the realm, they race to recover the real sword, only to stumble into a conspiracy that leads all the way back to the Darassan queen and her secretive advisors. They must find a way to clear their names and set things right, all while dodging friends determined to kill them--and the Naor hordes, invading at last with a new and deadly weapon\"-- Provided by publisher.

Key Points DNA methylation is an epigenetic mark that can be mitotically inherited and is involved in adding stability to the repression of transcription when it is located at the start sites of mammalian genes. Our ability to obtain complete methylomes has transformed our appreciation of the role of DNA methylation in epigenetic processes. DNA methylation in the bodies of genes has long been ignored but might be involved in differential promoter usage and also in transcription elongation and alternative splicing. Repetitive DNA from intragenomic parasites is heavily methylated, which allows transcription of the host gene at the same time as preventing transcription initiation of the repetitive DNA. Methylation of control regions outside of the transcription start sites — such as enhancers and insulators — is increasingly being recognized as being functionally important. Demethylation of DNA is now accepted as being essential for embryonic development and seems to occur mainly in regions of DNA that are not CpG islands; thus, methylation patterns are increasingly being realized as being far more dynamic than previously recognized. Our understanding of the function of DNA methylation is developing now that we are able to look beyond CpG-rich regions at transcriptional start sites. The emerging picture is of a complex relationship between DNA methylation and transcription and of possible additional roles of methylation. DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

\"\"A fast-paced adventure combined with an engrossing mystery, all set in a unique and original fantasy world. I can't wait to find out what happens next!\" -Martha Wells, Hugo Award-winning author In this sequel to For the Killing of Kings, Howard Andrew Jones returns to the Nine Realms of the Dendressi in Upon the Flight of the Queen to continue this imaginative and fun epic fantasy trilogy. While the savage Naor clans prepare to march on the heart of the Five Realms, Rylin Corimel infiltrates the highest of the enemy ranks to learn their secrets and free hundreds of doomed prisoners. His ailing mentor Varama leads the Altenerai corps in a series of strikes to cripple the Naor. Kyrkenall, Elenai, and the kobalin Ortok ride for the storm-wracked shifting lands to rekindle the alliance with the winged lizards known as ko'aye, the only possible counter to the terrible Naor dragons. Meanwhile, the queen is delving further and deeper into the magic of the mysterious hearthstones, in a frantic attempt to save the realms that just might doom them all. Praised for his ability to write modern epic fantasy that engrosses and entertains, Howard Andrew Jones delivers a sequel that expands the amazing world, relationships, and adventure that he introduced in the first book of this series\"-- Provided by publisher.

Key Points Ectopic lymphoid-like structure neogenesis is a common clinical occurrence and contributes to the pathology that is associated with cancer, autoimmunity, infection and tissue rejection. In this Review, we discuss the mechanisms that drive the neogenesis of ectopic lymphoid-like structures and their involvement in disease processes. By drawing information from animal studies and clinical observations, we consider why certain patients develop ectopic lymphoid-like structures in inflamed tissues, whereas others do not. The current status of therapies that target ectopic lymphoid-like structures is discussed. We consider clinical approaches that may help to support the diagnosis, treatment and clinical management of patients who have ectopic lymphoid-like structures as part of their disease. Inflammation can promote the development of lymphoid structures in tissue sites at which they do not normally occur. Here, the authors discuss how these ectopic lymphoid-like structures arise and, furthermore, how they affect immune responses in the setting of infection and disease. Ectopic lymphoid-like structures often develop at sites of inflammation where they influence the course of infection, autoimmune disease, cancer and transplant rejection. These lymphoid aggregates range from tight clusters of B cells and T cells to highly organized structures that comprise functional germinal centres. Although the mechanisms governing ectopic lymphoid neogenesis in human pathology remain poorly defined, the presence of ectopic lymphoid-like structures within inflamed tissues has been linked to both protective and deleterious outcomes in patients. In this Review, we discuss investigations in both experimental model systems and patient cohorts to provide a perspective on the formation and functions of ectopic lymphoid-like structures in human pathology, with particular reference to the clinical implications and the potential for therapeutic targeting.

IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. Hunter and Jones discuss the effect of IL-6 on innate and adaptive immunity, and consider how the immunobiology of IL-6 may inform clinical decisions. Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

The world’s staple food crops, and other food crops that optimize human nutrition, suffer from global virus disease pandemics and epidemics that greatly diminish their yields and/or produce quality. This situation is becoming increasingly serious because of the human population’s growing food requirements and increasing difficulties in managing virus diseases effectively arising from global warming. This review provides historical and recent information about virus disease pandemics and major epidemics that originated within different world regions, spread to other continents, and now have very wide distributions. Because they threaten food security, all are cause for considerable concern for humanity. The pandemic disease examples described are six (maize lethal necrosis, rice tungro, sweet potato virus, banana bunchy top, citrus tristeza, plum pox). The major epidemic disease examples described are seven (wheat yellow dwarf, wheat streak mosaic, potato tuber necrotic ringspot, faba bean necrotic yellows, pepino mosaic, tomato brown rugose fruit, and cucumber green mottle mosaic). Most examples involve long-distance virus dispersal, albeit inadvertent, by international trade in seed or planting material. With every example, the factors responsible for its development, geographical distribution and global importance are explained. Finally, an overall explanation is given of how to manage global virus disease pandemics and epidemics effectively.