Its About TIME: A Rigorous New Process for Selecting Instructional Materials for Science

California counties and school districts are implementing a critically needed change in how they evaluate science instructional materials before investing in local adoption. Past adoptions were often too superficial in nature, focusing on candidate materials' overall look and feel, use of graphical elements, and availability of ancillary materials while insufficiently attending to the substance of the materials for high-quality teaching and learning. In contrast, the California NGSS Toolkit for Instructional Materials Evaluation (hereafter referred to as TIME) process enables participants to use evidence-based measures to choose materials aligned to the Next Generation Science Standards (NGSS) that meet their district's needs.This 11th report in the NGSS Early Implementers Initiative evaluation series is intended for school and district administrators, leaders of science professional learning, and state policymakers. It provides an overview of the full TIME process, including participants' perceptions, a detailed description of the statewide TIME trainings of 2018-19, and a vignette that illustrates a portion of the TIME process

Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells

Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients

Conserved ‘Hypothetical’ Proteins: New Hints and New Puzzles

Conserved hypothetical proteins, i.e. conserved proteins whose functions are still unknown, pose a challenge not just to functional genomics but also to general biology. For many conserved proteins, computational analysis provides only a general prediction of biochemical function; their exact biological functions have to be established through direct experimentation. In the few cases when this has been accomplished, the results were remarkable, revealing the deoxyxylulose pathway and a new essential enzyme, the ITP pyrophosphatase. Comparative genome analysis is also instrumental in illuminating unsolved problems in biology, e.g. the mechanism of FtsZ-independent cell division in Chlamydia, Ureaplasma and Aeropyrum or the role of uncharacterized conserved domains in signal transduction

Structural basis for RNA recognition by NusB and NusE in the initiation of transcription antitermination

Processive transcription antitermination requires the assembly of the complete antitermination complex, which is initiated by the formation of the ternary NusB–NusE–BoxA RNA complex. We have elucidated the crystal structure of this complex, demonstrating that the BoxA RNA is composed of 8 nt that are recognized by the NusB–NusE heterodimer. Functional biologic and biophysical data support the structural observations and establish the relative significance of key protein–protein and protein–RNA interactions. Further crystallographic investigation of a NusB–NusE–dsRNA complex reveals a heretofore unobserved dsRNA binding site contiguous with the BoxA binding site. We propose that the observed dsRNA represents BoxB RNA, as both single-stranded BoxA and double-stranded BoxB components are present in the classical lambda antitermination site. Combining these data with known interactions amongst antitermination factors suggests a specific model for the assembly of the complete antitermination complex