Dynamic Range Majority Data Structures

Given a set $P$ of coloured points on the real line, we study the problem of answering range $\alpha$-majority (or "heavy hitter") queries on $P$. More specifically, for a query range $Q$, we want to return each colour that is assigned to more than an $\alpha$-fraction of the points contained in $Q$. We present a new data structure for answering range $\alpha$-majority queries on a dynamic set of points, where $\alpha \in (0,1)$. Our data structure uses O(n) space, supports queries in $O((\lg n) / \alpha)$ time, and updates in $O((\lg n) / \alpha)$ amortized time. If the coordinates of the points are integers, then the query time can be improved to $O(\lg n / (\alpha \lg \lg n) + (\lg(1/\alpha))/\alpha))$. For constant values of $\alpha$, this improved query time matches an existing lower bound, for any data structure with polylogarithmic update time. We also generalize our data structure to handle sets of points in d-dimensions, for $d \ge 2$, as well as dynamic arrays, in which each entry is a colour.Comment: 16 pages, Preliminary version appeared in ISAAC 201

Possible common central pathway for resistin and insulin in regulating food intake.

Aim: Adipose tissue has been the object of intense research in the field of obesity and diabetes diseases in the last decade. Examination of adipocyte-secreted peptides led to the identification of a unique polypeptide, resistin (RSTN), which has been suggested as a link between obesity and diabetes. RSTN plays a clearly documented role in blocking insulin (INS)-induced hypoglycaemia. As brain injection of INS affects feeding behaviour, we studied the possible interaction between INS and RSTN in food-deprived rats, measuring effects on food intake. In addition, we examined how RSTN might affect neuropeptide Y (NPY)-induced feeding, as studies have shown that rat RSTN can interfere with the NPY system. Methods: Overnight food-deprived rats were injected into the third brain ventricle (3V) with either INS (10 or 20 mUI), RSTN (0.1–0.4 nmol/rat), or saline before access to food. Another group of rats was injected into the 3V with RSTN alone, NPY alone or RSTN plus NPY. Their food intake and body weight were measured. Results: Our results confirm the hypophagic effect of RSTN on food deprivation-induced food intake, and more importantly, show that RSTN neither potentiates nor blocks the effects of INS on food intake, but does reduce the hyperphagic effect of NPY. Conclusion:  The observation that RSTN does not modify feeding INS-induced hypophagia, but does influence NPY-induced feeding, points to the possibility that RSTN may be involved in control of food intake through an NPY-ergic mechanism as INS

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis

On Smooth Orthogonal and Octilinear Drawings: Relations, Complexity and Kandinsky Drawings

We study two variants of the well-known orthogonal drawing model: (i) the smooth orthogonal, and (ii) the octilinear. Both models form an extension of the orthogonal, by supporting one additional type of edge segments (circular arcs and diagonal segments, respectively). For planar graphs of max-degree 4, we analyze relationships between the graph classes that can be drawn bendless in the two models and we also prove NP-hardness for a restricted version of the bendless drawing problem for both models. For planar graphs of higher degree, we present an algorithm that produces bi-monotone smooth orthogonal drawings with at most two segments per edge, which also guarantees a linear number of edges with exactly one segment.Comment: Appears in the Proceedings of the 25th International Symposium on Graph Drawing and Network Visualization (GD 2017

Evaluation of repeat distal transradial access in the anatomic snuffbox

PurposeThere is increasing interest in the distal radial artery in the anatomic snuffbox as an alternative arterial access point, but the durability of the distal radial artery to support repetitive accesses over multiple procedures is not well established. The purpose of this study was therefore to evaluate success rates for repeated left-sided distal transradial access (ldTRA) in the anatomic snuffbox.MethodsIn this single institution retrospective study, all patients undergoing radioembolization treatments from January 1st, 2019 to May 1st, 2020 were prospectively evaluated for ldTRA. ldTRA was performed by 15 different operators. Exclusion criteria were a left radiocephalic hemodialysis fistula, inability to properly position the arm, Barbeau D waveform, or failed prior ldTRA due to tortuosity. Barbeau patterns, arterial sizes, and success rates at the first, second, and third ldTRA were compared.ResultsFifty patients were evaluated for ldTRA and 44, 39, and 10 underwent one, two, and three ldTRA attempts for a total of 93 procedures. There was no significant change in Barbeau patterns between the first and second (p = 0.13) or first and third (p = 1.0) ldTRA. There was no significant change in artery size between the first (mean, 2.3 mm; range, 1.5–3.4 mm) and second (mean, 2.3 mm; range, 1.6–3.3 mm) (p = 0.59) and first and third (mean, 2.4 mm; range, 1.9–3.3) (p = 0.45) ldTRA. The success rate was not significantly different between the first (93%, 41/44, 95% CI 81%–99%), second (95%, 37/39, 95% CI 83%–99%), and third (100%, 10/10, 95% CI 69%–100%) procedure (p = 1.0). The asymptomatic occlusion rate was 4.1% (2/49, 95% CI 0%–14%), and subsequent ldTRA was successfully completed in both patients with occlusions. There were no hemorrhagic or ischemic complications.ConclusionSuccess rates are indistinguishable among first, second, and third time ldTRA suggesting that this is a durable access point

In Situ Monitoring of Intracellular Glucose and Glutamine in CHO Cell Culture

The development of processes to produce biopharmaceuticals industrially is still largely empirical and relies on optimizing both medium formulation and cell line in a product-specific manner. Current small-scale (well plate-based) process development methods cannot provide sufficient sample volume for analysis, to obtain information on nutrient utilization which can be problematic when processes are scaled to industrial fermenters. We envision a platform where essential metabolites can be monitored non-invasively and in real time in an ultra-low volume assay in order to provide additional information on cellular metabolism in high throughput screens. Towards this end, we have developed a model system of Chinese Hamster Ovary cells stably expressing protein-based biosensors for glucose and glutamine. Herein, we demonstrate that these can accurately reflect changing intracellular metabolite concentrations in vivo during batch and fed-batch culture of CHO cells. The ability to monitor intracellular depletion of essential nutrients in high throughput will allow rapid development of improved bioprocesses

Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces

TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5αrh) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5αrh containing coiled-coil and SPRY domains (CC-SPRYrh). Concentration-dependent binding of CC-SPRYrh to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRYrh, but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5αrh on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction. © 2011 Zhao et al

Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma

Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1/2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL

PepCyber:P∼PEP: a database of human protein–protein interactions mediated by phosphoprotein-binding domains

Phosphoprotein-binding domains (PPBDs) mediate many important cellular and molecular processes. Ten PPBDs have been known to exist in the human proteome, namely, 14-3-3, BRCT, C2, FHA, MH2, PBD, PTB, SH2, WD-40 and WW. PepCyber:P∼PEP is a newly constructed database specialized in documenting human PPBD-containing proteins and PPBD-mediated interactions. Our motivation is to provide the research community with a rich information source emphasizing the reported, experimentally validated data for specific PPBD–PPEP interactions. This information is not only useful for designing, comparing and validating the relevant experiments, but it also serves as a knowledge-base for computationally constructing systems signaling pathways and networks. PepCyber:P∼PEP is accessible through the URL, http://www.pepcyber.org/PPEP/. The current release of the database contains 7044 PPBD-mediated interactions involving 337 PPBD-containing proteins and 1123 substrate proteins