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This Preliminary Investigation document, on one hand, outlines challenges encountered by SB/DBEs in the process of getting certified, entering into a contract, executing on projects or delivering services, and sustaining or growing their business. On the other hand, it summarizes OCR’s current ongoing efforts that are aiming to expand contracting with SB/DBEs. Along the way it identifies opportunities that warrant more in-depth investigation for OCR to target its programming and resource allocation as it aims to reduce obstacles or otherwise improve the ability of SBs/DBEs to successfully contract with Caltrans.

BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

How has the diffusion of online communities changed howtheir users construct, view, and define their identity? In thispaper, we choose to approach this issue by considering twoparticular philosophical problems related to personal identity:1) The Characterization Question, namely “which actions, ex-periences, beliefs, values, desires, character traits, and so oncan we attribute to a given person?” 2) “How do self-other re-lations affect the ethical implication of identity construction?”To address them, we adopt a comprehensive framework com-posed of cognitive niches and cognitive niche construction the-ories, and we discuss different philosophical and technologicalnotions. In particular: the Filter Bubble problem, the conceptof affordances, and the Sartrean idea of Bad Faith.

How we make decisions that have direct consequences for ourselves and others forms the moral foundation of our society. Whereas economic theory contends that humans aim at maximizing their own gains, recent seminal psychological work suggests that our behavior is instead hyperaltruistic: We are more willing to sacrifice gains to spare others from harm than to spare ourselves from harm. To investigate how such egoistic and hyperaltruistic tendencies influence moral decision making, we investigated trade-off decisions combining monetary rewards and painful electric shocks, administered to the participants themselves or an anonymous other. Whereas we replicated the notion of hyperaltruism (i.e., the willingness to forego reward to spare others from harm), we observed strongly egoistic tendencies in participants' unwillingness to harm themselves for others' benefit. The moral principle guiding intersubject trade-off decision making observed in our study is best described as egoistically biased altruism, with important implications for our understanding of economic and social interactions in our society.

ObjectivePsychopathy is a personality disorder with symptoms that include lack of empathy or remorse, antisocial behavior, and excessive self-focus. Previous neuroimaging studies have linked psychopathy to dysfunction in the default mode network (DMN), a brain network that deactivates during externally focused tasks and is more engaged during self-referential processing. Specifically, the DMN has been found to remain relatively active in individuals with psychopathic tendencies during externally focused tasks, suggesting a failure to properly deactivate. However, the exact extent and nature of task-induced DMN dysfunction is poorly understood, including (a) the degree to which specific DMN subregions are affected in criminal psychopaths, and (b) how activity in these subregions relates to affective/interpersonal and antisocial/lifestyle traits of psychopathy.MethodWe performed a group independent component analysis to assess DMN activation during a Go/NoGo task in a group of 22 high-psychopathy and 22 low-psychopathy prisoners. The identified group-level DMN was parcellated into 6 subregions, and group differences in task-induced activity were examined.ResultsIn general, DMN subregions failed to deactivate beneath baseline in the high-psychopathy group. A group comparison with the low-psychopathy group localized this attenuated task-induced deactivation to the posteromedial cortical (mPC) region of the DMN. Moreover, multiple regression analyses revealed that activity in the mPC was associated with affective/interpersonal traits of psychopathy.ConclusionThese findings suggest that attenuated deactivation of the mPC subregion of the DMN is intrinsic to psychopathy, and is a pattern that may be more associated with affective psychopathic traits, including lack of concern for others.

Converging lines of evidence from diverse research domains suggest that the left and right hemispheres play distinct, yet complementary, roles in inferential reasoning. Here, we review research on split-brain patients, brain-damaged patients, delusional patients, and healthy individuals that suggests that the left hemisphere tends to create explanations, make inferences, and bridge gaps in information, while the right hemisphere tends to detect conflict, update beliefs, support mental set-shifts, and monitor and inhibit behavior. Based on this evidence, we propose that the left hemisphere specializes in creating hypotheses and representing causality, while the right hemisphere specializes in evaluating hypotheses, and rejecting those that are implausible or inconsistent with other evidence. In sum, we suggest that, in the domain of inferential reasoning, the left hemisphere strives to reduce uncertainty while the right hemisphere strives to resolve inconsistency. The hemispheres' divergent inferential reasoning strategies may contribute to flexible, complex reasoning in the healthy brain, and disruption in these systems may explain reasoning deficits in the unhealthy brain.

Telomerase canonically maintains telomeres, but recent reports have suggested that the core protein mammalian telomerase reverse transcriptase (TERT) component, together with the chromatin remodeling factor BRG1 and β-catenin, may also bind to and promote expression of Wnt target genes. However, this proposed noncanonical role of TERT in Wnt signaling has been controversial. Here, we investigated the effects of human TERT (hTERT) on Wnt signaling in human breast cancer lines and HeLa cells. We failed to find evidence for physical association of hTERT with BRG1 or β-catenin; instead, we present evidence that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of hTERT with β-catenin. Furthermore, altering hTERT levels in four different breast cancer cell lines caused minimal and discordant effects on Wnt target and Wnt pathway gene expression. Although hTERT's role in Wnt signaling was addressed only indirectly, no significant representation of Wnt target genes was detected in chromatin immunoprecipitation-sequencing (ChIP-seq) and chromatin isolation by RNA purification and sequencing (ChIRP-seq) loci cooccupied in HeLa S3 cells by both BRG1 and hTR. In summary, our evidence fails to support the idea of a biologically consistent hTERT interaction with the Wnt pathway in human breast cancer cells, and any detectable influence of hTERT depended on cell type and experimental system.

Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β- or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology.