Approximability of Connected Factors

Finding a d-regular spanning subgraph (or d-factor) of a graph is easy by Tutte's reduction to the matching problem. By the same reduction, it is easy to find a minimal or maximal d-factor of a graph. However, if we require that the d-factor is connected, these problems become NP-hard - finding a minimal connected 2-factor is just the traveling salesman problem (TSP). Given a complete graph with edge weights that satisfy the triangle inequality, we consider the problem of finding a minimal connected $d$-factor. We give a 3-approximation for all $d$ and improve this to an (r+1)-approximation for even d, where r is the approximation ratio of the TSP. This yields a 2.5-approximation for even d. The same algorithm yields an (r+1)-approximation for the directed version of the problem, where r is the approximation ratio of the asymmetric TSP. We also show that none of these minimization problems can be approximated better than the corresponding TSP. Finally, for the decision problem of deciding whether a given graph contains a connected d-factor, we extend known hardness results.Comment: To appear in the proceedings of WAOA 201

AMLODIPINE BESYLATE LOADED POLYMERIC NANOPARTICLES: PREPARATION AND IN VITRO CHARACTERISATION

Objective: The present investigation aims to formulate the ideal drug formulation using different surfactants and optimize the amlodipine-loaded polymeric nanoparticles. Methods: The present work was to formulate the drug-loaded polymeric nanoparticles to enhance the dissolution rate of a poorly water-soluble drug, amlodipine besylate, using the anti-solvent precipitation method. The Characterisation studies include particle size (nm), Zeta potential (mV), polydispersity index, Drug entrapment efficiency (%), in vitro release drug release, and surface morphological studies like SEM and XRD. Results: The drug-loaded Polymeric nanoparticles of F3 containing PLGA and PVA shows the desired smaller particle size is 198.8±5.25, maximum zeta potential is-24.76±2.54 mv and the stable polydispersity index of 0.957±0.45. The drug entrapment efficiency is 93%, and the controlled dissolution of the ideal formulation pattern is about 94.88±2.45 in 24h. Conclusion: The release pattern observed that PNs significantly improved the dissolution character of amlodipine besylate. PNs have a controlled drug release pattern and can be used as a suitable drug delivery carrier for low solubility and poorly bioavailable drugs like amlodipine to improve its dissolution rate

Performance of improved varieties and technological interventions at farmers’ fields for cumin cultivation

Front line demonstrations on cumin consisting of two improved varieties (GC-4 and RZ-209) with scientific interventions viz., seed treatment (Bavistin @2.5 g kg-1 seed and Trichoderma viride @4 g kg-1 seed), and pre-emergence application of oxadiragil (Raft) @75 g a.i. ha-1 for effective weed management and application of recommended doses of nutrients (40:40:0 kg ha-1 NPK) for balanced nutrition and appropriate plant protection schedule [(Two sprays of malathion (0.2%), two sprays of Dithan M-45 (0.2%) and one spray of karathan (0.1%) for the control of aphids, blight and powdery mildew, respectively)] were carried out at farmers’ fields in two villages (Kajipura and Bhadal) of Jaipur and one village (Karad) of Sikar district of Rajasthan during Rabi season of 2011–12 and 2012–13. Study revealed that overall yield was increased by 21.09% over farmers’ practice due to the technological interventions with average yield of 536.50 kg ha-1. Overall extension gap of 112.50 kg ha-1 and technical gap of 463.50 kg ha-1 were recorded in the study with 46.35% technology index. Maximum additional return (Rs. 15,875 ha-1) with highest effective gain (Rs. 10,775 ha-1) and incremental B: C ratio (3.11) were obtained in the year 2011–12. However, the overall average additional return was Rs. 14601 ha-1 with effective gain of Rs. 9,401 ha-1 and incremental B: C ratio of 2.81. &nbsp

Synthesis, thermal and antitumour studies of Th(IV) complexes with furan-2-carboxaldehyde4-phenyl-3-thiosemicarbazone

Thorium(IV) complexes with the Schiff base furan-2-carboxaldehyde4-phenyl-3-thiosemicarbazone (L) were synthesised and characterized. The composition and structure of the metal complexes were proposed based on elemental analysis, molar conductivity measurements, FTIR and 1H-NMR spectroscopy. The Schiff base behaves as a neutral bidentate ligand coordinating through the azomethine N and the thioketo S atoms. From various studies, complexes were ascertained the general formula [ThL2X4] and [ThL2Y2], where X represents NO3–, NCS–, CH3COO–, CH3CHOHCOO–, ClO4– and Y SO42–and C2O42–. The thermal behaviour of the nitrato and oxalato complexes was studied and kinetic and thermodynamic parameters were calculated using the Coats-Redfern Equation. The ligand and a representative complex [ThL2(NO3)4] were screened in vitro for their antitumour activity against the human cervical cancer cell line (HeLa)

On the complexity of strongly connected components in directed hypergraphs

We study the complexity of some algorithmic problems on directed hypergraphs and their strongly connected components (SCCs). The main contribution is an almost linear time algorithm computing the terminal strongly connected components (i.e. SCCs which do not reach any components but themselves). "Almost linear" here means that the complexity of the algorithm is linear in the size of the hypergraph up to a factor alpha(n), where alpha is the inverse of Ackermann function, and n is the number of vertices. Our motivation to study this problem arises from a recent application of directed hypergraphs to computational tropical geometry. We also discuss the problem of computing all SCCs. We establish a superlinear lower bound on the size of the transitive reduction of the reachability relation in directed hypergraphs, showing that it is combinatorially more complex than in directed graphs. Besides, we prove a linear time reduction from the well-studied problem of finding all minimal sets among a given family to the problem of computing the SCCs. Only subquadratic time algorithms are known for the former problem. These results strongly suggest that the problem of computing the SCCs is harder in directed hypergraphs than in directed graphs.Comment: v1: 32 pages, 7 figures; v2: revised version, 34 pages, 7 figure

Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent

<p>Abstract</p> <p>Background</p> <p>Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell proliferation and angiogenesis. We observed that the proliferative index of nicotine is different in the lung cancer cell lines H1299 (p53-/-) and A549 (p53+/+) which indicates that the mode of up-regulation of survival signals by nicotine might be different in cells with and without p53.</p> <p>Results</p> <p>While low concentrations of nicotine induced activation of NF-κB, Akt, Bcl2, MAPKs, AP1 and IAPs in H1299, it failed to induce NF-κB in A549, and compared to H1299, almost 100 times higher concentration of nicotine was required to induce all other survival signals in A549. Transfection of WT-p53 and DN-p53 in H1299 and A549 respectively, reversed the mode of activation of survival signals. Curcumin down-regulated all the survival signals induced by nicotine in both the cells, irrespective of their p53 status. The hypothesis was confirmed when lower concentrations of nicotine induced NF-κB in two more lung cancer cells, Hop-92 and NCI-H522 with mutant p53 status. Silencing of p53 in A549 using siRNA made the cells susceptible to nicotine-induced NF-κB nuclear translocation as in A549 DN-p53 cells.</p> <p>Conclusions</p> <p>The present study reveals a detrimental role of nicotine especially in lung cancer patients with impaired p53 status and identifies curcumin as a potential chemopreventive.</p

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Calcium/Calmodulin Dependent Protein Kinase II Bound to NMDA Receptor 2B Subunit Exhibits Increased ATP Affinity and Attenuated Dephosphorylation

Calcium/calmodulin dependent protein kinase II (CaMKII) is implicated to play a key role in learning and memory. NR2B subunit of N-methyl-D-aspartate receptor (NMDAR) is a high affinity binding partner of CaMKII at the postsynaptic membrane. NR2B binds to the T-site of CaMKII and modulates its catalysis. By direct measurement using isothermal titration calorimetry (ITC), we show that NR2B binding causes about 11 fold increase in the affinity of CaMKII for ATPγS, an analogue of ATP. ITC data is also consistent with an ordered binding mechanism for CaMKII with ATP binding the catalytic site first followed by peptide substrate. We also show that dephosphorylation of phospho-Thr286-α-CaMKII is attenuated when NR2B is bound to CaMKII. This favors the persistence of Thr286 autophosphorylated state of CaMKII in a CaMKII/phosphatase conjugate system in vitro. Overall our data indicate that the NR2B- bound state of CaMKII attains unique biochemical properties which could help in the efficient functioning of the proposed molecular switch supporting synaptic memory