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Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain dilate and frequently hemorrhage. In this issue, Kleaveland et al. (p 169) and Whitehead et al. (p 177) reveal underlying defects in endothelial cell signaling and function. On the cover, a color-enhanced magnetic resonance image of the brain shows multiple congenital malformations of the cerebral vasculature (red). Credit: Living Art Enterprises, LLC/Photo Researchers, Inc.
Influenza virus vaccination for young children living in the US state of New Jersey and who are attending preschool is now compulsory—a mandate that has highlighted a flourishing public mistrust of vaccines.
Researchers are enrolling thousands of participants around the world in clinical trials in a massive effort to test whether a once-daily pill can prevent HIV. Cassandra Willyard explores why they are optimistic the strategy will work and why it might be difficult to implement.
Last month, Michel Sidibé assumed his new role as executive director of UNAIDS, the United Nations agency created more than a decade ago to foster global leadership in the response to the AIDS pandemic. Sidibé discussed his new goals as executive director of UNAIDS with Prashant Nair.
Experiments in mice and zebrafish uncover a pathway behind malformed blood vessels in the brain (pages 169–176 & 177–184). The findings provide a basis for understanding the development of cerebral vascular malformations, a common and deadly condition.
The inflammatory response goes haywire after stroke, and the brain floods with immune mediators that can injure tissue and worsen outcome. Experiments in mice suggest that regulatory T cells help contain the damage (pages 192–199).
A molecular pathway requiring vitamin B3 increases the production of neutrophils (pages 151–158). These findings could lead to new ways to treat neutropenias, diseases involving low neutrophil counts.
Osteoporosis researchers do not suffer from a lack of potential drug targets—so one challenge is to decide which ones to focus on. Yongwon Choi, Matthew C. Walsh and Joseph R. Arron now examine several molecules involved in bone biology and assess their prospects. In a second commentary, Cliff Rosen analyzes findings that serotonin, derived from the gut, regulates bone formation. The findings not only could lead to new drug targets, they also could help explain clinical data that serotonin reuptake inhibitors—widely prescribed as antidepressants—weaken bones.
In this report, Skokowa et al. delineate a new molecular pathway by which synthesis of the metabolite NAD+ through the action of the enzyme NAMPT promotes myeloid cell differentiation. The potential clinical relevance of this pathway was demonstrated by showing that administration of vitamin B3, a precursor to NAD+, increases neutrophil counts in healthy individuals, and that defective myeloid cell differentiation in individuals with congenital neutropenia can be rescued in vitro by administration of NAMPT.
A main function of fat cells is to store fuel for future use, which is released when the fat is broken down in a process called lipolysis. Here Hei Sook Sul and colleagues describe a new enzyme in fat, AdPLA, that inhibits lipolysis and shows that genetic deletion results in protection from obesity in two mouse models.
Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain dilate and frequently hemorrhage. Benjamin Kleaveland et al. now provide evidence that CCM arises from defects in a signaling pathway involving the KRIT1 and CCM2 intracellular proteins (which have been previously implicated in CCM) and the HEG1 receptor; this pathway acts in endothelial cells and is required for vascular integrity. The role of the CCM2 protein in the endothelium is also explored in another paper published in this issue of Nature Medicine, by Kevin Whitehead et al.
Cerebral cavernous malformation (CCM) is a life-threatening disorder in which blood vessels in the brain are prone to hemorrhage. Kevin Whitehead et al. now show that CCM2, mutations in which are associated with CCM, is needed for specific aspects of endothelial cell function involving RhoA GTPase. These defects can be partially restored by statin treatment, suggesting a potential therapeutic intervention for individuals with CCM. The role of CCM2 in the endothelium is also explored in another paper published in this issue of Nature Medicine, by Benjamin Kleaveland et al
After injury to the spinal cord, hemorrhages occur both near and far from the initial lesion. J. Marc Simard and his colleagues demonstrate that spinal cord injury induces expression of the channel Trpm4 on endothelial cells in the spinal cord, which leads to their fragmentation and the spread of the hemorrhage.
Inflammation plays a detrimental role in ischemic stroke. Now, Roland Veltkamp and his colleagues show that endogenous immunomodulatory T regulatory cells play a key part to dampen inflammation after stroke.
Ethylmalonic encephalopathy is an autosomal recessive developmental disorder that is characterized by chronic diarrhea and multiple neurological deficits. It is associated with loss-of-function mutations in the ETHE1 gene. Now, Massimo Zeviani and his colleagues report that ETHE1 is a dioxygenase that is responsible for breaking down toxic sulfide in a variety of organs.
TNF is a key pathogenic cytokine in sepsis. Oberdan Leo and colleagues show that production of TNF during sepsis is regulated by the coenzyme NAD and that inhibition of the enzyme NAMPT, which generates NAD from nicotinamide, can improve survival during sepsis in mice. NAD seems to act via sirtuin-6 to increase the translation of TNF.
Does Mycobacterium tuberculosis replicate in vivo, or does it persist in the host in a nonreplicating latent state? David Sherman and his colleagues have developed a technique to answer this question in mice and find that the mycobacteria do replicate in vivo. It is unknown whether these findings will hold true in other animals, particularly nonhuman primates, but this technique could be applied to study the in vivo replication of other persistent pathogens responsible for chronic infections.
By capitalizing on copy number variation, Wu and his colleagues offer an approach for detecting cellular chimerism with fluorescent in situ hybridization probes that target polymorphic deletion loci. These probes can determine the fate of donor cells in situ, irrespective of gender, and should prove useful in understanding the dynamics of cellular chimerism after solid organ, bone marrow and hematopoietic stem cell transplantation.