Emergence of Anti-Cancer Drug Resistance: Exploring the Importance of the Microenvironmental Niche via a Spatial Model

Practically, all chemotherapeutic agents lead to drug resistance. Clinically, it is a challenge to determine whether resistance arises prior to, or as a result of, cancer therapy. Further, a number of different intracellular and microenvironmental factors have been correlated with the emergence of drug resistance. With the goal of better understanding drug resistance and its connection with the tumor microenvironment, we have developed a hybrid discrete-continuous mathematical model. In this model, cancer cells described through a particle-spring approach respond to dynamically changing oxygen and DNA damaging drug concentrations described through partial differential equations. We thoroughly explored the behavior of our self-calibrated model under the following common conditions: a fixed layout of the vasculature, an identical initial configuration of cancer cells, the same mechanism of drug action, and one mechanism of cellular response to the drug. We considered one set of simulations in which drug resistance existed prior to the start of treatment, and another set in which drug resistance is acquired in response to treatment. This allows us to compare how both kinds of resistance influence the spatial and temporal dynamics of the developing tumor, and its clonal diversity. We show that both pre-existing and acquired resistance can give rise to three biologically distinct parameter regimes: successful tumor eradication, reduced effectiveness of drug during the course of treatment (resistance), and complete treatment failure

Bribeproof mechanisms for two-values domains

Schummer (Journal of Economic Theory 2000) introduced the concept of bribeproof mechanism which, in a context where monetary transfer between agents is possible, requires that manipulations through bribes are ruled out. Unfortunately, in many domains, the only bribeproof mechanisms are the trivial ones which return a fixed outcome. This work presents one of the few constructions of non-trivial bribeproof mechanisms for these quasi-linear environments. Though the suggested construction applies to rather restricted domains, the results obtained are tight: For several natural problems, the method yields the only possible bribeproof mechanism and no such mechanism is possible on more general domains.Comment: Extended abstract accepted to SAGT 2016. This ArXiv version corrects typos in the proofs of Theorem 7 and Claims 28-29 of prior ArXiv versio

A New Lower Bound for Deterministic Truthful Scheduling

We study the problem of truthfully scheduling $m$ tasks to $n$ selfish unrelated machines, under the objective of makespan minimization, as was introduced in the seminal work of Nisan and Ronen [STOC'99]. Closing the current gap of $[2.618,n]$ on the approximation ratio of deterministic truthful mechanisms is a notorious open problem in the field of algorithmic mechanism design. We provide the first such improvement in more than a decade, since the lower bounds of $2.414$ (for $n=3$) and $2.618$ (for $n\to\infty$) by Christodoulou et al. [SODA'07] and Koutsoupias and Vidali [MFCS'07], respectively. More specifically, we show that the currently best lower bound of $2.618$ can be achieved even for just $n=4$ machines; for $n=5$ we already get the first improvement, namely $2.711$; and allowing the number of machines to grow arbitrarily large we can get a lower bound of $2.755$.Comment: 15 page

Anchoring Bias in Online Voting

Voting online with explicit ratings could largely reflect people's preferences and objects' qualities, but ratings are always irrational, because they may be affected by many unpredictable factors like mood, weather, as well as other people's votes. By analyzing two real systems, this paper reveals a systematic bias embedding in the individual decision-making processes, namely people tend to give a low rating after a low rating, as well as a high rating following a high rating. This so-called \emph{anchoring bias} is validated via extensive comparisons with null models, and numerically speaking, the extent of bias decays with interval voting number in a logarithmic form. Our findings could be applied in the design of recommender systems and considered as important complementary materials to previous knowledge about anchoring effects on financial trades, performance judgements, auctions, and so on.Comment: 5 pages, 4 tables, 5 figure

A chemical method for the assessment of grapes according to their seed content

Polyphenolic compounds, which are unevenly distributed between seed, pulp and skin, are the basis of a chemical method for the assessment of seedlessness in grapes. Known seedless and seeded grapes were evaluated using this method and a statistic test showed a significant difference between them. The color of the grapes did not interfere with this method. Frozen storage of samples at -20 °C for 3 months did not alter the results of the test. Hybrids of known progenies which were evaluated gave results which generally agree with those of the taste test. This chemical method, compared to assessment by taste, is more reliable, quantitative and relatively easy to perform.Une méthode chimique pour la détermination des raisins selon leur teneur en pépinsUne analyse chimique pour la détermination de l'absence de grains de raisins est décrite. La méthode est basée sur la détermination colorimétrique de composés phénoliques dans les raisins

Motility and morphodynamics of confined cells

We introduce a minimal hydrodynamic model of polarization, migration, and deformation of a biologicalcell confined between two parallel surfaces. In our model, the cell is driven out of equilibrium by an activecytsokeleton force that acts on the membrane. The cell cytoplasm, described as a viscous droplet in the Darcyflow regime, contains a diffusive solute that actively transduces the applied cytoskeleton force. While fairlysimple and analytically tractable, this quasi-two-dimensional model predicts a range of compelling dynamicbehaviours. A linear stability analysis of the system reveals that solute activity first destabilizes a globalpolarization-translation mode, prompting cell motility through spontaneous symmetry breaking. At higheractivity, the system crosses a series of Hopf bifurcations leading to coupled oscillations of droplet shape andsolute concentration profiles. At the nonlinear level, we find traveling-wave solutions associated with uniquepolarized shapes that resemble experimental observations. Altogether, this model offers an analytical paradigmof active deformable systems in which viscous hydrodynamics are coupled to diffusive force transducers

PENINGKATAN KEMAMPUAN KOMPUTER BAGI PERANGKAT BUMDES DESA ABUANG BANGLI

Abuan adalah desa yang berada di kecamatan Susut, Kabupaten Bangli, provinsi Bali. Kepala Desa Abuan  menyarankan kegiatan administrasi pada bumdes dilakukan dengan menggunakan media komputer. Sebagai media pendukung kebijakan tersebut, telah diberikan 1 unit komputer kepada Bumdes desa Abuan. Namun, pemanfaatan laptop tersebut belum maksimal dipergunakan, bahkan ada yang belum pernah digunakan untuk kegiatan administrasi seperti mengetik dokumen dan mengolah angka dengan microsoft excell. Kepala desa juga memberikan saran agar Bumdes diberikan pelatihan untuk menunjang kinerja secara online seperti bagaimana membuat email, mengirim email dan mencari informasi pada internet.. Solusi yang diberikan dalam pelaksanaan PKM ini yaitu dengan memberikan pelatihan aplikasi untuk mendukung penyelenggaraan administrasi manajemen data perkantoran, yakni menggunakan aplikasi Microsoft Office dan Pelatihan penggunaan  Internet. Target luaran yang direncanakan yaitu petugas administrasi Bumdes mampu menggunakan media komputer dalam urusan administrasi dan menggunakan internet sebagai media komunikasi online yang aman.. Kegiatan pengabdian dibagi menjadi beberapa tahapan kerja yaitu; Perencanaan, Pelaksanaan, Observasi dan Evaluasi. Pada tahap perencanaan dilakukan sosisalisasi PKM kepada mitra, menyusun program dan modul pelatihan. Tahap pelaksanaan dilakukan pelatihan penggunan Ms Office dan Penggunaan internet  . Pada tahap evaluasi dilakukan analisis terkait ketercapaian target pengabdian dan respon mitra terhadap pelaksanaan kegiatan. Tahap refleksi kegiatan dilakukan untuk mengetahui kelemahan dan kendala-kendala kegiatan. Hasil kegiatan pengabdian pelatihan yang diberikan menunjukkan bahwa para peserta telah mampu menggunakan ms office dan internet  dimana peningkatan pengetahuan peserta sebesar 23%   dan dari evaluasi pelatihan bahwa 33% menyatakan pelatihan baik dan 67% Menyatakan Pelatihan ini Sangat Baik.

Meta-Analysis of Cyber Intimate Partner Violence Perpetration and Victimization: Different Types and their Associations with Face-to-Face IPV among Men and Women

Cyber intimate partner violence (C-IPV) is a technology-mediated form of violence. It has been examined only in the last 10 years as a form of violence that can cause psychological damage to its victims. How this phenomenon connects to and differs from face-to-face IPV (F2F-IPV) has been, as yet, little studied. Research has not made clear whether sex differences may impact its use, particularly in light of the fact that no physical coercion is used in C-IPV. Thus, the current research aimed to investigate through a meta-analysis: differences between the average levels of different types of C-IPV victimization and perpetration; the association between C-IPV and F2F-IPV victimization and perpetration; and whether the answers to these questions were dependent on sex. The current meta-analysis drew on 46 studies, within 44 papers, with a total sample of 27,491 participants. Findings from 22 of these studies showed no significant sex differences between the average levels of different types of C-IPV victimization and between different types of C-IPV perpetration. These 22 studies showed positive large effect sizes for the correlation between C-IPV and F2F-IPV perpetration and victimization. Moreover, in both perpetration and victimization, sex did not impact the level of association. The findings suggested that C-IPV and F2F-IPV are highly correlated, and though not the same, they may share similar characteristics. Additionally, the results suggested that sex differences do not impact non-physical aggression, such as C-IPV. The implications for preventive strategies include that IPV interventions should also focus on alleviating instances of C-IPV

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Low-Level Laser Therapy Activates NF-kB via Generation of Reactive Oxygen Species in Mouse Embryonic Fibroblasts

Background Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear. Methodology/Principal Findings In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm2 and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration. Conclusion We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.National Institutes of Health (U.S.) (grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense (CDMRP Program in TBI, W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (FA9950-04-1-0079