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Abstract Neural fingerprinting is a method to identify individuals from a group of people. Here, we established a new connectome-based identification model and used diffusion maps to show that biological parent–child couples share functional connectivity patterns while listening to stories. These shared fingerprints enabled the identification of children and their biological parents from a group of parents and children. Functional patterns were evident in both cognitive and sensory brain networks. Defining “typical” shared biological parent–child brain patterns may enable predicting or even preventing impaired parent–child connections that develop due to genetic or environmental causes. Finally, we argue that the proposed framework opens new opportunities to link similarities in connectivity patterns to behavioral, psychological, and medical phenomena among other populations. To our knowledge, this is the first study to reveal the neural fingerprint that represents distinct biological parent–child couples.

Anatomic knowledge of the internal auditory canal (IAC) and surrounding structures is a prerequisite for performing skull base approaches to the IAC. We herein perform a morphometric analysis of the IAC and surgically relevant aspects of the posterior petrous bone during pediatric maturation, a region well-studied in adults but not children. Measurements of IAC length (IAC-L), porus (IAC-D) and midpoint (IAC-DM) diameter, and distance from the porus to the common crus (CC; P-CC) and posterior petrosal surface (PPS) to the posterior semicircular canal (PSC; PPS-PSC) were made on thin-cut axial CT scans from 60 patients (grouped by ages 0-3, 4-7, 8-11 12-15, 16-18, and > 18 years). IAC-L increased 27.5% from 8.7 ± 1.1 at age 0-3 to 11.1 ± 1.1 mm at adulthood (p = 0.001), with the majority of growth occurring by ages 8-11. IAC-D (p = 0.52) and IAC-DM (p = 0.167) did not significantly change from ages 0-3 to adult. P-CC increased 31.1% from 7.7 ± 1.5 at age 0-3 to 10.1 ± 1.5 mm at adulthood (p = 0.019). PPS-PSC increased 160% from 1.5 ± 0.7 at age 0-3 to 3.9 ± 1.2 mm at adulthood (p

An accurate urine test for diverse populations with active tuberculosis could be transformative for preventing TB deaths. Urinary liporabinomannan (LAM) testing has been previously restricted to HIV co-infected TB patients. In this study we evaluate urinary LAM in HIV negative, pediatric and adult, pulmonary and extrapulmonary tuberculosis patients. We measured 430 microbiologically confirmed pretreatment tuberculosis patients and controls from Peru, Guinea Bissau, Venezuela, Uganda and the United States using three monoclonal antibodies, MoAb1, CS35, and A194, which recognize distinct LAM epitopes, a one-sided immunoassay, and blinded cohorts. We evaluated sources of assay variability and comorbidities (HIV and diabetes). All antibodies successfully discriminated TB positive from TB negative patients. ROAUC from the average of three antibodies' responses was 0.90; 95% CI 0.87-0.93, 90% sensitivity, 73.5% specificity (80 pg/mL). MoAb1, recognizing the 5-methylthio-D-xylofuranose(MTX)-mannose(Man) cap epitope, performed the best, was less influenced by glycosuria and identified culture positive pediatric (N = 19) and extrapulmonary (N = 24) patients with high accuracy (ROAUC 0.87, 95% CI 0.77-0.98, 0.90 sensitivity 0.80 specificity at 80 pg/mL; ROAUC = 0.96, 95% CI 0.92-0.99, 96% sensitivity, 80% specificity at 82 pg/mL, respectively). The MoAb1 antibody, recognizing the MTX-Man cap epitope, is a novel analyte for active TB detection in pediatric and extrapulmonary disease.

Abstract Bacillus subtilis biofilms are well known for their complex and highly adaptive morphology. Indeed, their phenotypical diversity and intra-biofilm heterogeneity make this gram-positive bacterium the subject of many scientific papers on the structure of biofilms. The “robustness” of biofilms is a term often used to describe their level of susceptibility to antimicrobial agents and various mechanical and molecular inhibition/eradication methods. In this paper, we use computational analytics to quantify Bacillus subtilis morphological response to proximity to an antimicrobial source, in the form of the antiseptic chlorhexidine. Chlorhexidine droplets, placed in proximity to Bacillus subtilis macrocolonies at different distances result in morphological changes, quantified using Python-based code, which we have made publicly available. Our results quantify peripheral and inner core deformation as well as differences in cellular viability of the two regions. The results reveal that the inner core, which is often characterized by the presence of wrinkled formations in the macrocolony, is more preserved than the periphery. Furthermore, the paper describes a crescent-shaped colony morphology which occurs when the distance from the chlorhexidine source is 0.5 cm, as well as changes observed in the growth substrate of macrocolonies exposed to chlorhexidine.

Abstract Progesterone receptor (PR) transcriptional activity is a key factor in the differentiation of the uterine endometrium. By consequence, progestin has been identified as an important treatment modality for endometrial cancer. PR transcriptional activity is controlled by extracellular-signal-regulated kinase (ERK) mediated phosphorylation, downstream of growth factor receptors such as EGFR. However, phosphorylation of PR also targets it for ubiquitination and destruction in the proteasome. Quantitative studies of these opposing roles are much needed toward validation of potential new progestin-based therapeutics. In this work, we propose a spatial stochastic model to study the effects of the opposing roles for PR phosphorylation on the levels of active transcription factor. Our numerical simulations confirm earlier in vitro experiments in endometrial cancer cell lines, identifying clustering as a mechanism that amplifies the ability of progesterone receptors to influence gene transcription. We additionally show the usefulness of a statistical method we developed to quantify and control variations in stochastic simulations in general biochemical systems, assisting modelers in defining minimal but meaningful numbers of simulations while guaranteeing outputs remain within a pre-defined confidence level.

Abstract Extrusion-based printing enables simplified and economic manufacturing of surgical guides for oral implant placement. Therefore, the cytotoxicity of a biocopolyester (BE) and a polypropylene (PP), intended for the fused filament fabrication of surgical guides was evaluated. For comparison, a medically certified resin based on methacrylic esters (ME) was printed by stereolithography (n = 18 each group). Human gingival keratinocytes (HGK) were exposed to eluates of the tested materials and an impedance measurement and a tetrazolium assay (MTT) were performed. Modulations in gene expression were analyzed by quantitative PCR. One-way ANOVA with post-hoc Tukey tests were applied. None of the materials exceeded the threshold for cytotoxicity (

Abstract Inflammation is an essential process as a reaction towards infections or wounding. Exposure to hazardous environmental pollutants can lead to chronic inflammations, where the resolving phase is delayed or blocked. Very contradictory studies have been reported on the pro- and anti-inflammatory effects of humic substances (HSs) leading to significant disagreements between researchers. To a certain extent, this can be attributed to the chemical heterogeneity of this group of xenobiotics. Here we show for the first time that pro- and anti-inflammatory effects can occur by one HSs. We adapted an assay that uses green fluorescence-labeled zebrafish larvae and CuSO4 to indue an inflammation. In wild-type larvae, exposure to 50 µM CuSO4 for 2 h activated the production of reactive oxygen species, which can be monitored with a fluorescence dye (H2DCFDA) and a microplate reader. This allows not only the use of wild-type fish but also a temporal separation of copper exposure and inflammatory substance while retaining the high throughput. This modified assay was then used to evaluate the inflammatory properties of a fulvic acid (FA). We found, that the aromatic structure of the FA protects from inflammation at 5 and 50 mg C/L, while the persistent free radicals enhance the copper-induced inflammation at ≥ 300 mg C/L.

Abstract Anatomic knowledge of the internal auditory canal (IAC) and surrounding structures is a prerequisite for performing skull base approaches to the IAC. We herein perform a morphometric analysis of the IAC and surgically relevant aspects of the posterior petrous bone during pediatric maturation, a region well-studied in adults but not children. Measurements of IAC length (IAC-L), porus (IAC-D) and midpoint (IAC-DM) diameter, and distance from the porus to the common crus (CC; P-CC) and posterior petrosal surface (PPS) to the posterior semicircular canal (PSC; PPS-PSC) were made on thin-cut axial CT scans from 60 patients (grouped by ages 0–3, 4–7, 8–11 12–15, 16–18, and > 18 years). IAC-L increased 27.5% from 8.7 ± 1.1 at age 0–3 to 11.1 ± 1.1 mm at adulthood (p = 0.001), with the majority of growth occurring by ages 8–11. IAC-D (p = 0.52) and IAC-DM (p = 0.167) did not significantly change from ages 0–3 to adult. P-CC increased 31.1% from 7.7 ± 1.5 at age 0–3 to 10.1 ± 1.5 mm at adulthood (p = 0.019). PPS-PSC increased 160% from 1.5 ± 0.7 at age 0–3 to 3.9 ± 1.2 mm at adulthood (p

Abstract Previously published sub-site Australian projections for colon and rectal cancers to 2035 using the World Health Organization’s mortality database sourced from the Australian Bureau of Statistics (ABS) predicted mortality rate decreases for colon cancer and increases for rectal cancer. There are complexities related to the interpretation of ABS’s Australian colon and rectal cancer mortality rates, which could lead to possible inaccuracies in mortality rates for these sub-sites. The largest Australian population-wide registry, New South Wales Cancer Registry (NSWCR), compares routinely-reported causes of death with the recorded medical history from multiple data sources. Therefore, this study used the NSWCR data to project mortality rates for colon and rectal cancers separately to 2040 in Australia. The mortality rates for colon cancer are projected to continuously decline over the period 2015–2040, from 7.0 to 4.7 per 100,000 males, and from 5.3 to 3.2 per 100,000 females. Similar decreasing trends in mortality rates for rectal cancer were projected over the period 2015–2040, from 4.9 to 3.7 per 100,000 males, and from 2.6 to 2.3 per 100,000 females. These projections provide benchmark estimates for the colorectal cancer burden in Australia against which the effectiveness of cancer control interventions can be measured.

Abstract Young people worldwide face new challenges as climate change and complex family structures disrupt societies. These challenges impact on youth’s subjective well-being, with evidence of decline across many countries. While the burden of negative well-being on productivity is widely examined amongst adults, its cost among youth remains understudied. The current research comprehensively investigates the relationship between youth subjective well-being and standardized academic test scores. We use highly controlled machine learning models on a moderately-sized high-school student sample (N ~ 3400), with a composite subjective well-being index (composed of depression, anxiety and positive affect), to show that students with greater well-being are more likely to have higher academic scores 7–8 months later (on Numeracy: β* = .033, p = .020). This effect emerges while also accounting for previous test scores and other confounding factors. Further analyses with each well-being measure, suggests that youth who experience greater depression have lower academic achievement (Numeracy: β* = − .045, p = .013; Reading: β* = − .033, p = .028). By quantifying the impact of youth well-being, and in particular of lowering depression, this research highlights its importance for the next generation's health and productivity.

Abstract Saliva is an attractive sample for coronavirus disease 2019 testing due its ease of collection and amenability to detect viral RNA with minimal processing. Using a direct-to-RT-PCR method with saliva self-collected from confirmed COVID-19 positive volunteers, we observed 32% false negative results. Confirmed negative and healthy volunteer samples spiked with 106 genome copies/mL of heat-inactivated severe acute respiratory syndrome coronavirus 2 showed false negative results of 10% and 13%, respectively. Additional sample heating or dilution of the false negative samples conferred only modest improvements. These results highlight the potential to significantly underdiagnose COVID-19 infections when testing directly from minimally processed heterogeneous saliva samples.

Abstract Hyperinvariant tensor networks (hyMERA) were introduced as a way to combine the successes of perfect tensor networks (HaPPY) and the multiscale entanglement renormalization ansatz (MERA) in simulations of the AdS/CFT correspondence. Although this new class of tensor network shows much potential for simulating conformal field theories arising from hyperbolic bulk manifolds with quasiperiodic boundaries, many issues are unresolved. In this manuscript we analyze the challenges related to optimizing tensors in a hyMERA with respect to some quasiperiodic critical spin chain, and compare with standard approaches in MERA. Additionally, we show two new sets of tensor decompositions which exhibit different properties from the original construction, implying that the multitensor constraints are neither unique, nor difficult to find, and that a generalization of the analytical tensor forms used up until now may exist. Lastly, we perform randomized trials using a descending superoperator with several of the investigated tensor decompositions, and find that the constraints imposed on the spectra of local descending superoperators in hyMERA are compatible with the operator spectra of several minimial model CFTs.

Abstract Plasma-treatment of oral implant biomaterials prior to clinical insertion is envisaged as a potential surface modification method for enhanced implant healing. To investigate a putative effect of plasma-functionalized implant biomaterials on oral tissue cells, this investigation examined the response of alveolar bone osteoblasts and gingival fibroblasts to clinically established zirconia- and titanium-based implant surfaces for bone and soft tissue integration. The biomaterials were either functionalized with oxygen-plasma in a plasma-cleaner or left untreated as controls, and were characterized in terms of topography and wettability. For the biological evaluation, the cell adhesion, morphogenesis, metabolic activity and proliferation were examined, since these parameters are closely interconnected during cell-biomaterial interaction. The results revealed that plasma-functionalization increased implant surface wettability. The magnitude of this effect thereby depended on surface topography parameters and initial wettability of the biomaterials. Concerning the cell response, plasma-functionalization of smooth surfaces affected initial fibroblast morphogenesis, whereas osteoblast morphology on rough surfaces was mainly influenced by topography. The plasma- and topography-induced differential cell morphologies were however not strong enough to trigger a change in proliferation behaviour. Hence, the results indicate that oxygen plasma-functionalization represents a possible cytocompatible implant surface modification method which can be applied for tailoring implant surface wettability.

Abstract We report on a multi-technique analysis using publicly available data for investigating the huge, accidental explosion that struck the city of Beirut, Lebanon, on August 4, 2020. Its devastating shock wave led to thousands of injured with more than two hundred fatalities and caused immense damage to buildings and infrastructure. Our combined analysis of seismological, hydroacoustic, infrasonic and radar remote sensing data allows us to characterize the source as well as to estimate the explosive yield. The latter is determined within 0.13 to 2 kt TNT (kilotons of trinitrotoluene). This range is plausible given the reported 2.75 kt of ammonium nitrate as explosive source. As there are strict limitations for an on-site analysis of this catastrophic explosion, our presented approach based on data from open accessible global station networks and satellite missions is of high scientific and social relevance that furthermore is transferable to other explosions.

β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of β1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.

Abstract Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

Abstract Transcranial direct current stimulation (tDCS) is a promising tool to enhance cognitive performance. However, its effectiveness has not yet been unequivocally shown. Thus, here we tested whether coupling tDCS with a bout of aerobic exercise (AE) is more effective in modulating cognitive functions than tDCS or AE alone. One hundred twenty-two healthy participants were assigned to five randomized controlled crossover experiments. Two multimodal target experiments (EXP-4: anodal vs. sham tDCS during AE; EXP-5: cathodal vs. sham tDCS during AE) investigated whether anodal (a-tDCS) or cathodal tDCS (c-tDCS) applied during AE over the left dorsolateral prefrontal cortex (left DLPFC) affects executive functioning (inhibition ability). In three unimodal control experiments, the participants were either stimulated (EXP-1: anodal vs. sham tDCS, EXP-2: cathodal vs. sham tDCS) or did AE (EXP-3: AE vs. active control). Participants performed an Eriksen flanker task during ergometer cycling at moderate intensity (in EXP. 3-5). Only c-tDCS during AE had a significant adverse effect on the inhibition task, with decreased accuracy. This outcome provides preliminary evidence that c-tDCS during AE over the left DLPFC might effectively modulate inhibition performance compared to c-tDCS alone. However, more systematic research is needed in the future.

Abstract Antibiotic resistance is a serious public health problem throughout the world. Overcoming methicillin and multidrug-resistant Staphylococcus aureus (MRSA/MDRSA) infections has become a challenge and there is an urgent need for new therapeutic approaches. We have previously demonstrated that the endocannabinoid Anandamide (AEA) can sensitize MRSA to antibiotics. Here we have studied the mechanism of action using a MDRSA clinical isolate that are sensitized by AEA to methicillin and norfloxacin. We found that AEA treatment halts the growth of both antibiotic-sensitive and antibiotic-resistant S. aureus. The AEA-treated bacteria become elongated and the membranes become ruffled with many protrusions. AEA treatment also leads to an increase in the percentage of bacteria having a complete septum, suggesting that the cell division is halted at this stage. The latter is supported by cell cycle analysis that shows an accumulation of bacteria in the G2/M phase after AEA treatment. We further observed that AEA causes a dose-dependent membrane depolarization that is partly relieved upon time. Nile red staining of the bacterial membranes indicates that AEA alters the membrane structures. Importantly, 4′-6-diamidino-2-phenylindole (DAPI) accumulation assay and ethidium bromide efflux (EtBr) assay unveiled that AEA leads to a dose-dependent drug accumulation by inhibiting drug efflux. In conclusion, our study demonstrates that AEA interferes with cell division, alters the membrane properties of MDRSA, and leads to increased intracellular drug retention, which can contribute to the sensitization of MDRSA to antibiotics.

Abstract Allogenic transplants of the cornea are prone to rejection, especially in repetitive transplantation and in scarred or highly vascularized recipient sites. Patients with these ailments would particularly benefit from the possibility to use non-immunogenic decellularized tissue scaffolds for transplantation, which may be repopulated by host cells in situ or in vitro. So, the aim of this study was to develop a fast and efficient decellularization method for creating a human corneal extracellular matrix scaffold suitable for repopulation with human cells from the corneal limbus. To decellularize human donor corneas, sodium deoxycholate, deoxyribonuclease I, and dextran were assessed to remove cells and nuclei and to control tissue swelling, respectively. We evaluated the decellularization effects on the ultrastructure, optical, mechanical, and biological properties of the human cornea. Scaffold recellularization was studied using primary human limbal epithelial cells, stromal cells, and melanocytes in vitro and a lamellar transplantation approach ex vivo. Our data strongly suggest that this approach allowed the effective removal of cellular and nuclear material in a very short period of time while preserving extracellular matrix proteins, glycosaminoglycans, tissue structure, and optical transmission properties. In vitro recellularization demonstrated good biocompatibility of the decellularized human cornea and ex vivo transplantation revealed complete epithelialization and stromal repopulation from the host tissue. Thus, the generated decellularized human corneal scaffold could be a promising biological material for anterior corneal reconstruction in the treatment of corneal defects.

Abstract Early life stress disrupts growth and creates horizontal grooves on the tooth surface in humans and other mammals, yet there is no consensus for their quantitative analysis. Linear defects are considered to be nonspecific stress indicators, but evidence suggests that intermittent, severe stressors create deeper defects than chronic, low-level stressors. However, species-specific growth patterns also influence defect morphology, with faster-growing teeth having shallower defects at the population level. Here we describe a method to measure the depth of linear enamel defects and normal growth increments (i.e., perikymata) from high-resolution 3D topographies using confocal profilometry and apply it to a diverse sample of Homo neanderthalensis and H. sapiens anterior teeth. Debate surrounds whether Neanderthals exhibited modern human-like growth patterns in their teeth and other systems, with some researchers suggesting that they experienced more severe childhood stress. Our results suggest that Neanderthals have shallower features than H. sapiens from the Upper Paleolithic, Neolithic, and medieval eras, mirroring the faster growth rates in Neanderthal anterior teeth. However, when defect depth is scaled by perikymata depth to assess their severity, Neolithic humans have less severe defects, while Neanderthals and the other H. sapiens groups show evidence of more severe early life growth disruptions.

Abstract Aquaculture has become imperative to cover the demands for dietary animal protein. Simultaneously, it has to overcome prejudices from excessive use of antibiotics and environmental impacts. Natural supplements are traditionally applied orally. In this study, we demonstrated another pathway: the gills. Humic substances are immunostimulants and a natural part of every aquatic ecosystem, making them ideal to be used as bath stimulants. Five and 50 mg C/L of a fulvic acid-rich humic substance was added for 28 days to the water of juvenile rainbow trout (Oncorhynchus mykiss). This fulvic acid is characterized by a high content of phenolic moieties with persistent free radicals and a high electron exchange capacity. The high concentration of the fulvic acid significantly increased growth and reduced the food conversion ratio and the response to a handling-stressor. Phagocytosis and potential killing activity of head kidney leukocytes were increased, as well as the total oxyradical scavenging capacity (TOSC) and lysozyme activity in the gills. In conclusion, immunostimulation via gills is possible with our fulvic acid, and the high phenolic content improved overall health and stress resistance of fish.

Abstract Exposures to cancer risk factors such as smoking and alcohol are not mutually independent. We aimed to identify risk factor exposure patterns and their associations with sociodemographic characteristics and cancer incidence. We considered 120,771 female and, separately, 100,891 male participants of the Australian prospective cohort 45 and Up Study. Factor analysis grouped 36 self-reported variables into 8 combined factors each for females (largely representing ‘smoking’, ‘alcohol’, ‘vigorous exercise’, ‘age at childbirth’, ‘Menopausal Hormone Therapy’, ‘parity and breastfeeding’, ‘standing/sitting’, ‘fruit and vegetables’) and males (largely representing ‘smoking’, ‘alcohol’, ‘vigorous exercise’, ‘urology and health’, ‘moderate exercise’, ‘standing/sitting’, ‘fruit and vegetables’, ‘meat and BMI’). Associations with cancer incidence were investigated using multivariable logistic regression (4–8 years follow-up: 6193 females, 8749 males diagnosed with cancer). After multiple-testing correction, we identified 10 associations between combined factors and cancer incidence for females and 6 for males, of which 14 represent well-known relationships (e.g. bowel cancer: females ‘smoking’ factor Odds Ratio (OR) 1.16 (95% Confidence Interval (CI) 1.08–1.25), males ‘smoking’ factor OR 1.15 (95% CI 1.07–1.23)), providing evidence for the validity of this approach. The catalogue of associations between exposure patterns, sociodemographic characteristics, and cancer incidence can help inform design of future studies and targeted prevention programmes.

Abstract In-vivo single cell clonal analysis in the adult mouse kidney has previously shown lineage-restricted clonal proliferation within varying nephron segments as a mechanism responsible for cell replacement and local regeneration. To analyze ex-vivo clonal growth, we now preformed limiting dilution to generate genuine clonal cultures from one single human renal epithelial cell, which can give rise to up to 3.4 * 106 cells, and analyzed their characteristics using transcriptomics. A comparison between clonal cultures revealed restriction to either proximal or distal kidney sub-lineages with distinct cellular and molecular characteristics; rapidly amplifying de-differentiated clones and a stably proliferating cuboidal epithelial-appearing clones, respectively. Furthermore, each showed distinct molecular features including cell-cycle, epithelial-mesenchymal transition, oxidative phosphorylation, BMP signaling pathway and cell surface markers. In addition, analysis of clonal versus bulk cultures show early clones to be more quiescent, with elevated expression of renal developmental genes and overall reduction in renal identity markers, but with an overlapping expression of nephron segment identifiers and multiple identity. Thus, ex-vivo clonal growth mimics the in-vivo situation displaying lineage-restricted precursor characteristics of mature renal cells. These data suggest that for reconstruction of varying renal lineages with human adult kidney based organoid technology and kidney regeneration ex-vivo, use of multiple heterogeneous precursors is warranted.

Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Abstract Bacteria in nature often reside in differentiated communities termed biofilms, which are an active interphase between uni-cellular and multicellular life states for bacteria. Here we demonstrate that the development of B. subtilis biofilms is dependent on the use of glutamine or glutamate as a nitrogen source. We show a differential metabolic requirement within the biofilm; while glutamine is necessary for the dividing cells at the edges, the inner cell mass utilizes lactic acid. Our results indicate that biofilm cells preserve a short-term memory of glutamate metabolism. Finally, we establish that drugs that target glutamine and glutamate utilization restrict biofilm development. Overall, our work reveals a spatial regulation of nitrogen and carbon metabolism within the biofilm, which contributes to the fitness of bacterial complex communities. This acquired metabolic division of labor within biofilm can serve as a target for novel anti-biofilm chemotherapies