Detection of patient- and tumor-specific clonally rearranged immune receptor genes using real-time quantitative (RQ)-PCR is an accepted method in the field of precision medicine for hematologic... Show moreDetection of patient- and tumor-specific clonally rearranged immune receptor genes using real-time quantitative (RQ)-PCR is an accepted method in the field of precision medicine for hematologic malignancies. As individual primers are needed for each patient and leukemic clone, establishing performance specifications for the method faces unique challenges. Results for series of diagnostic assays for CLL and ALL patients demonstrate that the analytic performance of the method is not dependent on patients' disease characteristics. The calibration range is linear between 10(-1) and 10(-5) for 90% of all assays. The detection limit of the current standardized approach is between 1.8 and 4.8 cells among 100,000 leukocytes. RQ-PCR has about 90% overall agreement to flow cytometry and next generation sequencing as orthogonal methods. Accuracy and precision across different labs, and above and below the clinically applied cutoffs for minimal/measurable residual disease (MRD) demonstrate the robustness of the technique. The here reported comprehensive, IVD-guided analytical validation provides evidence that the personalized diagnostic methodology generates robust, reproducible and specific MRD data when standardized protocols for data generation and evaluation are used. Our approach may also serve as a guiding example of how to accomplish analytical validation of personalized in-house diagnostics under the European IVD Regulation. Show less
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models... Show moreEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals. Show less
Social cognition emerged in the 1970s and 80s as an attempt to answer social-psychological questions by adopting experimental techniques and theoretical concepts from cognitive psychology. Recently... Show moreSocial cognition emerged in the 1970s and 80s as an attempt to answer social-psychological questions by adopting experimental techniques and theoretical concepts from cognitive psychology. Recently, cognitive psychologists began to build complementary bridges between cognitive and social psychology by showing increasing interest in the cognitive implications of social situations. Here, we take a closer look at the remaining obstacles to join cognitive and social perspectives on human behavior. Using conformity as an example, we attempt to demonstrate that the social-cognition approach has been successful in adopting cognitive concepts and experimental methods, but is still lagging behind with respect to (1) mechanistic theorizing, as it often engages in merely describing phenomena in terms of reasons rather than explaining it in terms of causes and (2) reflecting the sociohistorical context of the phenomenon under investigation. As we try to show, developing mechanistic theories for social phenomena, including the effects of individual differences and their sociohistorical dependencies, is not only possible but necessary to eliminate the boundaries between cognitive and social accounts of human behavior. Show less
Tam, O.H.; Rozhkov, N.V.; Shaw, R.; Kim, D.; Hubbard, I.; Fennessey, S.; ... ; NYGC ALS Consortium 2019
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast... Show moreAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo. Show less
Zhou, X.; Paushter, D.H.; Pagan, M.D.; Kim, D.; Nunez Santos, M.; Lieberman, R.L.; ... ; Hu, F. 2019
Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and... Show moreMutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GCase), and is essential for proper GCase activity. GCase activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL. Show less
Windhorst, R.; Alpaslan, M.; Andrews, S.; Ashcraft, T.; Broadhurst, T.; Coe, D.; ... ; Zitrin, A. 2019
This book is a synchronic description of the syntax of Sarikoli, an Eastern Iranian and Pamir language spoken exclusively in China. It is the first modern linguistic description of Sarikoli... Show moreThis book is a synchronic description of the syntax of Sarikoli, an Eastern Iranian and Pamir language spoken exclusively in China. It is the first modern linguistic description of Sarikoli syntax in English. The approach is theory-neutral, presenting and describing language data with commonly-accepted linguistic terminology. It includes copious linguistic examples transcribed in IPA accompanied by morpheme glosses and free translations. The entire corpus of texts and all linguistic research were gathered and conducted in the field by the researcher in cooperation with native speakers of Sarikoli. The introductory chapter provides an overview of the Sarikoli people and language in their geographical, historical, and cultural context. The typological profile, sociolinguistic situation, and previous research conducted on the language are discussed, along with short summaries on phonology, morphology, and verbs. The following chapters focus on different topics in the syntax of Sarikoli: noun phrase, pronouns and demonstratives, possession, comparison, adverbial modifiers, mood, clause structure, negation, clause combinations, modality, and evidentiality and new information. The concluding chapter introduces routine phrases and expressions. The appendices include transcripts of oral texts covering a wide range of genre and topics, as well as an orthography proposed by a native Sarikoli scholar. Show less
