Are we on the same page? Knowledge boundaries and transactive memory system development in cross-functional teams

One of the key challenges that organizations face when trying to integrate knowledge across different functions is the need to overcome knowledge boundaries between team members. In cross-functional teams, these boundaries, associated with different knowledge backgrounds of people from various disciplines, create communication problems, necessitating team members to engage in complex cognitive processes when integrating knowledge toward a joint outcome. This research investigates the impact of syntactic, semantic, and pragmatic knowledge boundaries on a team’s ability to develop a transactive memory system (TMS)—a collective memory system for knowledge coordination in groups. Results from our survey show that syntactic and pragmatic knowledge boundaries negatively affect TMS development. These findings extend TMS theory beyond the information-processing view, which treats knowledge as an object that can be stored and retrieved, to the interpretive and practice-based views of knowledge, which recognize that knowledge (in particular specialized knowledge) is localized, situated, and embedded in practice

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy

The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance

Payload Hardware and Experimental Protocol for Testing the Effect of Space Microgravity on the Resistance to Gentamicin of Stationary-Phase Uropathogenic Escherichia Coli and Its Sigma (sup S)-Deficient Mutant

Human immune response is compromised and bacteria can become more antibiotic resistant in space microgravity (MG). We report that under low-shear modeled microgravity (LSMMG) stationary-phase uropathogenic Escherichia coli (UPEC) become more resistant to gentamicin (Gm). UPEC causes urinary tract infections (UTIs), reported to afflict astronauts; Gm is a standard treatment, so these findings could impact astronaut health. Because LSMMG has been shown to differ from MG, we report here preparations to examine UPEC's Gm sensitivity during spaceflight using the E. coli Anti-Microbial Satellite (EcAMSat) on a free flying nanosatellite in low Earth orbit. Within EcAMSats payload, a 48-microwell fluidic card contains and supports study of bacterial cultures at constant temperature; optical absorbance changes in cell suspensions are made at three wavelengths for each microwell and a fluid-delivery system provides growth medium and predefined Gm concentrations. Performance characterization is reported for spaceflight prototypes of this payload system. Using conventional microtiter plates, we show that Alamar Blue (AB) absorbance changes due to cellular metabolism accurately reflect E. coli viability changes: measuring AB absorbance onboard EcAMSat will enable telemetry of spaceflight data to Earth. Laboratory results using payload prototypes are consistent with wellplate and flask findings of differential sensitivity of UPEC and its delta rpoS strain to Gm. Space MG studies using EcAMSat should clarify inconsistencies from previous space experiments on bacterial antibiotic sensitivity. Further, if sigma (sup s) plays the same role in space MG as in LSMMG and Earth gravity, EcAMSat results would facilitate utilizing our previously developed terrestrial UTI countermeasures in astronauts

SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis

Background: Although the use of proliferation markers/profiles has been recommended when choosing the appropriate systemic-treatment for breast cancer (BC), the best molecular-marker/test that should be used needs to be identified. Methods: To identify factors that drive proliferation and its associated features in BC an artificial neural network (ANN) based integrative data-mining methodology was applied to three cohorts [(Nottingham-discovery (ND), Uppsala and METABRIC (Molecular Taxonomy of Breast Cancer International Consortium)]. The most prominent genes in the resulting interactome-map were then identified. Given that SPAG5 was associated with many features of proliferation, featured prominently in the interactome-map and has a fundamental role in mitotic-progression,, we hypothesized that it could be a better indicator of proliferation activity. (BC). Subsequently to test if it could provide a more accurate guide for the delivery of systemic therapies in BC, we investigated the clinico-pathological utility of SPAG5: gene copy number aberrations (CNAs); mRNA and protein expression, in over 10,000 BCs. Integrated analysis of SPAG5-gene CNAs, transcript and protein expression was conducted in the ND cohort (n=171) and validated in the METABRIC cohort (n=1980). In addition, the associations of SPAG5 CNAs, transcript and/or protein with BC specific survival (BCSS), disease free survival (DFS) and/or distant relapse free survival (DRFS) were analysed in multiple cohorts including Uppsala (n=249), METABRIC, three-untreated lymph node (LN) negative cohorts (n=684), a combined multicentre clinical data set (n=5439), Nottingham historical early-stage-primary BC (Nottingham-HES-BC; n=1650), Nottingham oestrogen receptor (ER) negative BC (n=697), Nottingham anthracycline-Neoadjuvant-chemotherapy (Nottingham-AC-Neo-ACT; n=200), and MD Anderson Cancer Centre Taxane/anthracycline (MDACC-T/AC-Neo-ACT; n=508) cohorts. The association of SPAG5 transcript and protein expression with pathological response rate (pCR) were also tested in [MDACC-T/AC-Neo-ACT (n=508) and the phase II trial NCT00455533; n=253)] and [Nottingham-AC-Neo-ACT (n=200)] cohorts; respectively. Findings: SPAG5 gene gain/amplification at the Ch17q11·2 locus was found in 10.4% of BC (206/1980 (; METABRIC) and was reported in 19·4% of PAM50-HER2 (46/237) and 17·8% of PAM50-LumB (87/488). SPAG5-CNA gain/amplification and high SPAG5-transcript and SPAG5-protein were associated with increased risk of death from BC [Uppsala; (HR (CI 95%): 1·50 (1·18-1·92); p=0·00010, METABRIC; (HR (CI 95%): 1·68 (1·40-2·01) p<0·0001), and Nottingham-HSE-BC; (HR (CI 95%): 1·68 (1·32-2·12), p<0·0001); respectively]. Multivariable Cox regression models, including other validated-prognostic factors, (Uppsala: age, size, LN-stage, genomic grade index (GGI), ER, TP53 mutation and MKi67; METABRIC: age, size, LN-stage, histologic-grade, ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), hormone-therapy, chemotherapy, interaction term of SPAG5 and both chemotherapyy and hormonotherapy; Desmedt-untreated LN- cohort: ER, Nottingham prognostic index (NPI), 76-gene prognostic signature (Veridex) and Adjuvant-Online (AOL); Nottingham-HES-BC: menopausal status, size, LN- stage, histologic-grade, ER, PR, HER2, ki67, hormone-therapy, chemotherapy, interaction term of SPAG5 and both chemotherapy[y and hormonotherapy), showed that high SPAG5-transcript and high SPAG5-protein were associated with shorter BCSS [Uppsala: (HR (CI 95%): 1·62 (1·03-2·53) p=0·036); METABRIC: (HR (CI 95%): 1·27 (1·02-1·58) p=0·034); Desmedt-untreated LN- cohort: (HR (CI 95%): 2·34 (1·24-4·42) p=0·0090), and Nottingham-HES-BC (HR (CI 95%): 1·73 (1·23-2·46) p=0·0020); respectively]. In ER-negative-BC with high SPAG5-protein, administration of anthracycline-adjuvant-chemotherapy had reduced the risk of death by 60% compared to chemotherapy-naive (HR (95% CI): 0·37 (0·20-0·60); p=0·0010). A multivariable Cox regression analysis, which included other validated prognostic factors for chemotherapy (e.g., menopausal status, size, lymph node stage, histologic grade, ER, PR, HER2, Bcl2, chemotherapy, interaction term of SPAG5 and both chemotherapy[y), revealed that SPAG5-transcript+ was independently associated with decreased risk of DRFS after receiving Taxane/anthracycline-Neo-ACT [MDACC-T/AC-Neo-ACT: (HR (CI 95%): 0·68 (0·48-0·97); p=0·0070)]. In multivariable logistic regression analysis, both SPAG5-transcript+ and SPAG5-protein+ and were independent predictors for higher pCR after combination-cytotoxic chemotherapy [MDACC-T/AC-Neo-ACT: (OR (95% CI) 1·71 (1·07-2·74); p=0·024), and Nottingham-AC-Neo-AC: (OR (95% CI): 8·75 (2·42-31); p=0·0010); respectively]. Interpretation: SPAG5 is a novel amplified gene on Ch17q11.2 in PAM50-LumB and PAM-HER2 BC, and its transcript and protein products are independent prognostic and predictive biomarkers, with potential clinical utility as a biomarker for combination cytotoxic chemotherapy sensitivity, especially in ER- BC

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.Funding support for this project was obtained from the European Research Council (project number 250157) and BGI. The study was also supported by TwinsUK, which is funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007-2013); and also receives support from the National Institute for Health Research (NIHR) BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas' NHS Foundation Trust and King’s College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. M.M. is the holder of Wellcome Trust Senior Investigator Award (Wellcome 098381). T.D.S. is the holder of an ERC Advanced Principal Investigator award (ERC 250157). A.P.M. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Skeletal muscle 450k methylation project is supported by European Community's Seventh Framework Programme (FP7/2007-2013) under DEXLIFE project (grant agreement no. HEALTH-F2-2011-279228)

Interdisciplinary views of fNIRS: Current advancements, equity challenges, and an agenda for future needs of a diverse fNIRS research community

Functional Near-Infrared Spectroscopy (fNIRS) is an innovative and promising neuroimaging modality for studying brain activity in real-world environments. While fNIRS has seen rapid advancements in hardware, software, and research applications since its emergence nearly 30 years ago, limitations still exist regarding all three areas, where existing practices contribute to greater bias within the neuroscience research community. We spotlight fNIRS through the lens of different end-application users, including the unique perspective of a fNIRS manufacturer, and report the challenges of using this technology across several research disciplines and populations. Through the review of different research domains where fNIRS is utilized, we identify and address the presence of bias, specifically due to the restraints of current fNIRS technology, limited diversity among sample populations, and the societal prejudice that infiltrates today's research. Finally, we provide resources for minimizing bias in neuroscience research and an application agenda for the future use of fNIRS that is equitable, diverse, and inclusive

GOBO: Gene Expression-Based Outcome for Breast Cancer Online

Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo), allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1) rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2) identification of co-expressed genes for creation of potential metagenes, 3) association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881-sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies