Noncytotoxic functions of killer cell granzymes in viral infections.

Cytotoxic lymphocytes produce granules armed with a set of 5 serine proteases (granzymes (Gzms)), which, together with the pore-forming protein (perforin), serve as a major defense against viral infections in humans. This granule-exocytosis pathway subsumes a well-established mechanism in which target cell death is induced upon perforin-mediated entry of Gzms and subsequent activation of various (apoptosis) pathways. In the past decade, however, a growing body of evidence demonstrated that Gzms also inhibit viral replication and potential reactivation in cell death-independent manners. For example, Gzms can induce proteolysis of viral or host cell proteins necessary for the viral entry, release, or intracellular trafficking, as well as augment pro-inflammatory antiviral cytokine response. In this review, we summarize current evidence for the noncytotoxic mechanisms and roles by which killer cells can use Gzms to combat viral infections, and we discuss the potential thereof for the development of novel therapies.

The Impact of Alcohol on L1 versus L2.

Alcohol intoxication is known to affect many aspects of human behavior and cognition; one of such affected systems is articulation during speech production. Although much research has revealed that alcohol negatively impacts pronunciation in a first language (L1), there is only initial evidence suggesting a potential beneficial effect of inebriation on articulation in a non-native language (L2). The aim of this study was thus to compare the effect of alcohol consumption on pronunciation in an L1 and an L2. Participants who had ingested different amounts of alcohol provided speech samples in their L1 (Dutch) and L2 (English), and native speakers of each language subsequently rated the pronunciation of these samples on their intelligibility (for the L1) and accent nativelikeness (for the L2). These data were analyzed with generalized additive mixed modeling. Participants' blood alcohol concentration indeed negatively affected pronunciation in L1, but it produced no significant effect on the L2 accent ratings. The expected negative impact of alcohol on L1 articulation can be explained by reduction in fine motor control. We present two hypotheses to account for the absence of any effects of intoxication on L2 pronunciation: (1) there may be a reduction in L1 interference on L2 speech due to decreased motor control or (2) alcohol may produce a differential effect on each of the two linguistic subsystems.

Metabolic programming of tumor associated macrophages in the context of cancer treatment.

Tumor associated macrophages (TAMs) are important components of the tumor microenvironment (TME). They are characterized by a remarkable functional plasticity, thereby mostly promoting cancer progression. Changes in immune cell metabolism are paramount for this functional adaptation. Here, we review the functional consequences of the metabolic programming of TAMs and the influence of local and systemic targeted therapies on the metabolic characteristics of the TME that shape the functional phenotype of the TAMs. Understanding these metabolic changes within the context of the cross-talk between the different components of the TME including the TAMs and the tumor cells is an essential step that can pave the way towards identifications of ways to improve responses to different treatments, to overcome resistance to treatments, tumor progression and reduce treatment-specific toxicity.

Customized recommendations for production management clusters of North American automatic milking systems.

Automatic milking systems (AMS) are implemented in a variety of situations and environments. Consequently, there is a need to characterize individual farming practices and regional challenges to streamline management advice and objectives for producers. Benchmarking is often used in the dairy industry to compare farms by computing percentile ranks of the production values of groups of farms. Grouping for conventional benchmarking is commonly limited to the use of a few factors such as farms' geographic region or breed of cattle. We hypothesized that herds' production data and management information could be clustered in a meaningful way using cluster analysis and that this clustering approach would yield better peer groups of farms than benchmarking methods based on criteria such as country, region, breed, or breed and region. By applying mixed latent-class model-based cluster analysis to 529 North American AMS dairy farms with respect to 18 significant risk factors, 6 clusters were identified. Each cluster (i.e., peer group) represented unique management styles, challenges, and production patterns. When compared with peer groups based on criteria similar to the conventional benchmarking standards, the 6 clusters better predicted milk produced (kilograms) per robot per day. Each cluster represented a unique management and production pattern that requires specialized advice. For example, cluster 1 farms were those that recently installed AMS robots, whereas cluster 3 farms (the most northern farms) fed high amounts of concentrates through the robot to compensate for low-energy feed in the bunk. In addition to general recommendations for farms within a cluster, individual farms can generate their own specific goals by comparing themselves to farms within their cluster. This is very comparable to benchmarking but adds the specific characteristics of the peer group, resulting in better farm management advice. The improvement that cluster analysis allows for is characterized by the multivariable approach and the fact that comparisons between production units can be accomplished within a cluster and between clusters as a choice.

Factors associated with increased milk production for automatic milking systems.

Automatic milking systems (AMS) are increasingly popular throughout the world. Our objective was to analyze 635 North American dairy farms with AMS for (risk) factors associated with increased milk production per cow per day and milk production per robot per day. We used multivariable generalized mixed linear regressions, which identified several significant risk factors and interactions of risk factors associated with milk production. Free traffic was associated with increased production per cow and per robot per day compared with forced systems, and the presence of a single robot per pen was associated with decreased production per robot per day compared with pens using 2 robots. Retrofitted farms had significantly less production in the first 4 yr since installation compared with production after 4 yr of installation. In contrast, newly built farms did not see a significant change in production over time since installation. Overall, retrofitted farms did not produce significantly more or less milk than newly constructed farms. Detailed knowledge of factors associated with increased production of AMS will help guide future recommendations to producers looking to transition to an AMS and maximize their production.