Jacob Holm

Poly-logarithmic deterministic fully-dynamic algorithms for connectivity, minimum spanning tree, 2-edge, and biconnectivity

Deterministic fully dynamic graph algorithms are presented for connectivity, minimum spanning tree, 2-edge connectivity, and biconnectivity. Assuming that we start with no edges in a graph with <i>n</i> vertices, the amortized operation costs are <i>O</i>(log² <i>n</i>) for connectivity, <i>O</i>(log⁴ <i>n</i>) for minimum spanning forest, 2-edge connectivity, and <i>O</i>(log⁵ <i>n</i>) biconnectivity.

Human gut microbes impact host serum metabolome and insulin sensitivity

Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders.

Physiological role of taurine--from organism to organelle.

Taurine is often referred to as a semi‐essential amino acid as newborn mammals have a limited ability to synthesize taurine and have to rely on dietary supply. Taurine is not thought to be incorporated into proteins as no aminoacyl tRNA synthetase has yet been identified and is not oxidized in mammalian cells. However, taurine contributes significantly to the cellular pool of organic osmolytes and has accordingly been acknowledged for its role in cell volume restoration following osmotic perturbation. This review describes taurine homeostasis in cells and organelles with emphasis on taurine biophysics/membrane dynamics, regulation of transport proteins involved in active taurine uptake and passive taurine release as well as physiological processes, for example, development, lung function, mitochondrial function, antioxidative defence and apoptosis which seem to be affected by a shift in the expression of the taurine transporters and/or the cellular taurine content.

Chronic Trichuris muris Infection Decreases Diversity of the Intestinal Microbiota and Concomitantly Increases the Abundance of Lactobacilli.

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes.

Maintaining information in fully dynamic trees with top trees

We design top trees as a new simpler interface for data structures maintaining information in a fully dynamic forest. We demonstrate how easy and versatile they are to use on a host of different applications. For example, we show how to maintain the diameter, center, and median of each tree in the forest. The forest can be updated by insertion and deletion of edges and by changes to vertex and edge weights. Each update is supported in O(log n) time, where n is the size of the tree(s) involved in the update. Also, we show how to support nearest common ancestor queries and level ancestor queries with respect to arbitrary roots in O(log n) time. Finally, with marked and unmarked vertices, we show how to compute distances to a nearest marked vertex. The latter has applications to approximate nearest marked vertex in general graphs, and thereby to static optimization problems over shortest path metrics.Technically speaking, top trees are easily implemented either with Fredericksons [1997a] topology trees or with Sleator and Tarjans [1983] dynamic trees. However, we claim that the interface is simpler for many applications, and indeed our new bounds are quadratic improvements over previous bounds where they exist.

Improved Algorithms for Finding Level Ancestors in Dynamic Trees

Given a node x at depth d in a rooted tree Level Ancestor(x; i) returns the ancestor to x in depth d - i. We show how to maintain a tree under addition of new leaves so that updates and level ancestor queries are being performed in worst case constant time. Given a forest of trees with n nodes where edges can be added, m queries and updates take O(mα(m, n)) time. This solves two open problems (P.F. Dietz, Finding level-ancestors in dynamic trees, LNCS, 519:32-40, 1991). In a tree with node weights, min(x, y) report the node with minimum weight on the path between the nodes x and y. We can substitute the Level Ancestor query with min, without increasing the complexity for updates and queries. Previously such results have been known only for special cases (e.g. R. E. Tarjan. Applications of path compression on balanced trees. J. ACM, 26(4):690-715, 1979).

IRF8 Transcription-Factor-Dependent Classical Dendritic Cells Are Essential for Intestinal T Cell Homeostasis

The role of dendritic cells (DCs) in intestinal immune homeostasis remains incompletely defined. Here we show that mice lacking IRF8 transcription-factor-dependent DCs had reduced numbers of T cells in the small intestine (SI), but not large intestine (LI), including an almost complete absence of SI CD8αβ(+) and CD4(+)CD8αα(+) T cells; the latter requiring β8 integrin expression by migratory IRF8 dependent CD103(+)CD11b(-) DCs. SI homing receptor induction was impaired during T cell priming in mesenteric lymph nodes (MLN), which correlated with a reduction in aldehyde dehydrogenase activity by SI-derived MLN DCs, and inefficient T cell localization to the SI. These mice also lacked intestinal T helper 1 (Th1) cells, and failed to support Th1 cell differentiation in MLN and mount Th1 cell responses to Trichuris muris infection. Collectively these results highlight multiple non-redundant roles for IRF8 dependent DCs in the maintenance of intestinal T cell homeostasis.

Maintaining Center and Median in Dynamic Trees

We show how to maintain centers and medians for a collection of dynamic trees where edges may be inserted and deleted and node and edge weights may be changed. All updates are supported in O(log n) time, where n is the size of the tree(s) involved in the update.

Pinpointing differences in cisplatin-induced apoptosis in adherent and non-adherent cancer cells.

Platinum compounds are used in the treatment of cancer. We demonstrate that cisplatin-induced (10 µM) apoptosis (caspase-3 activity) is pronounced within 18 hours in non-adherent Ehrlich ascites tumour cells (EATC), whereas there is no increase in caspase-3 activity in the adherent Ehrlich LettrÉ ascites tumour cells (ELA). Loss of KCl and cell shrinkage are hallmarks in apoptosis and has been shown in EATC. However, we find no reduction in cell volume and only a minor loss of K+ which is accompanied by net uptake of Na+ following 18 hours cisplatin exposure in ELA. Glutathione and taurine have previously been demonstrated to protect cells from apoptosis. We find, however, that increase or decrease in the cellular content of glutathione and taurine has no effect on cisplatin-induced cell death in EATC and ELA. Nevertheless, knock-down of the taurine transporter TauT leads to a significant increase in apoptosis in ELA following cisplatin exposure. We find that cytosolic accumulation of cisplatin is similar in EATC and ELA. However, the nuclear accumulation and DNA-binding of cisplatin is significant lower in ELA compared to EATC. We suggest three putative reasons for the observed cisplatin insensitivity in the adherent tumor cells (ELA) compared to the non-adherent tumor cells (EATC): less nuclear cisplatin accumulation, increased TauT activity, and decreased anion and water loss.

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase.

Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration, and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT₁) with the antiasthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium-sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H₂O₂. Ca²⁺ mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca²⁺ (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H₂O₂, ATP, and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT₁ as essential elements in the swelling-induced activation of VSOAC with ROS and Ca²⁺ as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase-3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT₁ but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia.