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PurposeThe aim of this study was to evaluate the choroidal and photoreceptor thickness in highly myopic eyes and its correlation with visual acuity.MethodsThis is a cross-sectional, observational study involving 57 eyes of 57 highly myopic subjects [spherical equivalent ≥ –6 diopters (D) or axial length ≥ 26 mm] seen in a tertiary institutional center. Eyes with any clinical evidence of maculopathy or amblyopia were excluded. All subjects underwent a refraction assessment, visual acuity, axial length measurement using the IOL Master, and full ocular assessment. Eyes were imaged using Spectralis Optical Coherence Tomography by one experienced operator. Two independent investigators manually measured subfoveal choroidal thickness (SFCT) and foveal photoreceptor thickness (FPT).ResultsThe mean SFCT was 195.88 ± 87.63 μm (range: 32–373) and mean FPT was 96.68 ± 11.23 μm (range: 67–100), after correction for ocular magnification. The best corrected visual acuity (BCVA) in LogMAR was negatively correlated with SFCT (r = –0.510, p = 0.001) and FPT (r = –0.397, p = 0.002) and positively correlated with age (r = 0.418, p = 0.001) and axial length (r = 0.551, p = 0.001). Multiple linear regression analysis showed that age, axial length, and corrected FPT were significant risk factors for poorer BCVA (p = 0.021, < 0.001, and 0.02, respectively).ConclusionFPT, age, and axial length are significant moderate predictive factors for poorer visual acuity in highly myopic eyes without myopic maculopathy. Thinner SFCT does not translate into poorer vision.

We engineered fluorene-based dyes with various π-bridge motifs for indoor photovoltaic applications. Density functional theory (DFT) calculations with B3LYP/6-31G(d,p), validated through benchmark studies, revealed comprehensive structure-property relationships governing optical and electronic characteristics. Quantitative analysis identified four absorption spectral types (A-D), characterized by distinct intramolecular charge transfer (ICT) patterns and chemical reactivity parameters. Type A dyes exhibited optimal characteristics for indoor applications with balanced light harvesting and transparency, while Type B dyes demonstrated superior performance under AM 1.5G and LED 3200 K conditions. Types C and D showed higher transparency but varying performance under different indoor light sources. These findings provide experimentally verifiable molecular design principles for optimizing indoor dye-sensitized solar cells (DSSCs), emphasizing spectral matching while maintaining aesthetic integration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Background: Sirolimus-coated balloon (SCB), a relatively novel technology appears attractive due to the drug properties (safety and efficacy) and sirolimus remains the drug of choice in stents. However, there is limited data long-term data on SCB. In this study, we have explored the clinical outcomes following the use of SCB in de-novo lesions from a real-world practice., Aims: To report long-term clinical outcomes following the use of Siroliumus coated balloon in de novo lesions., Methods and Results: We analyzed all patients treated with an SCB in de novo lesions between 2016 and 2023 at four high-volume centers in UK and Italy. The outcomes measured included cardiac death, target vessel myocardial infarction (TVMI), target lesion revascularization (TLR) and major adverse cardiac events (MACE). During the study period, 771 patients had SCB in de novo lesions. Diabetes mellitus was noted in 36% of patients (n = 280), of which 14% (n = 108) were insulin dependent. Fifteen percent (n = 117) had chronic kidney disease, Fifty-two percent (n = 398) of cases were in the setting acute coronary syndrome (ACS) and of which 51 cases (7%) were ST-segment elevation myocardial infarction. Small vessels (<3.0 mm) accounted for 78% (n = 601) of cases and 76% (n = 584) were long lesions ( ≥ 20 mm). The mean diameter of SCB was 2.6 ± 0.4 mm and the mean length was 25 ± 10.39 mm. Bailout stenting following SCB was required in 9% lesions (n = 67). During the median follow-up 640 days, total death occurred in 39 (5%) patients and of which, cardiac death occurred in 10 patients (1.3%). TVMI occurred in 20 patients (2.6%). TLR and TVR were 5.6% and 5.8% respectively. The overall MACE rate was 8%. We had no documented case of acute vessel closure., Conclusions: The results from this long-term follow-up in a real-world population are encouraging with low rates of hard endpoints and acceptable rates of TLR and MACE despite a complex group of patients. Our data suggest that SCBs are safe in coronary intervention with good clinical outcomes in the long term., (© 2024 Wiley Periodicals LLC.)

Background: Acrylamide polymers with zwitterionic carboxybetaine (CB) side groups have attracted attention as stealth polymers that do not induce antibodies when conjugated to proteins. However, they induce antibodies when modified onto liposomes. We hypothesized that antibodies are produced against polymer backbones rather than CB side groups. Objectives: In this study, we designed and synthesized a polymer employing CB in its main chain, poly( N -acetic acid- N -methyl-propyleneimine) (PAMPI), and evaluated the blood retention of PAMPI-modified liposomes in mice. Results: The non-fouling nature of PAMPI-modified liposomes estimated from serum protein adsorption was found to be not inferior to PCB- and PEG-modified liposomes. However, to our surprise, the PAMPI-modified liposomes showed an instantaneous clearance less than 1 h post-injection, comparable to the naked liposomes. Conclusions: The extent of the blood retention of polymer-modified liposomes cannot be predicted by their susceptibility to serum protein adsorption and semi-flexible conformation.

Pulu Mandoti, a local red rice (Oryza sativa L.) variety popular among Sulawesi residents, has gained recognition for its perceived health benefits, especially as a preferred dietary option for individuals with diabetes or those seeking to prevent obesity. Given the increasing consumption of mushrooms, particularly Pleurotus species, renowned for their nutritional and medicinal attributes, this study delves into the transformative effects of Pleurotus spp. fermentation on Pulu Mandoti, the indigenous rice variety. Proximate analysis disclosed elevated dry matter (91.99 ± 0.61%), crude protein (8.55 ± 0.15%), and crude fat (1.34 ± 0.05%) in Pleurotus cystidiosus fermentation compared to Pleurotus ostreatus and Pleurotus djamor. Concurrently, antioxidant and antidiabetic activities were notably improved in all Pleurotus fermentations. Pulu Mandoti fermented with P. cystidiosus outperformed other treatments, aligning with molecular docking results pinpointing 11-Eicosenoic acid, methyl ester, and butylated hydroxytoluene as optimal interactors with antioxidant receptors 5O0x and 2CKJ. Butylated hydroxytoluene demonstrated interactions with the antidiabetic receptor 2QV4, along with 9-Octadecenoic acid, methyl ester. These compounds, previously unreported in Pleurotus, displayed promising attributes as antioxidants and antidiabetic agents. Furthermore, the investigation delved into the fatty acid profiles, emphasizing the diverse range of potential bioactive compounds in fermented Pulu Mandoti. The findings of this research present a potential functional food rich in natural antioxidants and antidiabetic compounds, highlighting the yet undiscovered capabilities of Pleurotus spp. fermentation in augmenting the nutritional composition and bioactivity of indigenous rice varieties, specifically Pulu Mandoti., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Breast cancer ranks second in terms of the highest number of cancer deaths for women worldwide and is one of the leading causes of death from cancer in women. The drug that is often used for chemotherapy is cisplatin. However, cisplatin drugs have a number of problems, including lack of selectivity, unwanted side effects, resistance, and toxicity in the body. In this work, we investigated Ni(II) cysteine-tyrosine dithiocarbamate complex against breast cancer., Methods: Research on the new complex compound Ni(II) cysteine-tyrosine dithiocarbamate have several stages including synthesis, characterization, in-silico and in-vitro testing of MCF-7 cells for anticancer drugs. The synthesis involved reacting cysteine, CS2, KOH and tyrosine with Mn metal. The new complex compound Ni(II) cysteine-tyrosine dithiocarbamate has been synthesized, characterized, and tested in vitro MCF-7 cells for anticancer drugs. Characterization tests such as melting point, conductivity, SEM-EDS, UV Vis, XRD, and FT-IR spectroscopy have been carried out., Result: The synthesis yielded a 60,16%, conversion with a melting point of 216-218 oC and a conductivity value of 0.4 mS/cm. In vitro test results showed morphological changes (apoptosis) in MCF-7 cancer cells starting at a sample concentration of 250 µg/mL and an IC50 value of 618.40 µg/mL. Molecular docking study of Ni(II) cysteine-tyrosine dithiocarbamate complex identified with 4,4',4''-[(2R)-butane-1,1,2-triyl]triphenol - Estrogen α showing active site with acidic residue amino E323, M388, L387, G390 and I389. Hydrophobic and hydrophobic bonds are seen in Ni(II) cysteine-tyrosine dithiocarbamate - Estrogen α has a binding energy of -80.9429 kJ /mol., Conclusion: there were 5 residues responsible for maintaining the ligand binding stable. The compound had significant Hbond contact intensity, however, it was not strong enough to make a significant anticancer effect. Though the synthesized compound shows low bioactivity, this research is expected to give valuable insight into the effect of molecular structure on anticancer activity.

Background: Microarrays are a well-established and widely adopted technology capable of interrogating hundreds of thousands of loci across the human genome. Combined with imputation to cover common variants not included in the chip design, they offer a cost-effective solution for large-scale genetic studies. Beyond research applications, this technology can be applied for testing pharmacogenomics, nutrigenetics, and complex disease risk prediction. However, establishing clinical reporting workflows requires a thorough evaluation of the assay's performance, which is achieved through validation studies. In this study, we performed pre-clinical validation of a genetic testing workflow based on the Illumina Global Screening Array for 25 pharmacogenomic-related genes. Methods: To evaluate the accuracy of our workflow, we conducted multiple pre-clinical validation studies. Here, we present the results of accuracy and precision assessments, involving a total of 73 cell lines. These assessments encompass reference materials from the Genome-In-A-Bottle (GIAB), the Genetic Testing Reference Material Coordination Program (GeT-RM) projects, as well as additional samples from the 1000 Genomes project (1KGP). We conducted an accuracy assessment of genotype calls for target loci in each indication against established truth sets. Results: In our per-sample analysis, we observed a mean analytical sensitivity of 99.39% and specificity 99.98%. We further assessed the accuracy of star-allele calls by relying on established diplotypes in the GeT-RM catalogue or calls made based on 1KGP genotyping. On average, we detected a diplotype concordance rate of 96.47% across 14 pharmacogenomic-related genes with star allele-calls. Lastly, we evaluated the reproducibility of our findings across replicates and observed 99.48% diplotype and 100% phenotype inter-run concordance. Conclusion: Our comprehensive validation study demonstrates the robustness and reliability of the developed workflow, supporting its readiness for further development for applied testing., Competing Interests: Authors PG, MH, MY, JH, LS, AI, KC, and MG-P were employed by Nalagenetics Pte Ltd. Authors HM, DW, SS, DO, FD, TA, TP, PA, RP, RH, MK, and AP were employed by Genomik Solidaritas Indonesia., (Copyright © 2024 Gan, Hajis, Yumna, Haruman, Matoha, Wahyudi, Silalahi, Oktariani, Dela, Annisa, Pitaloka, Adhiwijaya, Pauzi, Hertanto, Kumaheri, Sani, Irwanto, Pradipta, Chomchopbun and Gonzalez-Porta.)

Epidermolysis bullosa (EB) is an inherited skin disease representing a spectrum of rare genetic disorders. These conditions share the common trait that causes fragile skin, resulting in the development of blisters and erosions. The inheritance follows an autosomal pattern, and the array of clinical presentations leads to significant physical suffering, considerable morbidity, and mortality. Despite EB having no cure, effectively managing EB remains an exceptional challenge due to its rarity and complexity, occasionally casting a profound impact on the lives of affected individuals. Considering that EB management requires a multidisciplinary approach, this sometimes worsens the condition of patients with EB due to inappropriate handling. Thus, more appropriate and precise treatment management of EB is essentially needed. Advanced technology in medicine and health comes into the bioinformatics era. Including treatment for skin diseases, omics-based approaches aim to evaluate and handle better disease management and treatment. In this work, we review several approaches regarding the implementation of omics-based technology, including genetics, pathogenic mutation, skin microbiomics, and metagenomics analysis for EB. In addition, we highlight recent updates on the potential of metagenomics analysis in precision medicine for EB., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Tear sampling is an attractive option for collecting biological samples in ophthalmology clinics, as it offers a non-invasive alternative to other invasive techniques. However, there are many tear sampling methods still in consideration. This study explores the suitability of Schirmer's test strip and microcapillary tube as reliable and satisfactory methods for tear sampling., Methods: Tear samples were collected from eight healthy volunteers using the standard Schirmer's test strip method with or without anesthesia and microcapillary tubes. The total tear protein concentrations were analyzed via spectrophotometry and bicinchoninic acid (BCA) protein assay. The protein profile was determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The optimal wetting length of Schirmer's strip and suitable buffer solutions were compared. Discomfort levels reported by participants and the ease of execution for ophthalmologists were also evaluated., Results: Tear samples exhibited typical protein profiles as shown by SDS-PAGE. The mean total protein obtained from an optimum wetting length of 20 mm using Schirmer's strip without anesthesia in phosphate-buffered saline (PBS) yielded substantial quantities of protein as measured by nanophotometer (220.20 ± 67.43 µg) and the BCA protein assay (210.34 ± 59.46 µg). This method collected a significantly higher quantity of protein compared to the microcapillary tube method (p=0.004) which was much more difficult to standardize. The clinician found it harder to utilize microcapillary tubes, while participants experienced higher insecurity and less discomfort with the microcapillary tube method. PBS used during the tear protein extraction process eluted higher tear protein concentration than ammonium bicarbonate, although the difference was not statistically significant. Using anaesthesia did not ease the sampling procedure substantially and protein quantity was maintained., Conclusion: Good quality and quantity of protein from tear samples were extracted with the optimized procedure. Schirmer's strip test in the absence of local anesthesia provided a standard, convenient, and non-invasive method for tear collection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tham et al.)

Objective: Cervical cancer is a malignancy originating from the cervix and often caused by oncogenic Human Papilloma Virus (HPV), specifically subtypes 16 and 18. Anticancer drugs are chemotherapeutic compounds used for cancer treatment. Therefore, this research aims to synthesize and characterize Zinc (II) dichloroethylenediamine (Zn(en)Cl2) complex, as well as determine its antiproliferative activity against HeLa cells. The Zn(en)Cl2 complex was successfully synthesized, and the antiproliferative activity was tested., Methods: The synthesis involved reacting ethylenediamine and KCl with Zn metal. The complex formed was characterized using a conductometer, UV-Vis spectroscopy, FT-IR spectroscopy, and XRD, while the activity was measured against HeLa cells., Result: The synthesis yielded a 56.12% conversion with a melting point of 198-200 oC and a conductivity value of 2.02 mS/cm. The Zn(en)Cl2 complex showed potential activity against HeLa cells with an IC50 value of 898.35 µg/mL, which was evidenced by changes in the morphological structure of HeLa cells. Its interaction with DNA targets was investigated by employing molecular docking., Conclusion: The observed data indicated that the Zn(en)Cl2 complex bound to DNA at the nitrogenous base Guanine (DG) by coordinate covalent bonds. Interestingly, DG maintained interaction with the complex until the end of the docking simulation. Additionally, molecular dynamics (MD) simulation was conducted, and the results showed that Zn(en)Cl2 remained bound to the DNA binding pocket all through the process.

Liver cancer is the fourth leading cause of death worldwide. Well-known risk factors include hepatitis B virus and hepatitis C virus, along with exposure to aflatoxins, excessive alcohol consumption, obesity, and type 2 diabetes. Genomic variants play a crucial role in mediating the associations between these risk factors and liver cancer. However, the specific variants involved in this process remain under-explored. This study utilized a bioinformatics approach to identify genetic variants associated with liver cancer from various continents. Single-nucleotide polymorphisms associated with liver cancer were retrieved from the genome-wide association studies catalog. Prioritization was then performed using functional annotation with HaploReg v4.1 and the Ensembl database. The prevalence and allele frequencies of each variant were evaluated using Pearson correlation coefficients. Two variants, rs2294915 and rs2896019, encoded by the PNPLA3 gene, were found to be highly expressed in the liver tissue, as well as in the skin, cell-cultured fibroblasts, and adipose-subcutaneous tissue, all of which contribute to the risk of liver cancer. We further found that these two SNPs (rs2294915 and rs2896019) were positively correlated with the prevalence rate. Positive associations with the prevalence rate were more frequent in East Asian and African populations. We highlight the utility of this population-specific PNPLA3 genetic variant for genetic association studies and for the early prognosis and treatment of liver cancer. This study highlights the potential of integrating genomic databases with bioinformatic analysis to identify genetic variations involved in the pathogenesis of liver cancer. The genetic variants investigated in this study are likely to predispose to liver cancer and could affect its progression and aggressiveness. We recommend future research prioritizing the validation of these variations in clinical settings.

Synthetic biology has gained many interest around the globe in the last two decades, not only due to its rapid development but also the potential to provide addressable solutions using standardized design of biological systems. Considering its huge population, biodiversity, and natural resources, Indonesia could play an important role in shaping the future of synthetic biology towards a sustainable bio-circular economy. Here, we provide an overview of synthetic biology development in Indonesia, especially on exploring the potential of our biodiversity. We also discuss some potentials of synthetic biology in solving national issues. Furthermore, we also provide the projection and future landscape of synthetic biology development in Indonesia. In addition, we briefly explain the potential challenges that may arise during the development., Competing Interests: All authors declare that they have no conflicting interests., (© 2023 The Authors.)

The reactivating of disseminated dormant breast cancer cells in a soft viscoelastic matrix is mostly correlated with metastasis. Metastasis occurs due to rapid stress relaxation owing to matrix remodeling. Here, we demonstrate the possibility of promoting the permanent cell cycle arrest of breast cancer cells on a viscoelastic liquid substrate. By controlling the molecular weight of the hydrophobic molten polymer, poly(ε-caprolactone- co -D,L-lactide) within 35-63 g/mol, this study highlights that MCF7 cells can sense a 1000 times narrower relaxation time range (80-290 ms) compared to other studies by using a crosslinked hydrogel system. We propose that the rapid bulk relaxation response of the substrate promotes more reactive oxygen species generation in the formed semi-3D multicellular aggregates of breast cancer cells. Our finding sheds light on the potential role of bulk stress relaxation in a viscous-dominant viscoelastic matrix in controlling the cell cycle arrest depth of breast cancer cells.

Pleiotropy, which refers to the ability of different mutations on the same gene to cause different pathological effects in human genetic diseases, is important in understanding system-level biological diseases. Although some biological experiments have been proposed, still little is known about pleiotropy on gene-gene dynamics, since most previous studies have been based on correlation analysis. Therefore, a new perspective is needed to investigate pleiotropy in terms of gene-gene dynamical characteristics. To quantify pleiotropy in terms of network dynamics, we propose a measure called in silico Pleiotropic Scores (sPS), which represents how much a gene is affected against a pair of different types of mutations on a Boolean network model. We found that our model can identify more candidate pleiotropic genes that are not known to be pleiotropic than the experimental database. In addition, we found that many types of functionally important genes tend to have higher sPS values than other genes; in other words, they are more pleiotropic. We investigated the relations of sPS with the structural properties in the signaling network and found that there are highly positive relations to degree, feedback loops, and centrality measures. This implies that the structural characteristics are principles to identify new pleiotropic genes. Finally, we found some biological evidence showing that sPS analysis is relevant to the real pleiotropic data and can be considered a novel candidate for pleiotropic gene research. Taken together, our results can be used to understand the dynamics pleiotropic characteristics in complex biological systems in terms of gene-phenotype relations., Competing Interests: The authors declare no conflicts of interest.

Purpose: Many studies have evaluated the impact of the COVID-19 pandemic on women's mental health and menstrual changes. However, most of these studies only included nonhospitalized COVID-19 patients, while information on hospitalized women is very limited. Thus, this study aimed to examine the mental health status and menstrual changes in hospitalized female COVID-19 patients., Methods: A survey was administered to female COVID-19 patients in the isolation ward of a national referral hospital in Indonesia between January and August 2021, and the women were followed up 3 months after discharge. The survey evaluated menstrual patterns and mental health using the Self Reporting Questionnaire-29 (SRQ-29)., Results: The study enrolled 158 female patients. There was an increase in patients who had a cycle length of > 32 or < 24 days, and significant increases in menstrual irregularity and heavy menstrual bleeding were noted. Overall, 37.3% of the patients reported a change in menstrual pattern after infection with COVID-19. Based on SRQ-29 scores, 32.3% of the women had neurotic symptoms, 12.7% had psychotic symptoms, and 38.0% had symptoms of posttraumatic stress disorder. Patients with symptoms of mental health disorders were twice as likely to report a menstrual change (OR 2.17, 95% CI 1.12-4.22; p = 0.021)., Conclusion: Menstrual changes and increased symptoms of mental health disorders occur in hospitalized female COVID-19 patients. The length of isolation was the key factor affecting overall menstrual changes and mental health in hospitalized female COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Endometriosis is a condition associated with pelvic pain, infertility, and possibly with decreased quality of life as well as psychiatric disorder. The purpose of our study was to evaluate the association between pain characteristic, psychiatric disorder, and quality of life in women with endometriosis., Methods: A cross-sectional study was done involving 160 women with medical diagnosis of endometriosis. Pain intensity was evaluated using Visual Analog Scale (VAS), Quality of Life with Endometriosis Health Profile (EHP-30), and psychologic condition with Mini International Neuropsychiatric Interview International Classification of Diseases (Mini-ICD)., Results: VAS and psychiatric disorder were associated with higher EHP-30 score (β = 9.3 (95% CI: 7.15-11.45; p < 0.001 and β = 28.51 (95% CI: 20.06-36.05; p < 0.001), respectively) and hence, lower quality of life. The strongest correlation between VAS and EHP-30 was in pain (r=0.586; p<0.001) and 'control and powerlessness' (r = 0.583; p < 0.001). VAS was also higher in subjects with depression (49.5 (25.4-77.8) vs 34.4 (6.1-74.6); p < 0.001)., Conclusion: We conclude that severe endometriosis-related pain and the presence of psychiatric disorder were associated with lower quality of life. Comprehensive management of endometriosis is crucial to improve patients' quality of life., Competing Interests: The authors declare that there is no conflict of interest., (© 2022 Muharam et al.)

Background: Age-related loss of female fertility is characterized by a decline in both the quantity and quality of ovarian follicles. Symptoms of ovarian stimulation, which is part of the process of in vitro fertilization (IVF), vary among women. This study was conducted to analyze the differences in menopausal timing and symptoms in women who had undergone IVF compared to those who had natural pregnancies., Methodology: In this cross-sectional study, menopausal women were categorized into two groups: those who had undergone IVF (n = 50) and those who had not (n = 50). Clinical data were obtained from the participants' medical records, and patient interviews were conducted using the menopause rating scale (MRS) questionnaires., Results: The IVF had no significant impact on psychological or somatic symptoms in either group (p>0.05). However, it affected urogenital symptoms (p<0.05). Additionally, there was a significant difference in the age of onset of menopause between the groups (p<0.05)., Conclusion: There is a significant correlation between IVF treatment, urogenital symptoms in menopause, and the age of onset of menopause., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2021 Muharam et al.)

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.

Background: Many previous clinical studies have found that accumulated sequential mutations are statistically related to tumorigenesis. However, they are limited in fully elucidating the significance of the ordered-mutation because they did not focus on the network dynamics. Therefore, there is a pressing need to investigate the dynamics characteristics induced by ordered-mutations., Methods: To quantify the ordered-mutation-inducing dynamics, we defined the mutation-sensitivity and the order-specificity that represent if the network is sensitive against a double knockout mutation and if mutation-sensitivity is specific to the mutation order, respectively, using a Boolean network model., Results: Through intensive investigations, we found that a signaling network is more sensitive when a double-mutation occurs in the direction order inducing a longer path and a smaller number of paths than in the reverse order. In addition, feedback loops involving a gene pair decreased both the mutation-sensitivity and the order-specificity. Next, we investigated relationships of functionally important genes with ordered-mutation-inducing dynamics. The network is more sensitive to mutations subject to drug-targets, whereas it is less specific to the mutation order. Both the sensitivity and specificity are increased when different-drug-targeted genes are mutated. Further, we found that tumor suppressors can efficiently suppress the amplification of oncogenes when the former are mutated earlier than the latter., Conclusion: Taken together, our results help to understand the importance of the order of mutations with respect to the dynamical effects in complex biological systems.

Background: Identification of novel gene-gene relations is a crucial issue to understand system-level biological phenomena. To this end, many methods based on a correlation analysis of gene expressions or structural analysis of molecular interaction networks have been proposed. They have a limitation in identifying more complicated gene-gene dynamical relations, though., Results: To overcome this limitation, we proposed a measure to quantify a gene-gene dynamical influence (GDI) using a Boolean network model and constructed a GDI network to indicate existence of a dynamical influence for every ordered pair of genes. It represents how much a state trajectory of a target gene is changed by a knockout mutation subject to a source gene in a gene-gene molecular interaction (GMI) network. Through a topological comparison between GDI and GMI networks, we observed that the former network is denser than the latter network, which implies that there exist many gene pairs of dynamically influencing but molecularly non-interacting relations. In addition, a larger number of hub genes were generated in the GDI network. On the other hand, there was a correlation between these networks such that the degree value of a node was positively correlated to each other. We further investigated the relationships of the GDI value with structural properties and found that there are negative and positive correlations with the length of a shortest path and the number of paths, respectively. In addition, a GDI network could predict a set of genes whose steady-state expression is affected in E. coli gene-knockout experiments. More interestingly, we found that the drug-targets with side-effects have a larger number of outgoing links than the other genes in the GDI network, which implies that they are more likely to influence the dynamics of other genes. Finally, we found biological evidences showing that the gene pairs which are not molecularly interacting but dynamically influential can be considered for novel gene-gene relationships., Conclusion: Taken together, construction and analysis of the GDI network can be a useful approach to identify novel gene-gene relationships in terms of the dynamical influence.