Search

ABSTRACTAlthough macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3deletion in pink1knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7KO mice showed significantly lower expression of Nlrp3in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.Abbreviations:ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.

IMPORTANCE: Use of cannulas with long and narrow tubing (CLNT) has gained increasing popularity for applying noninvasive respiratory support for newborn infants thanks to ease of use, perceived patient comfort, and reduced nasal trauma. However, there is concern that this interface delivers reduced and suboptimal support. OBJECTIVE: To determine whether CLNT is noninferior to short binasal prongs and masks (SPM) when providing nasal intermittent positive pressure ventilation (NIPPV) in preterm infants. DESIGN, SETTING, AND PARTICIPANTS: This randomized controlled, unblinded, prospective noninferiority trial was conducted between December 2017 and December 2019 at 2 tertiary neonatal intensive care units. Preterm infants born between 24 weeks’ and 33 weeks and 6 days’ gestation were eligible if presented with respiratory distress syndrome with the need for noninvasive ventilatory support either as initial treatment after birth or after first extubation. Analysis was performed by intention to treat. INTERVENTIONS: Randomization to NIPPV with either CLNT or SPM interface. MAIN OUTCOMES AND MEASURES: The primary outcome was the need for intubation within 72 hours after NIPPV treatment began. Noninferiority margin was defined as 15% or less absolute difference. RESULTS: Overall, 166 infants were included in this analysis, and infant characteristics and clinical condition (including fraction of inspired oxygen, Pco2, and pH level) were comparable at recruitment in the CLNT group (n = 83) and SPM group (n = 83). The mean (SD) gestational age was 29.3 (2.2) weeks vs 29.2 (2.5) weeks, and the mean (SD) birth weight was 1237 (414) g vs 1254 (448) g in the CLNT and SPM groups, respectively. Intubation within 72 hours occurred in 12 of 83 infants (14%) in the CLNT group and in 15 of 83 infants (18%) in the SPM group (risk difference, −3.6%; 95% CI, −14.8 to 7.6 [within the noninferiority margin], χ2 P = .53). Moderate to severe nasal trauma was significantly less common in the CLNT group compared with the SPM group (4 [5%] vs 14 [17%]; P = .01). There were no differences in other adverse events or in the course during hospitalization. CONCLUSIONS AND RELEVANCE: In this study, CLNT was noninferior to SPM in providing NIPPV for preterm infants, while causing significantly less nasal trauma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03081611

After publication of this Article, the Authors noticed errors in some of the Figures. In Figures 2e, 2f–g, 4a, 4j, 5a and 6b, unmatched β-actin was inadvertently used as loading control for the immunoblots. These have been corrected using repeat data from a similar set of samples and the revised Figures containing matched β-actin and their respective quantification data are included below. In Figure 7a, the same image was inadvertently used to represent tumors 3 and 5 in the control group. This error has been corrected using original images of tumors 3 and 5 in the control group. Additional corrections have been made in the Article and Figure legends to enhance the clarity of the description. NAD was replaced by NADP. NAD/NADP was replaced by NADP/NADPH. The description of the antibody source and dilution for the antigens PFKFB4 (Abcam, 1:1000), G6PD, and HK1 (Cell Signaling, 1:1,000) have been included in the Methods section for Western Blot. The legend for Figure 4e and 4j has been updated. The HTML and PDF versions of this Article have been corrected. The scientific conclusions of this paper have not been affected.

Advanced Bladder Cancer (BLCA) remains a clinical challenge that lacks effective therapeutic measures. Here, we show that distinct, stage-wise metabolic alterations in BLCA are associated with the loss of function of aldehyde oxidase (AOX1). AOX1 associated metabolites have a high predictive value for advanced BLCA and our findings demonstrate that AOX1 is epigenetically silenced during BLCA progression by the methyltransferase activity of EZH2. Knockdown (KD) of AOX1 in normal bladder epithelial cells re-wires the tryptophan-kynurenine pathway resulting in elevated NADP levels which may increase metabolic flux through the pentose phosphate (PPP) pathway, enabling increased nucleotide synthesis, and promoting cell invasion. Inhibition of NADP synthesis rescues the metabolic effects of AOX1 KD. Ectopic AOX1 expression decreases NADP production, PPP flux and nucleotide synthesis, while decreasing invasion in cell line models and suppressing growth in tumor xenografts. Further gain and loss of AOX1 confirm the EZH2-dependent activation, metabolic deregulation, and tumor growth in BLCA. Our findings highlight the therapeutic potential of AOX1 and provide a basis for the development of prognostic markers for advanced BLCA.

Objective: To compare coronary flows between premature infants with and without hemodynamically significant patent ductus arteriosus (hsPDA) and to determine if coronary flow is influenced by medical PDA treatment. Design: Prospective, observational pilot study. Forty-three infants <32 weeks gestation underwent echocardiography when routinely indicated. Study group included infants with hsPDA requiring treatment. Comparison groups included infants with nonsignificant PDA and infants without PDA. Results: The study group (n= 13), compared with the comparison groups with nonsignificant PDA (n= 12) and without PDA (n= 18) had higher troponin levels (p= 0.003 and 0.004, respectively). In infants with hsPDA compared with infants with no PDA there was a significant increase in myocardial oxygen demand and decrease in left main coronary artery flow, with nonsignificant increase in cardiac output. Conclusions: Decrease in coronary artery flows and higher troponin values may suggest a “steal effect,” not allowing to meet the elevated myocardial oxygen demand in infants with hsPDA.

Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg’s original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.

ABSTRACTIt is through the collective work of museum educators that an organization grows its social capital in its local community and beyond its physical footprint. Given the significant contributions of museum educators to an institution’s outcomes, we argue for a shift in mindset on investing in their growth and development. We share our reasoning for this change through our experiences from the Reflecting on Practiceprogram. Two leaders in our community offer their reflections on why they took this leap of faith and the outcomes 5–10 years since their first step.

A variety of large datasets, such as social networks or biological data, can be represented as graphs. A common query in graph analysis is to identify the most important vertices in a graph. Centrality metrics are used to obtain numerical scores for each vertex in the graph. The scores are then translated to rankings identifying relative importance of vertices. In this work, we focus on Katz centrality, a linear algebra-based metric. In many real applications, since data are constantly being produced and changed, it is necessary to have a dynamic algorithm to update centrality scores with minimal computation when the graph changes. We present an algorithm for updating Katz centrality scores in a dynamic graph that incrementally updates the centrality scores as the underlying graph changes. Our proposed method exploits properties of iterative solvers to obtain updated Katz scores in dynamic graphs. Our dynamic algorithm improves performance and achieves speedups of over two orders of magnitude compared to a standard static algorithm while maintaining high quality of results.

The progression of tau pathology in Alzheimer’s disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer’s disease.

Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves−/−mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves−/−mice inoculated with Citrobacter rodentiumhad greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves−/−mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. colishowed increased attaching/effacing lesions in the absence of BVES. Finally, BVESmRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.

Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves−/−mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves−/−mice inoculated with Citrobacter rodentiumhad greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves−/−mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. colishowed increased attaching/effacing lesions in the absence of BVES. Finally, BVESmRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.

Many real-world datasets can be represented as graphs. Using iterative solvers to approximate graph centrality measures allows us to obtain a ranking vector on the nodes of the graph, consisting of a number for each vertex in the graph identifying its relative importance. In this work the centrality measures we use are Katz Centrality and PageRank. Given an approximate solution, we use the residual to accurately estimate how much of the ranking matches the ranking given by the exact solution. Using probabilistic matrix norms, we obtain bounds on the accuracy of the approximation compared to the exact solution with respect to the highly ranked nodes and apply numerical analysis to the computation of centrality with iterative methods. This relates the numerical accuracy of the linear solver to the data analysis accuracy of finding the correct ranking. In particular, we answer the question of which pairwise rankings are reliable given an approximate solution to the linear system. Experiments on many real-world undirected and directed networks up to several million vertices and several hundred million edges validate our theory and show that we are able to accurately estimate large portions of the approximation. We also analyze the difference between global centrality scores and personalized scores (w.r.t. specific seed vertices). By analyzing convergence error, we develop confidence in the ranking schemes of data mining. We show we are able to accurately guarantee ranking of vertices with an approximation to centrality metrics faster than current methods. [ABSTRACT FROM AUTHOR]

Many common methods for data analysis rely on linear algebra. We provide new results connecting data analysis error to numerical accuracy in the context of spectral graph partitioning. We provide pointwise convergence guarantees so that spectral blends (linear combinations of eigenvectors) can be employed to solve data analysis problems with confidence in their accuracy. We apply this theory to an accessible model problem, the ring of cliques, by deriving the relevant eigenpairs and finding necessary and sufficient solver tolerances. Analysis of the ring of cliques provides an upper bound on eigensolver tolerances for graph partitioning problems. These results bridge the gap between linear algebra based data analysis methods and the convergence theory of iterative approximation methods. These results explain how the combinatorial structure of a problem can be recovered much faster than numerically accurate solutions to the associated linear algebra problem.

ObjectiveBlood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.DesignWe determined BVESpromoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVESmRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves−/−and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.ResultsBVESmRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVESpromoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bveswas underexpressed in experimental inflammatory carcinogenesis, and Bves−/−mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves−/−tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.ConclusionLoss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVESpromoter methylation status may serve as a CAC biomarker.

A variety of massive datasets, such as social networks and biological data, are represented as graphs that reveal underlying connections, trends, and anomalies. Community detection is the task of discovering dense groups of vertices in a graph. Its one specific form is seed set expansion, which finds the best local community for a given set of seed vertices. Greedy, agglomerative algorithms, which are commonly used in seed set expansion, have been previously designed only for a static, unchanging graph. However, in many applications, new data are constantly produced, and vertices and edges are inserted and removed from a graph. We present an algorithm for dynamic seed set expansion, which maintains a local community over time by incrementally updating as the underlying graph changes. We show that our dynamic algorithm outputs high-quality communities that are similar to those found when using a standard static algorithm. It works well both when beginning with an already existing graph and in the fully streaming case when starting with no data. The dynamic approach is also faster than re-computation when low latency updates are needed.

Genetic deletion of one microtubule-binding domain in CENP-F results in multiple cellular changes, including changes in cell migration, adhesion, and cilia formation. All of these changes are related to an increase in microtubule stabilization in CENP-F mutants. This suggests that CENP-F plays a role in microtubule organization outside of mitosis.

Blood vessel epicardial substance (BVES/Popdc1) is a junctional‐associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial‐to‐mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves–/–mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5compared to wild‐type (WT) mice. Intercross with Lgr5‐EGFP reporter mice confirmed expansion of the stem cell compartment in Bves–/–mice. To examine stem cell function after BVES deletion, we used ex vivo 3D‐enteroid cultures. Bves–/–enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt‐base columnar “CBC” and “+4” stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves–/–enteroids. Bvesexpression was downregulated after radiation in WT mice. Moreover, after radiation, Bves–/–mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves–/–mice also demonstrated elevations in Lgr5and Ascl2expression, and putative damage‐responsive stem cell populations marked by Bmi1and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis. StemCells2016;34:1626–1636

Background:Necrotizing enterocolitis is rare in full-term infants, and is currently not considered a known complication of phototherapy.

Insulin resistance and type 2 diabetes mellitus (T2DM) result from an inability to efficiently store and catabolize surplus energy in adipose tissue. Subcutaneous adipocytes protect against insulin resistance and T2DM by coupling differentiation with the induction of brown fat gene programs for efficient energy metabolism. Mechanisms that disrupt these programs in adipocytes are currently poorly defined, but represent therapeutic targets for the treatment of T2DM. To gain insight into these mechanisms, we performed a high-throughput microscopy screen that identified ubiquitin carrier protein 9 (Ubc9) as a negative regulator of energy storage in human sc adipocytes. Ubc9 depletion enhanced energy storage and induced the brown fat gene program in human sc adipocytes. Induction of adipocyte differentiation resulted in decreased Ubc9 expression commensurate with increased brown fat gene expression. Thiazolidinedione treatment reduced the interaction between Ubc9 and peroxisome proliferator-activated receptor (PPAR)γ, suggesting a mechanism by which Ubc9 represses PPARγ activity. In support of this hypothesis, Ubc9 overexpression remodeled energy metabolism in human sc adipocytes by selectively inhibiting brown adipocyte-specific function. Further, Ubc9 overexpression decreased uncoupling protein 1 expression by disrupting PPARγ binding at a critical uncoupling protein 1 enhancer region. Last, Ubc9 is significantly elevated in sc adipose tissue isolated from mouse models of insulin resistance as well as diabetic and insulin-resistant humans. Taken together, our findings demonstrate a critical role for Ubc9 in the regulation of sc adipocyte energy homeostasis.

AbstractObjective:This study explored clinical implications of tongue-tie (TT) on breastfeeding from the mothers' perspective and evaluated the assistance provided.Materials and Methods:This was a single-center observational study using a structured survey. All newborns with TT born in 2005–2010 were identified; two controls without TT were assigned for each. Mothers were interviewed using a uniform structured questionnaire regarding breastfeeding experience, challenges, lactation consultation, and frenotomy, if performed.Results:One hundred eighty-three TT mothers and 314 controls were interviewed. Although the overall rates of breastfeeding problems in the first month were similar (59% vs. 52%, respectively), TT mothers reported significantly more problems with latching, prolonged breastfeeding, and infant's exhaustion during feedings, but not pain or sore nipples. Breastfeeding rates at 6 months were similar. TT mothers more frequently used pumped breastmilk to supplement breastfeeding. Significantly more TT mothers sought consultation after discharge, and a significantly greater proportion of them felt that lactation consultation helped. Eighty-seven percent of the mothers were aware of their children's TT, yet only 50% associated it with breastfeeding problems. Of the TT infants at 2 years of age or older, 11.9% were reported to have speech problems. The possibility of frenotomy was mentioned to 69% of mothers, and it was performed in 35% of cases. Procedure satisfaction was generally poor, except for when done to solve breastfeeding problems.Conclusions:TT infants had significantly more breastfeeding problems in the first month, but similar rates and durations of breastfeeding. Early diagnosis and lactation consultation may assist mother–infant dyads substantially. Mothers whose infants underwent frenotomies for breastfeeding more frequently found the procedure alleviated breastfeeding problems.

Genossenschaftsbanken sind seit dem Ausbruch der Finanzkrise von besonders umfassenden Regulierung(sbestrebung)en betroffen. Ein Schwerpunkt liegt hierbei auf den eingerichteten Vergütungssystemen; die Vorgaben erstrecken sich gleichsam über deren Ausgestaltung wie die Berichterstattung über diese. Eine Gegenüberstellung dieser Regulierung mit den genossenschaftlichen Spezifika hinsichtlich Governance-Fragen und daraus abgeleiteten Einsatzbedingungen erfolgsbasierter Vergütungssysteme zeigt hier jedoch ins Leere gehende Bestimmungen bzw. unbeantwortete Fragen. Die zweckmäßige Ausgestaltung erfolgsbasierter Vergütungssysteme im Genossenschaftskontext erfordert ein hohes Maß an konzeptioneller Sorgfalt und kann nicht unmittelbar aus dem Rahmen für börsennotierte Unternehmen abgeleitet werden.

The Bves and NDRG4 proteins interact to regulate directional cell movement by mediating cell surface fusion of internalized fibronectin for resecretion. This provides the first evidence of Bves/NDRG4 protein function within subcellular trafficking pathways and explains how the Bves complex diversely influences development, cancer, and repair.

Palmitic acid (PA) constitutes 17 to 25 of the human milk fatty acids, and ∼70 is esterified in the sn-2 position of triglycerides (-palmitate). In the sn-2 position, PA is not hydrolyzed and thus is efficiently absorbed. The PA in palm oils, commonly used in infant formulas, is esterified in the sn-1 and sn-3 positions. In these positions, PA is hydrolyzed and forms poorly absorbed calcium complexes. The present study assessed whether high -palmitate in infant formulas affects the intestinal flora.

Palmitic acid (PA) constitutes 17% to 25% of the human milk fatty acids, and ~70% is esterified in the sn-2 position of triglycerides (ß-palmitate). In the sn-2 position, PA is not hydrolyzed and thus is efficiently absorbed. The PA in palm oils, commonly used in infant formulas, is esterified in the sn-1 and sn-3 positions. In these positions, PA is hydrolyzed and forms poorly absorbed calcium complexes. The present study assessed whether high ß-palmitate in infant formulas affects the intestinal flora. Thirty-six term infants were enrolled: 14 breast-fed (BF group) and 22 formula-fed infants who were randomly assigned to receive formula containing high ß-palmitate (HBP group, n = 14), or low ß-palmitate (LBP group, n = 8), where 44% and 14% of the PA was ß-palmitate, respectively. The total amount of PA in the formulas was 19% and 22% in the LBP and HBP groups, respectively. Neither formula contained pre- or probiotics. Stool samples were collected at enrollment and at 6 weeks for the quantification of bacteria. At 6 weeks, the HBP and BF groups had higher Lactobacillusand bifidobacteria counts than the LBP group (P< 0.01). The Lactobacilluscounts at 6 weeks were not significantly different between the HBP and BF groups. Lactobacilluscounts were 1.2 × 1010, 1.2 × 1011, and 5.6 × 1010CFU/g for LBP, HBP, and BF groups, respectively. Bifidobacteria counts were 5.1 × 109, 1.2 × 1011, and 3.9 × 1010CFU/g for LBP, HBP, and BF groups, respectively. HBP formula beneficially affected infant gut microbiota by increasing the Lactobacillusand bifidobacteria counts in fecal stools.

Analyzing massive streaming graphs efficiently requires new algorithms, data structures, and computing platforms.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. During NEC pathogenesis, bacteria are able to penetrate innate immune defenses and invade the intestinal epithelial layer, causing subsequent inflammation and tissue necrosis. Normally, Paneth cells appear in the intestinal crypts during the first trimester of human pregnancy. Paneth cells constitute a major component of the innate immune system by producing multiple antimicrobial peptides and proinflammatory mediators. To better understand the possible role of Paneth cell disruption in NEC, we quantified the number of Paneth cells present in infants with NEC and found that they were significantly decreased compared with age-matched controls. We were able to model this loss in the intestine of postnatal day (P)14-P16 (immature) mice by treating them with the zinc chelator dithizone. Intestines from dithizone-treated animals retained approximately half the number of Paneth cells compared with controls. Furthermore, by combining dithizone treatment with exposure to Klebsiella pneumoniae, we were able to induce intestinal injury and inflammatory induction that resembles human NEC. Additionally, this novel Paneth cell ablation model produces NEC-like pathology that is consistent with other currently used animal models, but this technique is simpler to use, can be used in older animals that have been dam fed, and represents a novel line of investigation to study NEC pathogenesis and treatment.

CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs.

OBJECTIVES To assess risk factors and develop a simple estimate method for poor neonatal outcomes for specific groups of extremely premature infants at birth. DESIGN Population-based study. SETTING Israel National Very Low Birth Weight Infant Database. PARTICIPANTS Infants born at 23 to 26 weeks' gestation between January 1, 1995, and December 31, 2008. INTERVENTION We developed a tool to estimate poor neonatal outcomes for infants born at 24 to 26 weeks' gestation (n = 2544) that incorporated factors at birth significantly associated with poor outcomes into a linear regression model. MAIN OUTCOME MEASURES Poor neonatal outcomes defined as the composite of mortality or severe neurologic or pulmonary morbidity at discharge from the hospital. RESULTS Major factors associated with poor outcomes at 24 to 26 weeks' gestation were gestational age, male sex, sex-specific birth weight percentile, and lack of prenatal steroid therapy. Estimated poor outcomes for January 1, 2000, to December 31, 2008, were calculated as the sum of the percentages determined for each of the 4 parameters: (1) gestational age (26, 25, and 24 weeks; 0%, 17%, and 34%, respectively), (2) birth weight percentile (>75th, 25th-75th, and &lt;25th percentiles; 0%, 13%, and 26%, respectively), (3) lack of prenatal steroids (16%), and (4) male sex (7%). There was also an intercept value of 25%. Estimated poor outcome rates for the 36 subgroups of infants ranged from 25% to 100% and correlated well with observed rates (intraclass correlation coefficient, 0.93). CONCLUSIONS The combined outcomes of deaths or severe morbidities in the neonatal period of infants born at 24 to 26 weeks' gestation could be simply estimated at birth. The provision of an appropriate and up-to-date estimate of poor neonatal outcomes for specific infants may be useful in counseling families on treatment options for these infants.

AbstractModern multicore and manycore systems have the strong potential to deliver both high performance and high power efficiency. The large variance in memory access latency, resource sharing, and the heterogeneity of processor architectures in modern multicore and manycore systems raise significant algorithm engineering challenges. In this article, we overview important algorithm engineering issues for modern multicore and manycore systems, and we present algorithm engineering techniques to address such problems as a guideline for practitioners.

Epicardial development is a process during which epithelial sheet movement, single cell migration, and differentiation are coordinated to generate coronary arteries. Signaling cascades regulate the concurrent and complex nature of these three events. Through simple and highly reproducible assays, we identified small organic molecules that impact signaling pathways regulating these epicardial behaviors. Subsequent biochemical analyses confirmed the specificity of these reagents and revealed novel targets for the widely used dorsomorphin (DM) and LDN-193189 molecules. Using these newly characterized reagents, we show the broad regulation of epicardial cell differentiation, sheet movement, and single cell migration by Transforming Growth Factor β (TGFβ). With the DM analogue DMH1, a highly specific Bone Morphogenetic Protein (BMP) inhibitor, we demonstrate the cooperative yet exclusive role for BMP signaling in regulation of sheet migration. The action of DMH1 reveals that small organic molecules (SOM) can intervene on a single epicardial behavior while leaving other concurrent behaviors intact. All SOM data were confirmed by reciprocal experiments using growth factor addition and/or application of established non-SOM inhibitors. These compounds can be applied to cell lines or native proepicardial tissue. Taken together, these data establish the efficacy of chemical intervention for analysis of epicardial behaviors and provide novel reagents for analysis of epicardial development and repair.

The microtubule (MT) network is essential in a broad spectrum of cellular functions. Many studies have linked CENP-F to MT-based activities as disruption of this protein leads to major changes in MT structure and function. Still, the basis of CENP-F regulation of the MT network remains elusive. Here, our studies reveal a novel and critical localization and role for CENP-F at the centrosome, the major MT organizing center (MTOC) of the cell. Using a yeast two-hybrid screen, we identify Hook2, a linker protein that is essential for regulation of the MT network at the centrosome, as a binding partner of CENP-F. With recently developed immunochemical reagents, we confirm this interaction and reveal the novel localization of CENP-F at the centrosome. Importantly, in this first report of CENP-F−/−cells, we demonstrate that ablation of CENP-F protein function eliminates MT repolymerization after standard nocodazole treatment. This inhibition of MT regrowth is centrosome specific because MT repolymerization is readily observed from the Golgi in CENP-F−/−cells. The centrosome-specific function of CENP-F in the regulation of MT growth is confirmed by expression of truncated CENP-F containing only the Hook2-binding domain. Furthermore, analysis of partially reconstituted MTOC asters in cells that escape complete repolymerization block shows that disruption of CENP-F function impacts MT nucleation and anchoring rather than promoting catastrophe. Our study reveals a major new localization and function of CENP-F at the centrosome that is likely to impact a broad array of MT-based actions in the cell.