Out of the Twilight Zone: The Implications of \u3ci\u3eDaubert v. Merrill Dow Pharmaceuticals, Inc.\u3c/i\u3e

In Daubert v. Merrell Dow Pharmaceuticals, Inc., the United States Supreme Court held that the Federal Rules of Evidence had not implicitly incorporated the general acceptance, or Frye, test for scientific evidence. Instead, the Court interpreted Rule 702 to mean that judges should admit challenged scientific testimony only after determining that its underlying method or theory is scientifically valid. This Note argues that the essence of the Daubert decision is that judges must ascertain whether or not the studies underlying proffered testimony have been performed in accordance with sound scientific principles. The Note analyzes several cases to illustrate appropriate and inappropriate applications of the new standard. Finally, the Note suggests a three-stage inquiry that will enable judges to elicit the information necessary for adequate evaluation of scientific studies

Spontaneous Preterm Birth Is Associated with Differential Expression of Vaginal Metabolites by Lactobacilli-Dominated Microflora

A major challenge in preventing preterm birth (PTB) is identifying women at greatest risk. This pilot study prospectively examined the differences in vaginal microbiota and metabolite profiles of women who delivered prematurely compared to their term counterparts in a cohort of asymptomatic (studied at 20–22, n = 80; and 26–28 weeks, n = 41) and symptomatic women (studied at 24–36 weeks, n = 37). Using 16S rRNA sequencing, the vaginal microbiota from cervicovaginal fluid samples was characterized into five Community State Types (CST) dominated by Lactobacillus spp.: CSTI (Lactobacillus crispatus), CSTII (Lactobacillus gasseri), CSTIII (Lactobacillus iners), CSTV (Lactobacillus jensenii); and mixed anaerobes—CSTIV. This was then related to the vaginal metabolite profile and pH determined by 1H-Nuclear Magnetic Resonance spectroscopy and pH indicator paper, respectively. At 20–22 weeks, the term-delivered women (TDW) indicated a proportion of CSTI-dominated microbiota >2-fold higher compared to the preterm-delivered women (PTDW) (40.3 vs. 16.7%, P = 0.0002), and a slightly higher proportion at 26–28 weeks (20.7 vs. 16.7%, P = 0.03). CSTV was >2-fold higher in the PTDW compared to TDW at 20–22 (22.2 vs. 9.7%, P = 0.0002) and 26–28 weeks (25.0 vs. 10.3%, P = 0.03). Furthermore, at 26–28 weeks no PTDW had a CSTII-dominated microbiome, in contrast to 28% of TDW (P < 0.0001). CSTI-dominated samples showed higher lactate levels than CSTV at 20–22 weeks (P < 0.01), and 26–28 weeks (P < 0.05), while CSTII-dominated samples indicated raised succinate levels over CSTV at 26–28 weeks (P < 0.05). These were supported by Principal coordinates analysis, which revealed strong clustering of metabolites according to CST. In addition, the CSTI-dominated samples had an average pH of 3.8, which was lower than those of CSTII—4.4, and CSTV—4.2 (P < 0.05). Elevated vaginal lactate and succinate were associated with predominance of CSTI and II over CSTV in women who delivered at term compared with their preterm counterparts. This suggests that L. jensenii-dominance and decreased lactate and/or succinate could increase the risk of PTB, while L. crispatus/gasseri may confer some protection against inflammation-associated PTB and highlight the need for further study in this area

Cell-Type Independent MYC Target Genes Reveal a Primordial Signature Involved in Biomass Accumulation

The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells

T cell metabolism drives immunity

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism