MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, a MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure, and maintenance of oligomeric ATP synthase. Our results provide insight into how MCL-1's surprisingly diverse salutary functions may control the survival of both normal and cancer cells.

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.

Purpose:To assess the prevalence and degree of lumbosacral transitional vertebrae (LSTV) in the Osteoarthritis Initiative (OAI) cohort, to assess whether LSTV correlates with low back pain (LBP) and buttock pain, and to assess the reproducibility of grading LSTV. Materials & Methods:Institutional review board approval was obtained, and informed consent documentation was approved for the study protocol. Standard standing pelvic radiographs that included the transverse processes of L5 were graded according to Castellvi classification of LSTV in 4636 participants (1992 men and 2804 women; aged 45-80 years) from the OAI cohort. These data were correlated with prevalence and severity of LBP and buttock pain. Results:Prevalence of LSTV was 18.1% (841 of 4636), with a higher rate in men than in women (28.1% vs 11.1%, respectively; P , .001). Of the 841 individuals with LSTV, 41.72% were type I (dysplastic enlarged transverse process), 41.4% were type II (pseudoarticulation), 11.5% were type III (fusion), and 5.2% were type IV (one transverse process fused and one with pseudoarticulation). Of the participants without LSTV, 53.9% reported LBP, while the prevalence of LBP for types I, II, III, and IV was 46%, 73%, 40%, and 66%, respectively (P , .05, x 2 test). Types II and IV had higher prevalence and severity of LBP and buttock pain (P , .001).

No abstract

Raw (unpasteurized) milk can be a source of food-borne pathogens. Raw milk consumption results in sporadic disease outbreaks. Pasteurization is designed to destroy all bacterial pathogens common to raw milk, excluding spore-forming bacteria and possibly Mycobacterium paratuberculosis, but some people continue to drink raw milk, believing it to be safe. Current methods for assessing the bacteriological quality of raw milk, such as aerobic plate counts, are not usually designed to detect specific pathogens. The objective of this study was to estimate the proportion of pick-ups (loads of raw milk from a single farm bulk tank) from Ontario farm bulk tanks that contained Listeria monocytogenes. Salmonella spp., Campylobacter spp., and/or verotoxigenic Escherichia coli (VTEC). Samples from 1,720 pick-ups of raw milk were tested for the presence of these pathogens, and 47 L. monocytogenes, three Salmonella spp., eight Campylobacter spp., and 15 VTEC isolates were detected, representing 2.73, 0.17, 0.47, and 0.87% of milk samples, respectively. Estimates of the proportion of theoretical tanker truck loads of pooled raw milk contaminated with pathogens ranged from a low of 0.51 % of tankers containing raw milk from 3 bulk tanks being contaminated with Salmonella spp. to a high of 34.41 % of tankers containing raw milk from 10 bulk tanks being contaminated with at least one of the pathogens. Associations between the presence of pathogens and raw milk sample characteristics were investigated. The mean somatic cell count was higher among VTEC- or L. monocytogenes-positive samples, and the mean aerobic plate count was found to be higher among L. monocytogenes-positive samples. These results confirm the presence of bacterial food pathogens in raw milk and emphasize the importance of continued diligence in the application of hygiene programs within dairies and the separation of raw milk from pasteurized milk and milk products.

No abstract

The increase in public representation of the science-based concept "genetics" in the mass media might be expected to have a major impact on public understanding of the concept of "race." A model of lay understandings of the role of genetics in the contemporary United States is offered based on focus group research, random digit dial surveys, and community based surveys. That model indicates that lay people identify are primarily by physical features, but these identifications are categorized into a variety of groupings that may be regional, national, or linguistic. Although they believe that physical appearance is caused largely by genetics, and therefore that race has a genetic basis, they do not uniformly conclude, however, that all perceived racial characteristics are genetically based. Instead, they vary in the extent to which they attribute differences to cultural, personal, and genetic factors.

To investigate the frequency of isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in pediatric acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), we sequenced these genes in diagnostic samples from 515 patients (227 AMLs and 288 ALLs). Somatic IDH1/IDH2 mutations were rare in ALL (N=1), but were more common in AML, occurring in 3.5% (IDH1 N=3 and IDH2 N=5), with the frequency higher in AMLs with a normal karyotype (9.8%). The identified IDH1 mutations occurred in codon 132 resulting in replacement of arginine with either cysteine (N=3) or histidine (N=1). By contrast, mutations in IDH2 did not affect the homologous residue but instead altered codon 140, resulting in replacement of arginine with either glutamine (N=4) or tryptophan (N=1). Structural modeling of IDH2 suggested that codon 140 mutations disrupt the enzyme's ability to bind its substrate isocitrate. Accordingly, recombinant IDH2 R140Q/W were unable to carry out the decarboxylation of isocitrate to α-ketoglutarate (α-KG), but instead gained the neomorphic activity to reduce α-KG to R(−)-2-hydroxyglutarete (2-HG). Analysis of primary leukemic blasts confirmed high levels of 2-HG in AMLs with IDH1/IDH2 mutations. Interestingly, 3/5 AMLs with IDH2 mutations had FLT3 activating mutations, raising the possibility that these mutations cooperate in leukemogenesis.