The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis ...can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and drive neurodegeneration. We discuss the biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold. These mechanistic insights into the functions of the BCL-2 family are illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCL-2 family.
Group B streptococcus (GBS) or Streptococcus agalactiae is a β-hemolytic, Gram-positive bacterium that is a leading cause of neonatal infections. GBS commonly colonizes the lower gastrointestinal and ...genital tracts and, during pregnancy, neonates are at risk of infection. Although intrapartum antibiotic prophylaxis during labor and delivery has decreased the incidence of early-onset neonatal infection, these measures do not prevent ascending infection that can occur earlier in pregnancy leading to preterm births, stillbirths, or late-onset neonatal infections. Prevention of GBS infection in pregnancy is complex and is likely influenced by multiple factors, including pathogenicity, host factors, vaginal microbiome, false-negative screening, and/or changes in antibiotic resistance. A deeper understanding of the mechanisms of GBS infections during pregnancy will facilitate the development of novel therapeutics and vaccines. Here, we summarize and discuss important advancements in our understanding of GBS vaginal colonization, ascending infection, and preterm birth.
Impaired apoptosis is both critical in cancer development and a major barrier to effective treatment. In response to diverse intracellular damage signals, including those evoked by cancer therapy, ...the cell's decision to undergo apoptosis is determined by interactions between three factions of the Bcl-2 protein family. The damage signals are transduced by the diverse 'BH3-only' proteins, distinguished by the BH3 domain used to engage their pro-survival relatives: Bcl-2, Bcl-x(L), Bcl-w, Mcl-1 and A1. This interaction ablates pro-survival function and allows activation of Bax and Bak, which commit the cell to apoptosis by permeabilizing the outer membrane of the mitochondrion. Certain BH3-only proteins (e.g. Bim, Puma) can engage all the pro-survival proteins, but others (e.g. Bad, Noxa) engage only subsets. Activation of Bax and Bak appears to require that the BH3-only proteins engage the multiple pro-survival proteins guarding Bax and Bak, rather than binding to the latter. The balance between the pro-survival proteins and their BH3 ligands regulates tissue homeostasis, and either overexpression of a pro-survival family member or loss of a proapoptotic relative can be oncogenic. Better understanding of the Bcl-2 family is clarifying its role in cancer development, revealing how conventional therapy works and stimulating the search for "BH3 mimetics" as a novel class of anticancer drugs.
Early in stress-induced apoptosis of vertebrate cells, the outer membrane of the mitochondria is permeabilized, releasing cytochrome c and other death-promoting proteins (Newmeyer and Ferguson-Miller ...2003). Because Bcl-2 can prevent this change, it has been widely assumed that commitment to all forms of stress-induced apoptosis, that is, all those regulated by the Bcl-2 family, requires this step to initiate all relevant caspase activation, and hence that Bcl-2 and its anti-apoptosic relatives function as guardians of mitochondrial integrity (Green and Reed 1998; Gross et al. 1999; Wang 2001). That viewpoint is challenged by recent findings. It will be argued here that in stress-induced apoptosis, as in death receptor signaling (Strasser et al. 2000; Ashkenazi 2002), caspases can be activated upstream or independently of mitochondria, and hence that the mitochondrial breach may often simply deliver the coup de grace to a cell already on the path to death. A related theme is that the Bcl-2 cohort must man checkpoints at several sites in the cell. Finally, the vexed unresolved issue of how the opposing factions of the Bcl-2 family govern caspase activation is addressed.
The ubiquity of video games in today's society has led to significant interest in their impact on the brain and behavior and in the possibility of harnessing games for good. The present meta-analyses ...focus on one specific game genre that has been of particular interest to the scientific community-action video games, and cover the period 2000-2015. To assess the long-lasting impact of action video game play on various domains of cognition, we first consider cross-sectional studies that inform us about the cognitive profile of habitual action video game players, and document a positive average effect of about half a standard deviation (g = 0.55). We then turn to long-term intervention studies that inform us about the possibility of causally inducing changes in cognition via playing action video games, and show a smaller average effect of a third of a standard deviation (g = 0.34). Because only intervention studies using other commercially available video game genres as controls were included, this latter result highlights the fact that not all games equally impact cognition. Moderator analyses indicated that action video game play robustly enhances the domains of top-down attention and spatial cognition, with encouraging signs for perception. Publication bias remains, however, a threat with average effects in the published literature estimated to be 30% larger than in the full literature. As a result, we encourage the field to conduct larger cohort studies and more intervention studies, especially those with more than 30 hours of training.
Public Significance Statement
Understanding the effects of action video game play is essential given that (a) a large number of individuals regularly spend many hours on these types of games, and (b) proponents are offering suites of video games that are claimed to change behavior or enhance cognition. The 2 meta-analyses in this paper present the current status of this field, concluding that playing action video games has some positive effects on improving cognitive skills. This review also identifies some limitations of current research.
Little is known about the factors affecting the relative influences of stochastic and deterministic processes that govern the assembly of microbial communities in successional soils. Here, we ...conducted a meta-analysis of bacterial communities using six different successional soil datasets distributed across different regions. Different relationships between pH and successional age across these datasets allowed us to separate the influences of successional age (i.e., time) from soil pH. We found that extreme acidic or alkaline pH conditions lead to assembly of phylogenetically more clustered bacterial communities through deterministic processes, whereas pH conditions close to neutral lead to phylogenetically less clustered bacterial communities with more stochasticity. We suggest that the influence of pH, rather than successional age, is the main driving force in producing trends in phylogenetic assembly of bacteria, and that pH also influences the relative balance of stochastic and deterministic processes along successional soils. Given that pH had a much stronger association with community assembly than did successional age, we evaluated whether the inferred influence of pH was maintained when studying globally distributed samples collected without regard for successional age. This dataset confirmed the strong influence of pH, suggesting that the influence of soil pH on community assembly processes occurs globally. Extreme pH conditions likely exert more stringent limits on survival and fitness, imposing strong selective pressures through ecological and evolutionary time. Taken together, these findings suggest that the degree to which stochastic vs. deterministic processes shape soil bacterial community assembly is a consequence of soil pH rather than successional age.
Apoptosis, the major form of programmed cell death in metazoan organisms, plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation contributes to many ...pathological states, including cancer, autoimmunity, infection and degenerative disorders. In vertebrates, it can be triggered either by engagement of ‘death receptors’ of the tumour necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the Bcl‐2 protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both pathways lead to cellular demolition by dedicated proteases termed caspases. This review discusses the groundbreaking experiments from many laboratories that have clarified cell death regulation and galvanised efforts to translate this knowledge into novel therapeutic strategies for the treatment of malignant and perhaps certain autoimmune and infectious diseases.
For this New EMBO member's review, three recognised experts joined forces to provide a comprehensive overview on the molecular control of apoptosis and to discuss prospects for therapies.
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