Whole-genome doubling drives oncogenic loss of chromatin segregation.

Whole-genome doubling (WGD) is a recurrent event in human cancers and it promotes chromosomal instability and acquisition of aneuploidies1-8. However, the three-dimensional organization of chromatin in WGD cells and its contribution to oncogenic phenotypes are currently unknown. Here we show that in p53-deficient cells, WGD induces loss of chromatin segregation (LCS). This event is characterized by reduced segregation between short and long chromosomes, A and B subcompartments and adjacent chromatin domains. LCS is driven by the downregulation of CTCF and H3K9me3 in cells that bypassed activation of the tetraploid checkpoint. Longitudinal analyses revealed that LCS primes genomic regions for subcompartment repositioning in WGD cells. This results in chromatin and epigenetic changes associated with oncogene activation in tumours ensuing from WGD cells. Notably, subcompartment repositioning events were largely independent of chromosomal alterations, which indicates that these were complementary mechanisms contributing to tumour development and progression. Overall, LCS initiates chromatin conformation changes that ultimately result in oncogenic epigenetic and transcriptional modifications, which suggests that chromatin evolution is a hallmark of WGD-driven cancer.

Dendritic cells direct circadian anti-tumour immune responses.

The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime1,2. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance.

Genomic identification and expression analysis of acid invertase (AINV) gene family in Dendrobium officinale Kimura et Migo.

BACKGROUND: Dendrobium officinale Kimura et Migo, a renowned traditional Chinese orchid herb esteemed for its significant horticultural and medicinal value, thrives in adverse habitats and contends with various abiotic or biotic stresses. Acid invertases (AINV) are widely considered enzymes involved in regulating sucrose metabolism and have been revealed to participate in plant responses to environmental stress. Although members of AINV gene family have been identified and characterized in multiple plant genomes, detailed information regarding this gene family and its expression patterns remains unknown in D. officinale, despite their significance in polysaccharide biosynthesis. RESULTS: This study systematically analyzed the D. officinale genome and identified four DoAINV genes, which were classified into two subfamilies based on subcellular prediction and phylogenetic analysis. Comparison of gene structures and conserved motifs in DoAINV genes indicated a high-level conservation during their evolution history. The conserved amino acids and domains of DoAINV proteins were identified as pivotal for their functional roles. Additionally, cis-elements associated with responses to abiotic and biotic stress were found to be the most prevalent motif in all DoAINV genes, indicating their responsiveness to stress. Furthermore, bioinformatics analysis of transcriptome data, validated by quantitative real-time reverse transcription PCR (qRT-PCR), revealed distinct organ-specific expression patterns of DoAINV genes across various tissues and in response to abiotic stress. Examination of soluble sugar content and interaction networks provided insights into stress release and sucrose metabolism. CONCLUSIONS: DoAINV genes are implicated in various activities including growth and development, stress response, and polysaccharide biosynthesis. These findings provide valuable insights into the AINV gene amily of D. officinale and will aid in further elucidating the functions of DoAINV genes.

MicroRNA482/2118 is lineage-specifically involved in gibberellin signalling via the regulation of GID1 expression by targeting noncoding PHAS genes and subsequently instigated phasiRNAs.

MicroRNA482/2118 (miR482/2118) is a 22-nt miRNA superfamily, with conserved functions in disease resistance and plant development. It usually instigates the production of phased small interfering RNAs (phasiRNAs) from its targets to expand or reinforce its silencing effect. Using a new high-quality reference genome sequence and comprehensive small RNA profiling, we characterized a newly evolved regulatory pathway of miR482/2118 in litchi. In this pathway, miR482/2118 cleaved a novel noncoding trans-acting gene (LcTASL1) and triggered phasiRNAs to regulate the expression of gibberellin (GA) receptor gene GIBBERELLIN INSENSITIVE DWARF1 (GID1) in trans; another trans-acting gene LcTASL2, targeted by LcTASL1-derived phasiRNAs, produced phasiRNAs as well to target LcGID1 to reinforce the silencing effect of LcTASL1. We found this miR482/2118-TASL-GID1 pathway was likely involved in fruit development, especially the seed development in litchi. In vivo construction of the miR482a-TASL-GID1 pathway in Arabidopsis could lead to defects in flower and silique development, analogous to the phenotype of gid1 mutants. Finally, we found that a GA-responsive transcription factor, LcGAMYB33, could regulate LcMIR482/2118 as a feedback mechanism of the sRNA-silencing pathway. Our results deciphered a lineage-specifically evolved regulatory module of miR482/2118, demonstrating the high dynamics of miR482/2118 function in plants.

Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL.

NOTCH1 is a well-established lineage specifier for T cells and among the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology, allowing aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone epigenetic landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered a unique evolutionarily conserved Tcf1-regulated enhancer element in the distal Myc-enhancer, which is important for the transition of preleukemic cells to full-blown disease.

SapBase: A central portal for functional and comparative genomics of Sapindaceae species.

The Sapindaceae family, encompassing a wide range of plant forms such as herbs, vines, shrubs, and trees, is widely distributed across tropical and subtropical regions. This family includes economically important crops like litchi, longan, rambutan, and ackee. With the wide application of genomic technologies in recent years, several Sapindaceae plant genomes have been decoded, leading to an accumulation of substantial omics data in this field. This surge in data highlights the pressing need for a unified genomic data center capable of storing, sharing, and analyzing these data. Here, we introduced SapBase, that is, the Sapindaceae Genome Database. SapBase houses seven published plant genomes alongside their corresponding gene structure and functional annotations, small RNA annotations, gene expression profiles, gene pathways, and synteny block information. It offers user-friendly features for gene information mining, co-expression analysis, and inter-species comparative genomic analysis. Furthermore, we showcased SapBase's extensive capacities through a detailed bioinformatic analysis of a MYB gene in litchi. Thus, SapBase could serve as an integrative genomic resource and analysis platform for the scientific exploration of Sapinaceae species and their comparative studies with other plants.

Cytological observation and RNA-seq analysis reveal novel miRNAs high expression associated with the pollen fertility of neo-tetraploid rice.

BACKGROUND: Neo-tetraploid rice lines exhibit high fertility and strong heterosis and harbor novel specific alleles, which are useful germplasm for polyploid rice breeding. However, the mechanism of the fertility associated with miRNAs remains unknown. In this study, a neo-tetraploid rice line, termed Huaduo21 (H21), was used. Cytological observation and RNA-sequencing were employed to identify the fertility-related miRNAs in neo-tetraploid rice. RESULTS: H21 showed high pollen fertility (88.08%), a lower percentage of the pollen mother cell (PMC) abnormalities, and lower abnormalities during double fertilization and embryogenesis compared with autotetraploid rice. A total of 166 non-additive miRNAs and 3108 non-additive genes were detected between H21 and its parents. GO and KEGG analysis of non-additive genes revealed significant enrichments in the DNA replication, Chromosome and associated proteins, and Replication and repair pathways. Comprehensive multi-omics analysis identified 32 pairs of miRNA/target that were associated with the fertility in H21. Of these, osa-miR408-3p and osa-miR528-5p displayed high expression patterns, targeted the phytocyanin genes, and were associated with high pollen fertility. Suppression of osa-miR528-5p in Huaduo1 resulted in a low seed set and a decrease in the number of grains. Moreover, transgenic analysis implied that osa-MIR397b-p3, osa-miR5492, and osa-MIR5495-p5 might participate in the fertility of H21. CONCLUSION: Taken together, the regulation network of fertility-related miRNAs-targets pairs might contribute to the high seed setting in neo-tetraploid rice. These findings enhance our understanding of the regulatory mechanisms of pollen fertility associated with miRNAs in neo-tetraploid rice.

PhasiRNAs in Plants: Their Biogenesis, Genic Sources, and Roles in Stress Responses, Development, and Reproduction.

Phased secondary small interfering RNAs (phasiRNAs) constitute a major category of small RNAs in plants, but most of their functions are still poorly defined. Some phasiRNAs, known as trans-acting siRNAs, are known to target complementary mRNAs for degradation and to function in development. However, the targets or biological roles of other phasiRNAs remain speculative. New insights into phasiRNA biogenesis, their conservation, and their variation across the flowering plants continue to emerge due to the increased availability of plant genomic sequences, deeper and more sophisticated sequencing approaches, and improvements in computational biology and biochemical/molecular/genetic analyses. In this review, we survey recent progress in phasiRNA biology, with a particular focus on two classes associated with male reproduction: 21-nucleotide (accumulate early in anther ontogeny) and 24-nucloetide (produced in somatic cells during meiosis) phasiRNAs. We describe phasiRNA biogenesis, function, and evolution and define the unanswered questions that represent topics for future research.

MicroRNA482/2118, a miRNA superfamily essential for both disease resistance and plant development.

MicroRNAs (miRNAs) are a class of 21-24 nucleotides (nt) noncoding small RNAs ubiquitously distributed across the plant kingdom. miR482/2118, one of the conserved miRNA superfamilies originating from gymnosperms, has divergent main functions in core-angiosperms. It mainly regulates NUCLEOTIDE BINDING SITE-LEUCINE-RICH REPEAT (NBS-LRR) genes in eudicots, functioning as an essential component in plant disease resistance; in contrast, it predominantly targets numerous long noncoding RNAs (lncRNAs) in monocot grasses, which are vital for plant reproduction. Usually, miR482/2118 is 22-nt in length, which can trigger the production of phased small interfering RNAs (phasiRNAs) after directed cleavage. PhasiRNAs instigated from target genes of miR482/2118 enhance their roles in corresponding biological processes by cis-regulation on cognate genes and expands their function to other pathways via trans activity on different genes. This review summarizes the origin, biogenesis, conservation, and evolutionary characteristics of the miR482/2118 superfamily and delineates its diverse functions in disease resistance, plant development, stress responses, etc.

Clinical observation of posterior scleral reinforcement in the treatment of progressive high myopia in Chinese children: a retrospective study.

OBJECTIVE: To observe the efficacy and safety of posterior sclera reinforcement over time. METHODS: This retrospective single-arm cohort study included children with high myopia who underwent the modified Snyder-Thompson type posterior sclera reinforcement surgery from 03/2015 to 08/2018 at Fuzhou Children's Hospital of Fujian Medical University. Axial length (AL), corneal radius of curvature (CRC), AL/CRC, refractive error, and best-corrected visual acuity (BCVA) were observed from 1 year before the operation to 2 years after. RESULTS: Nineteen children (33 eyes) with high myopia were included. The patients were 4.9 ± 2.7 (range, 2-10) years of age (three patients were 10 years old, all others were ≤ 7 years old). AL increased from 1 year before surgery to 2 years after surgery (from 25.31 ± 1.59 to 26.76 ± 1.52, P < 0.001). The refractive error was smaller 1 year before surgery than at the other timepoints (all P < 0.05). BCVA improved over time (P < 0.001). Changes over time were also observed in horizontal CRC (hCRC), AL/hCRC, AL/vertical CRC (vCRC), and AL/CRC (all P < 0.001), but not in vCRC (P = 0.304). The increase of AL at 2 years after surgery was smaller than at 1 year before surgery and 1 year after surgery (both P < 0.001). The increase of AL/CRC at 2 years after surgery was smaller than at 1 year before surgery (0.04 ± 0.04 vs. 0.07 ± 0.04; P = 0.008). CONCLUSION: In the short term, posterior scleral reinforcement surgery can delay the increase of AL of progressive high myopia.

The GRAS gene family and its roles in seed development in litchi (Litchi chinensis Sonn).

BACKGROUND: The GRAS gene family plays crucial roles in multiple biological processes of plant growth, including seed development, which is related to seedless traits of litchi (Litchi chinensis Sonn.). However, it hasn't been fully identified and analyzed in litchi, an economic fruit tree cultivated in subtropical regions. RESULTS: In this study, 48 LcGRAS proteins were identified and termed according to their chromosomal location. LcGRAS proteins can be categorized into 14 subfamilies through phylogenetic analysis. Gene structure and conserved domain analysis revealed that different subfamilies harbored various motif patterns, suggesting their functional diversity. Synteny analysis revealed that the expansion of the GRAS family in litchi may be driven by their tandem and segmental duplication. After comprehensively analysing degradome data, we found that four LcGRAS genes belong to HAM subfamily were regulated via miR171-mediated degradation. The various expression patterns of LcGRAS genes in different tissues uncovered they were involved in different biological processes. Moreover, the different temporal expression profiles of LcGRAS genes between abortive and bold seed indicated some of them were involved in maintaining the normal development of the seed. CONCLUSION: Our study provides comprehensive analyses on GRAS family members in litchi, insight into a better understanding of the roles of GRAS in litchi development, and lays the foundation for further investigations on litchi seed development.

Relationships between physical characteristics and biomechanics of lower extremity during the squat.

BACKGROUND/OBJECTIVE: There is a lack of information about relationship between physical characteristics and biomechanics of the lower extremity during the squat. Additionally, studies did not examine sex-related differences. The purpose of this study was to investigate relationships between physical characteristics and biomechanics of the lower extremity during the squat, and to determine if any sex differences are present. METHODS: Fifty three participants recruited (21.82 ± 2.3 years; 75.56 ± 14.98 kg; 171.57 ± 8.38 cm) performed three squats with 75% of one repetition maximum. Femur to tibia length ratio, hip and ankle joints' flexibilities, and relative muscular strength were measured and used as physical characteristics. Net joint torques (NJT) and flexion angles of the lower extremity were extracted as dependent variables. Multiple regression (stepwise) analysis was conducted to examine the relationships with physical characteristics being factors. Pearson correlation coefficients were calculated to determine intercorrelations among the dependent variables. RESULTS: Relative muscular strength was related to hip NJT and knee flexion angle, and hip flexibility was related to ankle dorsiflexion. Hip and knee NJT showed moderate correlations with the corresponding flexion angles (r = 0.48-0.53; p < .01). Ankle dorsiflexion angle showed weak to moderate correlations with hip NJT and hip flexion angle (r = -0.36-0.50; p < .01) and a moderate correlation with knee NJT. No significant sex difference was observed (r = 0.52; p < .05). CONCLUSION: Biomechanics of the lower extremity has been shown to correlate more with relative muscular strength and joint flexibility than with leg length ratio.

Evolutionary dynamics of lincRNA transcription in nine citrus species.

Long intergenic non-coding RNAs (lincRNAs) play important roles in various biological processes in plants. However, little information is known about the evolutionary characteristics of lincRNAs among closely related plant species. Here, we present a large-scale comparative study of lincRNA transcription patterns in nine citrus species. By strand-specific RNA-sequencing, we identified 18 075 lincRNAs (14 575 lincRNA loci) from 34 tissue samples. The results indicated that the evolution of lincRNA transcription is more rapid than that of mRNAs. In total, 82.8-97.6% of sweet orange (Citrus sinensis) lincRNA genes were shown to have homologous sequences in other citrus genomes. However, only 15.5-28.8% of these genes had transcribed homologous lincRNAs in these citrus species, presenting a strong contrast to the high conservation of mRNA transcription (81.6-84.7%). Moreover, primitive and modern citrus lincRNAs were preferentially expressed in reproductive and vegetative organs, respectively. Evolutionarily conserved lincRNAs showed higher expression levels and lower tissue specificity than species-specific lincRNAs. Notably, we observed a similar tissue expression pattern of homologous lincRNAs in sweet orange and pummelo (Citrus grandis), suggesting that these lincRNAs may be functionally conserved and selectively maintained. We also identified and validated a lincRNA with the highest expression in fruit that acts as an endogenous target mimic (eTM) of csi-miR166c, and two lincRNAs that act as a precursor and target of csi-miR166c, respectively. These lincRNAs together with csi-miR166c could form an eTM166-miR166c-targeted lincRNA regulatory network that possibly affects citrus fruit development.

MicroRNA528, a hub regulator modulating ROS homeostasis via targeting of a diverse set of genes encoding copper-containing proteins in monocots.

Plant microRNAs (miRNAs) regulate vital cellular processes, including responses to extreme temperatures with which reactive oxygen species (ROS) are often closely associated. In the present study, it was found that aberrant temperatures caused extensive changes in abundance to numerous miRNAs in banana fruit, especially the copper (Cu)-associated miRNAs. Among them, miR528 was significantly downregulated under cold stress and it was found to target genes encoding polyphenol oxidase (PPO), different from those identified in rice and maize. Expression of PPO genes was upregulated by > 100-fold in cold conditions, leading to ROS surge and subsequent peel browning of banana fruit. Extensive comparative genomic analyses revealed that the monocot-specific miR528 can potentially target a large collection of genes encoding Cu-containing proteins. Most of them are actively involved in cellular ROS metabolism, including not only ROS generating oxidases, but also ROS scavenging enzymes. It also was demonstrated that miR528 has evolved a distinct preference of target genes in different monocots, with its target site varying in position among/within gene families, implying a highly dynamic process of target gene diversification. Its broad capacity to target genes encoding Cu-containing protein implicates miR528 as a key regulator for modulating the cellular ROS homeostasis in monocots.

The effect of ammonia exposure on energy metabolism and mitochondrial dynamic proteins in chicken thymus: Through oxidative stress, apoptosis, and autophagy.

Ammonia (NH3) gas is an atmospheric pollutant, produced from different sources. In poultry houses NH3 is produced from the biological process of liter, manure, and protein composition. It has been well documented that NH3 adversely effects the health of chickens. However, the underlying mechanism of NH3 toxicity on chicken thymus is still unknown. Thymus is an important immune organ, which play a critical role in eliciting protective immune responses to ensure healing process and elimination of harmful stimuli. The results showed that NH3 exposure reduced antioxidant activities and induced oxidative stress in thymus tissues. Histological observation showed normal morphology of chicken thymus in control group. In contrast, increased number of nuclear debris, vacuoles, and cristae break were seen in NH3 affected chickens. Ultrastructural analysis indicated mitochondrial breakdown, disappearance, vacuoles, and chromatin condensation in NH3 treated groups. The mRNA and protein expression of apoptosis related genes were significantly enhanced in the chicken thymus of NH3 affected chickens compared to control group. Moreover, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay results suggested that NH3 exposure increased positive stained nuclei in the chicken thymus. Meanwhile, NH3 exposure reduced the number of CD8+ T-lymphocytes, decreased the adenosine triphosphate (ATPase) activities. The mRNA and protein expression of autophagy, energy metabolism, and mitochondrial dynamics proteins were altered by NH3 exposure. In summary, these results showed that NH3 induced oxidative stress, apoptosis and autophagic cell death (ACD), which could be the possible causes of immune damage and structural impairment in chicken thymus.

Long Non-Coding RNAs, the Dark Matter: An Emerging Regulatory Component in Plants.

Long non-coding RNAs (lncRNAs) are pervasive transcripts of longer than 200 nucleotides and indiscernible coding potential. lncRNAs are implicated as key regulatory molecules in various fundamental biological processes at transcriptional, post-transcriptional, and epigenetic levels. Advances in computational and experimental approaches have identified numerous lncRNAs in plants. lncRNAs have been found to act as prime mediators in plant growth, development, and tolerance to stresses. This review summarizes the current research status of lncRNAs in planta, their classification based on genomic context, their mechanism of action, and specific bioinformatics tools and resources for their identification and characterization. Our overarching goal is to summarize recent progress on understanding the regulatory role of lncRNAs in plant developmental processes such as flowering time, reproductive growth, and abiotic stresses. We also review the role of lncRNA in nutrient stress and the ability to improve biotic stress tolerance in plants. Given the pivotal role of lncRNAs in various biological processes, their functional characterization in agriculturally essential crop plants is crucial for bridging the gap between phenotype and genotype.

Changes in blood lactate and muscle activation in elite rock climbers during a 15-m speed climb.

PURPOSE: The purpose of this study was to investigate the changes in blood lactate concentration (BL) and muscle activity patterns during a 15-m speed climbing competition that consisted of ten consecutive climbing actions on a standardized artificial wall in trained rock climbers. METHODS: Twelve trained rock climbers participated in this study. Surface electromyography (sEMG) and video signals were synchronized and recorded during climbing. The blood lactate was also tested 3 min after completing the climb. RESULTS: The average climbing time was 8.1 ± 2.1 s for the 15-m speed climb across all subjects, accompanied by a BL of 7.6 ± 1.9 mmol/L. The climbing speed and power firstly increased and then slightly decreased relative to peak value during the 15-m speed climbing. The results showed there was a positive correlation between the BL and the climbing time, r = 0.59, P = 0.043. The sEMG showed the flexor digitorum superficialis (FDS) electric activity was the highest, followed by the biceps brachii (BB) and latissimus dorsi. The instantaneous median frequency of sEMG of FDS and BB significantly decreased during the 15-m speed climbing. All the participants showed the higher sEMG RMS (%) in the terminal phase than that in the initial phase, especially with a greater increase in the left upper limbs. However, the lower limbs muscles presented no significant changes in the sEMG amplitude during climbing. CONCLUSIONS: The FDS and BB play an important role in completing the 15-m speed climbing. The median frequency of arm EMG decreased more than that of legs, suggesting more fatigue. The blood lactate concentration increases in the current study suggest that a certain amount of glycolysis supplies energy in completing 15-m speed rock climbing. Based on the current data, it is suggested that muscular endurance of FDS and BB muscles in upper limbs should be improved for our climbers in this study.

miR3954 is a trigger of phasiRNAs that affects flowering time in citrus.

In plant, a few 22-nt miRNAs direct cleavages of their targets and trigger the biogenesis of phased small interfering RNAs (phasiRNAs) in plant. In this study, we characterized a miRNA triggering phasiRNAs generation, miR3954, and explored its downstream target genes and potential function. Our results demonstrated that miR3954 showed specific expression in the flowers of citrus species, and it targeted a NAC transcription factor (Cs7 g22460) and two non-coding RNA transcripts (lncRNAs, Cs1 g09600 and Cs1 g09635). The production of phasiRNAs was detected from transcripts targeted by miR3954, and was further verified in both sequencing data and transient expression experiments. PhasiRNAs derived from the two lncRNAs targeted not only miR3954-targeted NAC gene but also additional NAC homologous genes. No homologous genes of these two lncRNAs were found in plants other than citrus species, implying that this miR3954-lncRNAs-phasiRNAs-NAC pathway is likely citrus-specific. Transgenic analysis indicated that the miR3954-overexpressing lines showed decreased transcripts of lncRNA, elevated abundance of phasiRNAs and reduced expression of NAC genes. Interestingly, the overexpression of miR3954 leads to early flowering in citrus plants. In summary, our results illustrated a model of the regulatory network of miR3954-lncRNA-phasiRNAs-NAC, which may be functionally involved in flowering in citrus.

SigMod: an exact and efficient method to identify a strongly interconnected disease-associated module in a gene network.

MOTIVATION: Apart from single marker-based tests classically used in genome-wide association studies (GWAS), network-assisted analysis has become a promising approach to identify a set of genes associated with disease. To date, most network-assisted methods aim at finding genes connected in a background network, whatever the density or strength of their connections. This can hamper the findings as sparse connections are non-robust against noise from either the GWAS results or the network resource. RESULTS: We present SigMod, a novel and efficient method integrating GWAS results and gene network to identify a strongly interconnected gene module enriched in high association signals. Our method is formulated as a binary quadratic optimization problem, which can be solved exactly through graph min-cut algorithms. Compared to existing methods, SigMod has several desirable properties: (i) edge weights quantifying confidence of connections between genes are taken into account, (ii) the selection path can be computed rapidly, (iii) the identified gene module is strongly interconnected, hence includes genes of high functional relevance, and (iv) the method is robust against noise from either the GWAS results or the network resource. We applied SigMod to both simulated and real data. It was found to outperform state-of-the-art network-assisted methods in identifying disease-associated genes. When SigMod was applied to childhood-onset asthma GWAS results, it successfully identified a gene module enriched in consistently high association signals and made of functionally related genes that are biologically relevant for asthma. AVAILABILITY AND IMPLEMENTATION: An R package SigMod is available at: https://github.com/YuanlongLiu/SigMod. CONTACT: yuanlong.liu@inserm.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.