Pharmacogenetic tests to guide drug treatment in depression: Comparison of the available testing kits and clinical trials.

Prog Neuropsychopharmacol Biol Psychiatry. 2018 May 16;:

Authors: Fabbri C, Zohar J, Serretti A

Abstract
The empirical approach to drug choice and dosing in depression often results into inadequate response and side effects. Pharmacogenetic (PGx) testing appears a promising way to implement personalized treatments. A systematic review was performed to identify available PGx tests, compare the genes they include with clinical guidelines and drug labels, and assess the quality of published clinical studies. ~40 commercial PGx tests are available and potential benefits were estimated for nine of them by clinical studies. The most part of studies are observational (9/21) or non-randomized case-control trials that compared standard care with PGx-guided treatment (6/21), six randomized controlled trials (RCTs) are available. The only genes included in all the available PGx tests and with recommendations in current clinical guidelines and drug labels are CYP2D6 and CYP2C19. There is heterogeneity among outcome measures across studies (response, remission, improvement, health care utilization, medication tolerability), as well as in trial design. Relatively weak clinical benefits were reported by RCTs and higher clinical benefits by non-RCTs, but the last group showed greater risk of bias. Lack of patient and rater's blindness, retrospective design and possible confounders (concomitant medications and medical diseases, lack of wash out prior to inclusion, no assessment of compliance etc.) were the main issues. Estimations of cost savings provided heterogeneous findings. Variants in CYP2D6 and CYP2C19 have already adequate support for clinical application. The development of future PGx tests should include best practices for clinical evidence development and for health economic assessment.

PMID: 29777729 [PubMed - as supplied by publisher]

Clopidogrel Pharmacogenetics in Iranian Patients Undergoing Percutaneous Coronary Intervention.

Cardiovasc Toxicol. 2018 May 18;:

Authors: Mahdieh N, Rabbani A, Firouzi A, Zahedmehr A, Hoseinimoghaddam M, Saeidi S, Sanati H, Basiri H, Noohi F, Rabbani B, Maleki M

Abstract
Clopidogrel is used in patients with coronary syndromes and at risk of thrombotic events or receiving percutaneous coronary intervention (PCI) for reducing heart attack and stroke. Here we present genotype and phenotype study of Iranian patients undergoing PCI treated with clopidogrel during a 6-month period of follow-up; common variants of CYP2C19, CYP3A5, CYP3A4, and ABCB1 genes were determined as well as the patients' cardiovascular outcomes to find out the effect of these variants individually and in combination. 388 individuals receiving PCI were enrolled in this study. Different pretreatment doses of clopidogrel were prescribed under the interventional cardiologists' guidance. The patients were followed for a duration of 1 month, and 6 months. Six SNPs were selected for genotyping including CYP2C19*2 (c.681G > A), CYP2C19*3 (c.636G > A), CYP2C19*17 allele (c.-806C > T), ABCB1 (c.3435C > T), CYP3A5 (c.6986A > G), and CYP3A4 (c.1026 + 12G > A). The mean loading dose was 600 mg/day in 267 (68.8%) individuals, 300 mg/day in 121 (31.2%). 8 patients had cardiovascular events such as thrombosis, unstable angina, and non-STEMI. The studied alleles and genotypes were in Hardy-Weinberg equilibrium. None of the SNPs individually were significantly associated with outcome events. Our results indicate that combinations of different alleles of genes are involved in pharmacokinetic variability and joint factors are important; this means that genotyping and analysis of an individual variant may not be as straightforward in risk assessment and pharmacogenetics. This highlights the importance of personalized medicine in risk assessment and treatment.

PMID: 29777510 [PubMed - as supplied by publisher]

Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro.

Cancer Chemother Pharmacol. 2018 May 18;:

Authors: Huang JF, Wen CJ, Zhao GZ, Dai Y, Li Y, Wu LX, Zhou HH

Abstract
PURPOSE: Doxorubicin is one of the most active agents in the first-line therapy for metastatic breast cancer, but its utility is partially limited by the frequent emergence of doxorubicin resistance. In this study, we aimed to investigate the role of ATP-binding cassette sub-family B, member 4 (ABCB4) in acquired doxorubicin resistance in breast cancer cells, as well as its potential mechanism.
METHODS: In doxorubicin-sensitive and -resistant breast cancer cell lines MCF-7 and MDA-MB-231, the expression levels of ABCB4 were detected using real-time quantitative PCR and Western blot analysis, the DNA methylation and histone acetylation status of ABCB4 gene were investigated by bisulfite-sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) assays, and the doxorubicin sensitivity and intracellular doxorubicin accumulation were observed using cell cytotoxicity assay and flow cytometry. In Madin-Darby Canine Kidney (MDCKII) cells, In vitro transport assay was used to assess the ABCB4-mediated transport of doxorubicin.
RESULTS: ABCB4 was overexpressed in doxorubicin-resistant breast cancer cells compared to their doxorubicin-sensitive counterparts, which was associated with reduced DNA methylation as well as increased histone acetylation at the ABCB4 promoter. ABCB4 could actively pump doxorubicin out of the cells, and knockdown of ABCB4 increased doxorubicin sensitivity and intracellular accumulation in doxorubicin-resistant breast cancer cells.
CONCLUSIONS: Our results indicate that ABCB4 is overexpressed in breast cancer cells with acquired doxorubicin resistance, which could be attributed, at least partially, to the epigenetic modifications of ABCB4 gene. ABCB4 mediates the efflux transport of doxorubicin, and contributes to the acquired resistance of doxorubicin in breast cancer cells.

PMID: 29777275 [PubMed - as supplied by publisher]

Neutrophils in traumatic brain injury (TBI): friend or foe?

J Neuroinflammation. 2018 May 17;15(1):146

Authors: Liu YW, Li S, Dai SS

Abstract
Our knowledge of the pathophysiology about traumatic brain injury (TBI) is still limited. Neutrophils, as the most abundant leukocytes in circulation and the first-line transmigrated immune cells at the sites of injury, are highly involved in the initiation, development, and recovery of TBI. Nonetheless, our understanding about neutrophils in TBI is obsolete, and mounting evidences from recent studies have challenged the conventional views. This review summarizes what is known about the relationships between neutrophils and pathophysiology of TBI. In addition, discussions are made on the complex roles as well as the controversial views of neutrophils in TBI.

PMID: 29776443 [PubMed - in process]

Phage therapy against Achromobacter xylosoxidans lung infection in a Patient with Cystic Fibrosis: A Case Report.

Res Microbiol. 2018 May 16;:

Authors: Hoyle N, Zhvaniya P, Balarjishvili N, Bolkvadze D, Nadareishvili L, Nizharadze D, Wittmann J, Rohde C, Kutateladze M

Abstract
Respiratory infections can lead to serious complications in CF patients, especially when infected with antibiotic resistant bacteria. Alternative treatments for these infections are being sought out to help address this problem. We present a clinical case of a cystic fibrosis (CF) patient, with multi-drug resistant (MDR) Achromobacter xylosoxidans chronic lung infection who was successfully managed with bacteriophage therapy.

PMID: 29777836 [PubMed - as supplied by publisher]

Prevalence of Depression among Caregivers of Indian Children with Cystic Fibrosis.

Indian J Pediatr. 2018 May 19;:

Authors: Bhat JI, Wani WA, Charoo BA, Ali SW, Ahmad QI, Ahangar AA

Abstract
OBJECTIVE: To study the prevalence of depression among caregivers of children with cystic fibrosis and its impact on the health and well being of these children.
METHODS: This cross-sectional study was conducted in a tertiary care hospital from September 2015 through August 2016. Forty one parents of children receiving treatment at the Cystic fibrosis (CF) clinic were approached to be part of the study. Six families declined the request resulting in 85% recruitment rate. The Centre for Epidemiological Studies Depression Scale (CES-D) was used to assess depression score among caregivers. The CES-D provides clinical cut-off scores of ≥16 that help in identifying persons at risk for depression. CES-D was completed by the parent closely associated with care of the affected child. Main outcome measure was to find the number of caregivers of patients who has score of ≥16 on CES-D scale, and its effect on growth and respiratory exacerbations of the affected child.
RESULTS: A total of 23 fathers and 12 mothers participated in the study. The mean age of male and female caregivers was 30.9 ± 5.4 and 27.8 ± 4.7 y respectively. Eighteen (51.4%) caregivers scored above the clinical cut-off on the CES-D in the index study with mean score of 22.0 ± 4.0. The mean CES-D score among non-depressive caregivers was 7.76 ± 4.2. Significant negative association was found between parental depression and child's health. Children with high parental CES-D score suffered significantly more respiratory exacerbations (3.83 ± 1.2 episodes) in last six months than parents with low CES-D score (2.18 ± 1.28 episodes) (p value = 0.00). Similarly, stunting was more commonly seen in patients with high caregiver CES-D score (15 vs. 7; P value = 0.01).
CONCLUSIONS: A very high prevalence of caregiver depression was found in cystic fibrosis, which negatively impacted care and well being of the affected patients. Depression was more common in families with poor economic and education level.

PMID: 29777470 [PubMed - as supplied by publisher]

Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking.

Nat Commun. 2018 May 18;9(1):1988

Authors: Porrello A, Leslie PL, Harrison EB, Gorentla BK, Kattula S, Ghosh SK, Azam SH, Holtzhausen A, Chao YL, Hayward MC, Waugh TA, Bae S, Godfrey V, Randell SH, Oderup C, Makowski L, Weiss J, Wilkerson MD, Hayes DN, Earp HS, Baldwin AS, Wolberg AS, Pecot CV

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival.

PMID: 29777108 [PubMed - in process]

Comprehensive molecular diagnosis of Epstein-Barr virus-associated lymphoproliferative diseases using next-generation sequencing.

Int J Hematol. 2018 May 18;:

Authors: Ono S, Nakayama M, Kanegane H, Hoshino A, Shimodera S, Shibata H, Fujino H, Fujino T, Yunomae Y, Okano T, Yamashita M, Yasumi T, Izawa K, Takagi M, Imai K, Zhang K, Marsh R, Picard C, Latour S, Ohara O, Morio T

Abstract
Epstein-Barr virus (EBV) is associated with several life-threatening diseases, such as lymphoproliferative disease (LPD), particularly in immunocompromised hosts. Some categories of primary immunodeficiency diseases (PIDs) including X-linked lymphoproliferative syndrome (XLP), are characterized by susceptibility and vulnerability to EBV infection. The number of genetically defined PIDs is rapidly increasing, and clinical genetic testing plays an important role in establishing a definitive diagnosis. Whole-exome sequencing is performed for diagnosing rare genetic diseases, but is both expensive and time-consuming. Low-cost, high-throughput gene analysis systems are thus necessary. We developed a comprehensive molecular diagnostic method using a two-step tailed polymerase chain reaction (PCR) and a next-generation sequencing (NGS) platform to detect mutations in 23 candidate genes responsible for XLP or XLP-like diseases. Samples from 19 patients suspected of having EBV-associated LPD were used in this comprehensive molecular diagnosis. Causative gene mutations (involving PRF1 and SH2D1A) were detected in two of the 19 patients studied. This comprehensive diagnosis method effectively detected mutations in all coding exons of 23 genes with sufficient read numbers for each amplicon. This comprehensive molecular diagnostic method using PCR and NGS provides a rapid, accurate, low-cost diagnosis for patients with XLP or XLP-like diseases.

PMID: 29777376 [PubMed - as supplied by publisher]

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma.

BMC Cancer. 2018 May 18;18(1):571

Authors: Ahn SM, Haq F, Park I, Nault JC, Zucman-Rossi J, Yu E

Abstract
BACKGROUND: Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions.
METHODS: Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS).
RESULTS: The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival.
CONCLUSION: The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.

PMID: 29776391 [PubMed - in process]

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis.

Cancer Lett. 2018 May 16;:

Authors: Halama A, Kulinski M, Dib SS, Zaghlool SB, Siveen KS, Iskandarani A, Zierer J, Prabhu KS, Satheesh NJ, Bhagwat AM, Uddin S, Kastenmüller G, Elemento O, Gross SS, Suhre K

Abstract
Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.

PMID: 29777783 [PubMed - as supplied by publisher]

Probing the binding site of novel selective positive allosteric modulators at the M1 mAChR.

Biochem Pharmacol. 2018 May 16;:

Authors: Khajehali E, Valant C, Jörg M, Tobin AB, Jeffrey Conn P, Lindsley CW, Sexton PM, Scammells PJ, Christopoulos A

Abstract
Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one). Given these diverse scaffolds and pharmacodynamics, the current study combined pharmacological analysis and site-directed mutagenesis to explore the potential binding site and function of newer M1 mAChR PAMs relative to BQCA. Interestingly, the mechanism of action of the novel PAMs was consistent with a common model of allostery, as previously described for BQCA. Key residues involved in the activity of BQCA, including Y179 in the second extracellular loop (ECL) and W4007.35 in transmembrane domain (TM) 7, were critical for the activity of all PAMs tested. Overall, our data indicate that structurally distinct PAMs share a similar binding site with BQCA, specifically, an extracellular allosteric site defined by residues in TM2, TM7 and ECL2. These findings provide valuable insights into the structural basis underlying modulator binding, cooperativity and signaling at the M1 mAChR, which is essential for the rational design of PAMs with tailored pharmacological properties.

PMID: 29777683 [PubMed - as supplied by publisher]

Development of an Algorithm to Identify Patients with Physician-Documented Insomnia.

Sci Rep. 2018 May 18;8(1):7862

Authors: Kartoun U, Aggarwal R, Beam AL, Pai JK, Chatterjee AK, Fitzgerald TP, Kohane IS, Shaw SY

Abstract
We developed an insomnia classification algorithm by interrogating an electronic medical records (EMR) database of 314,292 patients. The patients received care at Massachusetts General Hospital (MGH), Brigham and Women's Hospital (BWH), or both, between 1992 and 2010. Our algorithm combined structured variables (such as International Classification of Diseases 9th Revision [ICD-9] codes, prescriptions, laboratory observations) and unstructured variables (such as text mentions of sleep and psychiatric disorders in clinical narrative notes). The highest classification performance of our algorithm was achieved when it included a combination of structured variables (billing codes for insomnia, common psychiatric conditions, and joint disorders) and unstructured variables (sleep disorders and psychiatric disorders). Our algorithm had superior performance in identifying insomnia patients compared to billing codes alone (area under the receiver operating characteristic curve [AUROC] = 0.83 vs. 0.55 with 95% confidence intervals [CI] of 0.76-0.90 and 0.51-0.58, respectively). When applied to the 314,292-patient population, our algorithm classified 36,810 of the patients with insomnia, of which less than 17% had a billing code for insomnia. In conclusion, an insomnia classification algorithm that incorporates clinical notes is superior to one based solely on billing codes. Compared to traditional methods, our study demonstrates that a classification algorithm that incorporates physician notes can more accurately, comprehensively, and quickly identify large cohorts of insomnia patients.

PMID: 29777125 [PubMed - in process]

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNFα pathway.

Blood. 2018 May 18;:

Authors: Haxaire C, Hakobyan N, Pannellini T, Carballo C, McIlwain D, Mak TW, Rodeo S, Acharya S, Li D, Szymonifka J, Song X, Monette S, Srivastava A, Salmon JE, Blobel CP

Abstract
Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder Hemophilia A. HA typically begins with hemophilic synovitis (HS) that resembles inflammatory arthritides such as rheumatoid arthritis (RA) and frequently results in bone loss in patients. A major cause of RA is inappropriate release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) by the TNFα convertase (TACE, also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNFα also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNFα shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8-/- mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNFα levels in the affected joint of F8-/- mice. Moreover, inactivation of TNFα or iRhom2 in F8-/- mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNFα pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this pro-inflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients.

PMID: 29776906 [PubMed - as supplied by publisher]

Clinical Implication of MicroRNAs in Molecular Pathology: An Update for 2018.

Clin Lab Med. 2018 Jun;38(2):237-251

Authors: Sethi S, Sethi S, Bluth MH

Abstract
MicroRNAs (miRNAs) are poised to provide diagnostic, prognostic, and therapeutic targets for several diseases including malignancies for precision medicine applications. The miRNAs have immense potential in the clinical arena because they can be detected in the blood, serum, tissues (fresh and formalin-fixed paraffin-embedded), and fine-needle aspirate specimens. The most attractive feature of miRNA-based therapy is that a single miRNA could be useful for targeting multiple genes that are deregulated in cancers, which can be further investigated through systems biology and network analysis that may provide cancer-specific personalized therapy.

PMID: 29776629 [PubMed - in process]

A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy.

BMC Cancer. 2018 May 18;18(1):569

Authors: Buetti-Dinh A, Jensen R, Friedman R

Abstract
BACKGROUND: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations.
METHODS: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors.
RESULTS: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and PI3K appeared as a significant factor in controlling tumour proliferation.
CONCLUSIONS: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

PMID: 29776351 [PubMed - in process]

Universal principles governing multiple random searchers on complex networks: The logarithmic growth pattern and the harmonic law.

Phys Rev E. 2018 Mar;97(3-1):032320

Authors: Weng T, Zhang J, Small M, Harandizadeh B, Hui P

Abstract
We propose a unified framework to evaluate and quantify the search time of multiple random searchers traversing independently and concurrently on complex networks. We find that the intriguing behaviors of multiple random searchers are governed by two basic principles-the logarithmic growth pattern and the harmonic law. Specifically, the logarithmic growth pattern characterizes how the search time increases with the number of targets, while the harmonic law explores how the search time of multiple random searchers varies relative to that needed by individual searchers. Numerical and theoretical results demonstrate these two universal principles established across a broad range of random search processes, including generic random walks, maximal entropy random walks, intermittent strategies, and persistent random walks. Our results reveal two fundamental principles governing the search time of multiple random searchers, which are expected to facilitate investigation of diverse dynamical processes like synchronization and spreading.

PMID: 29776160 [PubMed - in process]

Post-transcriptional bursting in genes regulated by small RNA molecules.

Phys Rev E. 2018 Mar;97(3-1):032401

Authors: Rodrigo G

Abstract
Gene expression programs in living cells are highly dynamic due to spatiotemporal molecular signaling and inherent biochemical stochasticity. Here we study a mechanism based on molecule-to-molecule variability at the RNA level for the generation of bursts of protein production, which can lead to heterogeneity in a cell population. We develop a mathematical framework to show numerically and analytically that genes regulated post transcriptionally by small RNA molecules can exhibit such bursts due to different states of translation activity (on or off), mostly revealed in a regime of few molecules. We exploit this framework to compare transcriptional and post-transcriptional bursting and also to illustrate how to tune the resulting protein distribution with additional post-transcriptional regulations. Moreover, because RNA-RNA interactions are predictable with an energy model, we define the kinetic constants of on-off switching as functions of the two characteristic free-energy differences of the system, activation and formation, with a nonequilibrium scheme. Overall, post-transcriptional bursting represents a distinctive principle linking gene regulation to gene expression noise, which highlights the importance of the RNA layer beyond the simple information transfer paradigm and significantly contributes to the understanding of the intracellular processes from a first-principles perspective.

PMID: 29776125 [PubMed - in process]

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Web pages: What can you see in a single fixation?

Cogn Res Princ Implic. 2018;3(1):14

Authors: Jahanian A, Keshvari S, Rosenholtz R

Abstract
Research in human vision suggests that in a single fixation, humans can extract a significant amount of information from a natural scene, e.g. the semantic category, spatial layout, and object identities. This ability is useful, for example, for quickly determining location, navigating around obstacles, detecting threats, and guiding eye movements to gather more information. In this paper, we ask a new question: What can we see at a glance at a web page - an artificial yet complex "real world" stimulus? Is it possible to notice the type of website, or where the relevant elements are, with only a glimpse? We find that observers, fixating at the center of a web page shown for only 120 milliseconds, are well above chance at classifying the page into one of ten categories. Furthermore, this ability is supported in part by text that they can read at a glance. Users can also understand the spatial layout well enough to reliably localize the menu bar and to detect ads, even though the latter are often camouflaged among other graphical elements. We discuss the parallels between web page gist and scene gist, and the implications of our findings for both vision science and human-computer interaction.

PMID: 29774229 [PubMed]