Photoperiodic and lighting treatments for flowering control and its genetic regulation in sugarcane breeding.

Improvement of sugarcane is hampered due to its narrow genetic base, and the difficulty in synchronizing flowering further hinders the exploitation of the genetic potential of available germplasm resources. Therefore, the continuous evaluation and optimization of flowering control and induction techniques are vital for sugarcane improvement. In view of this, the review was conducted to investigate the current understanding of photoperiodic and lighting treatment effects on sugarcane flowering and its genetic regulation. Photoperiod facilities have made a significant contribution to flowering control in sugarcane; however, inductive photoperiods are still unknown for some genotypes, and some intended crosses are still impossible to produce because of unresponsive varieties. The effectiveness of lower red/far-red ratios in promoting sugarcane flowering has been widely understood. Furthermore, there is vast potential for utilizing blue, red, and far-red light wavelengths in the flowering control of sugarcane. In this context, light-emitting diodes (LEDs) remain efficient sources of light. Therefore, the combined use of photoperiod regimes with different light wavelengths and optimization of such treatment combinations might help to control and induce flowering in sugarcane parental clones. In sugarcane, FLOWERING LOCUS T (ScFT) orthologues from ScFT1 to ScFT13 have been identified, and interestingly, ScFT3 has evidently been identified as a floral inducer in sugarcane. However, independent assessments of different FT-like gene family members are recommended to comprehensively understand their role in the regulation of flowering. Similarly, we believe this review provides substantial information that is vital for the manipulation of flowering and exploitation of germplasm resources in sugarcane breeding.

The relationship between anxiety symptoms and disturbances in biological rhythms in patients with depression.

BACKGROUND: Biological rhythms denote the cyclical patterns of life activities anchored to a 24-hour cycle. Research shows that depression exhibits disturbances in biological rhythms. Yet, the relationship between these biological rhythms and concomitant anxiety symptoms is insufficiently investigated in structured clinical assessments. METHODS: This multicenter study, carried out in four Chinese hospitals, comprehensively examined the relationship between anxiety and disruptions in biological rhythms among patients with depression. The study encompassed 218 patients diagnosed with depression and 205 matched healthy controls. The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry was utilized to evaluate the participants' biological rhythms, focusing on four dimensions: sleep, activity, social, and diet. RESULTS: In patients with depression, there is a significant positive correlation between the severity of anxiety symptoms and the disturbances in biological rhythms. The severity of anxiety and depression, along with the quality of life, are independently associated with disruptions in biological rhythms. The mediation model reveals that anxiety symptoms mediate the relationship between depressive symptoms and biological rhythms. CONCLUSION: This research highlights the role of anxiety within the spectrum of depressive disorders and the associated disturbances in biological rhythms. Our findings shed light on potential pathways towards more targeted preventive strategies and therapeutic interventions for individuals battling depression and anxiety.

Current perspectives on the regulatory mechanisms of sucrose accumulation in sugarcane.

Sugars transported from leaves (source) to stems (sink) energize cell growth, elongation, and maintenance. which are regulated by a variety of genes. This review reflects progress and prospects in the regulatory mechanism for maximum sucrose accumulation, including the role of sucrose metabolizing enzymes, sugar transporters and the elucidation of post-transcriptional control of sucrose-induced regulation of translation (SIRT) in the accumulation of sucrose. The current review suggests that SIRT is emerging as a significant mechanism controlling Scbzip44 activities in response to endogenous sugar signals (via the negative feedback mechanism). Sucrose-controlled upstream open reading frame (SC-uORF) exists at the 5' leader region of Scbzip44's main ORF, which inhibits sucrose accumulation through post-transcriptional regulatory mechanisms. Sucrose transporters (SWEET1a/4a/4b/13c, TST, SUT1, SUT4 and SUT5) are crucial for sucrose translocation from source to sink. Particularly, SWEET13c was found to be a major contributor to the efflux in the transportation of stems. Tonoplast sugar transporters (TSTs), which import sucrose into the vacuole, suggest their tissue-specific role from source to sink. Sucrose cleavage has generally been linked with invertase isozymes, whereas sucrose synthase (SuSy)-catalyzed metabolism has been associated with biosynthetic processes such as UDP-Glc, cellulose, hemicellulose and other polymers. However, other two key sucrose-metabolizing enzymes, such as sucrose-6-phosphate phosphohydrolase (S6PP) and sucrose phosphate synthase (SPS) isoforms, have been linked with sucrose biosynthesis. These findings suggest that manipulation of genes, such as overexpression of SPS genes and sucrose transporter genes, silencing of the SC-uORF of Scbzip44 (removing the 5' leader region of the main ORF that is called SIRT-Insensitive) and downregulation of the invertase genes, may lead to maximum sucrose accumulation. This review provides an overview of sugarcane sucrose-regulating systems and baseline information for the development of cultivars with higher sucrose accumulation.

Robust, Fully Biodegradable Films of Polyesters Realized by In Situ Formation of an Interconnected Multi-Nanolayer Structure under Extensional Flow.

Multilayer structures are not only applied to manipulate properties of synthetic polymer materials such as rainbow films and barrier films but also widely discovered in natural materials like nacre. In this work, in situ formation of an interconnected multi-nanolayer (IMN) structure in poly(butylene adipate-co-terephthalate) (PBAT)/poly(butylene succinate) (PBS) cocontinuous blends is designed by an extensional flow field during a "casting-thermal stretching" process, combining the properties of two components to a large extent. Hierarchical structures including phase morphology, crystal structure, and lamellar crystals in IMN films have been revealed, which clearly identifies the crucial role of extensional flow. The oriented PBAT phase in the IMN structure can be beneficial to the epitaxial growth of PBS crystals onto the PBAT nanolayers, thus improving interfacial adhesions. Furthermore, intense extensional stress can also promote crystallinity and thicken the lamellar structure. Given such distinct features in the fully biodegradable films, a simultaneous enhancement in tear strength, tensile strength, and puncture resistance has been achieved. To the best of our knowledge, the tear strength of IMN films about 285.9 kN/m is the highest level in the previous works of this system. Moreover, the proposed fabrication way of the IMN structure is facile and scalable, which is highly expected to be an efficient strategy for development of structured biodegradable polymers with excellent comprehensive properties.

Extensional Stress-Induced Ductility of Poly(l-lactide) Films: Role of the Entangled Network in Amorphous Regions.

The relationship between the density of the entangled amorphous network and the ductility of oriented poly(l-lactide) (PLLA) films is explored based on the preferential hydrolysis of the amorphous regions in phosphate buffer solution (PBS). PLLA films with a balance of ductility and stiffness have been prepared by the "casting-annealing stretching" based on mechanical rejuvenation, and the structural evolution and mechanical properties at different hydrolysis durations have been identified. Various stages are found during the transition of ductility to brittleness for hydrolyzed PLLA films. First, the elongation at break for hydrolyzed PLLA films remains unchanged in the first stage of hydrolysis and then gradually decreases. Eventually, the films turn to be brittle in the third stage. The strain-hardening modulus (GR) of the hydrolyzed films is utilized to reflect the density of the entangled amorphous network, and a gradual decrease of GR with hydrolysis time indicates the decisive role of the amorphous entanglement network in the mechanical rejuvenation-induced ductility of PLLA. The quantitative relationship between the entangled amorphous network and the stress-induced ductility of PLLA films is revealed. The dependence of deformation behavior on entangled amorphous network density is closely correlated to activated primary structure during deformation. The intact chain network plays a crucial role in sufficiently activating the primary structure to yield and disentanglement during the subsequent necking. These findings could advance the understanding of the PLLA's ductility induced by mechanical rejuvenation and offer guidance for awakening the intrinsic toughness of PLLA.

Haplotype variations of sucrose phosphate synthase B gene among sugarcane accessions with different sucrose content.

BACKGROUND: Sucrose phosphate synthase B (SPSB) gene encoding an important rate-limiting enzyme for sucrose synthesis in sugarcane is mainly expressed on leaves, where its alleles control sucrose synthesis. In this study, genetic variation of SPSB gene represented by different haplotypes in sugarcane was investigated in hybrid clones with high and low sugar content and various accessory species. RESULTS: A total of 39 haplotypes of SPSB gene with 2, 824 bp in size were identified from 18 sugarcane accessions. These haplotypes mainly distributed on Chr3B, Chr3C, and Chr3D according to the AP85-441 reference genome. Single nucleotide polymorphisms (SNPs) and insertion/deletion (InDels) were very dense (42 bp/sequence variation) including 44 transitional and 23 transversional SNPs among the 39 haplotypes. The sequence diversity related Hd, Eta, and Pi values were all lower in clones of high sucrose content (HS) than those in clones of low sucrose content (LS). The evolutionary network analysis showed that about half SPSB haplotypes (19 out of 39) were clustered into one group, including 6 (HAP4, HAP6, HAP7, HAP9, HAP17 and HAP20) haplotypes under positive selection in comparison to HAP26 identified in Badila (S. officinarum), an ancestry noble cane species and under purification selection (except HAP19 under neutral selection) in comparison to HAP18 identified from India1 (S. spontaneum), an ancestry species with low sugar content but high stress tolerance. The average number of haplotypes under positive selection in HS clones was twice as that in LS. Most of the SNPs and InDels sequence variation sites were positively correlated with sucrose and fiber content and negatively correlated with reducing sugar. CONCLUSIONS: A total of 39 haplotypes of SPSB gene were identified in this study. Haplotypes potentially associated with high sucrose synthesis efficiency were identified. The mutations of SPSB haplotypes in HS were favorable and tended to be selected and fixed. The results of this study are informative and beneficial to the molecular assisted breeding of sucrose synthesis in sugarcane in the future.

Vimentin Inhibits Dengue Virus Type 2 Invasion of the Blood-Brain Barrier.

Dengue virus (DENV) causes dengue fever, which is prevalent in the tropical and subtropical regions, and in recent years, has resulted in several major epidemics. Vimentin, a cytoskeletal component involved in DENV infection, is significantly reorganized during infection. However, the mechanism underlying the association between DENV infection and vimentin is still poorly understood. We generated vimentin-knockout (Vim-KO) human brain microvascular endothelial cells (HBMECs) and a Vim-KO SV129 suckling mouse model, combining the dynamic vimentin changes observed in vitro and differences in disease course in vivo, to clarify the role of vimentin in DENV-2 infection. We found that the phosphorylation and solubility of vimentin changed dynamically during DENV-2 infection of HBMECs, suggesting the regulation of vimentin by DENV-2 infection. The similar trends observed in the phosphorylation and solubility of vimentin showed that these characteristics are related. Compared with that in control cells, the DENV-2 viral load was significantly increased in Vim-KO HBMECs, and after DENV-2 infection, Vim-KO SV129 mice displayed more severe disease signs than wild-type SV129 mice, as well as higher viral loads in their serum and brain tissue, demonstrating that vimentin can inhibit DENV-2 infection. Moreover, Vim-KO SV129 mice had more disordered cerebral cortical nerve cells, confirming that Vim-KO mice were more susceptible to DENV-2 infection, which causes severe brain damage. The findings of our study help clarify the mechanism by which vimentin inhibits DENV-2 infection and provides guidance for antiviral treatment strategies for DENV infections.

Reliability and validity of clinically useful depression outcome scale identifying mixed features in patients with manic episode.

OBJECTIVES: This study aims to explore the reliability, validity, and feasibility of Clinically Useful Depression Outcome Scale (CUDOS) in screening mixed features in patients diagnosed with mania. METHODS: A total of 109 patients with (hypo-) manic episode were recruited. The reliability of Chinese version of CUDOS (CUDOS-C) were analyzed with Cronbach's alpha and intraclass correlation coefficient (ICC). Spearman correlation coefficient was used to analyze the validity by comparing the correlation between CUDOS-C and Patient Health Questionnaire-9 (PHQ-9), 32-item Hypomania Checklist (HCL-32). The score of MINI (hypo-) manic episode with mixed features-DSM-5 Module-Chinese version(MINI-M-C) ≥ 2 was considered as the gold standard of mixed features, and the receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cut-off values of CUDOS-C score. RESULTS: The Cronbach's alpha value of CUDOS-C was 0.898, and the ICC of CUDOS-C test-retest was 0.880 (95% CI: 0.812-0.923, p < .05).The CUDOS-C score was significantly correlated with PHQ-9 score (r = 0.893, p = .000), but not with HCL-32 score(r = 0.088, p = .364).The area under ROC curve was 0.909 (95% CI: 0.855 to 0.963, p < .001) for CUDOS-C identifying mixed features in mania. The optimal cut-off value was 11 with a sensitivity of 0.854 and a specificity of 0.868. The CUDOS-C (score ≥ 12) identified 40.4% of the patients with mixed features, which was higher than those diagnosed by clinicians (18.3%) and screened using MINI-M-C (37.6%). CONCLUSIONS: The results indicate the CUDOS-C is a reliable and valid self-administered questionnaire for assessing depressive symptoms and screening patients with mixed mania.

Reliability and validity of the Chinese version of the CUDOS-M in patients with mood disorders: A multicenter study across China.

BACKGROUND: A useful scale for identification of mixed features in major depressive episodes (MDE) patients is urgent in China. This study aimed to evaluate the reliability and validity of the Chinese version of the Clinically Useful Depression Outcome Scale supplemented with questions for the DSM-5 mixed features specifier (Chinese-CUDOS-M) in MDE patients. METHODS: A total of 152 MDE patients were recruited and assessed using Chinese-CUDOS-M, Patient Health Questionnaire-9 (PHQ-9) and 32-item Hypomania Checklist (HCL-32). Principal component analysis (PCA) and exploratory factor analysis (EFA) were conducted. The predictive validity was calculated by the area under the receiver operating characteristic curve (AUROC). RESULTS: The Cronbach's alpha of Chinese-CUDOS-M was 0.85. PCA showed three common factors with eigenvalue greater than 1; the eigenvalue of factor I was 4.96, with 38.1% of variance explanation. Chinese-CUDOS-M depression subscale was associated with PHQ-9 (r = 0.83, p<0.01), and manic subscale was associated with HCL-32 (r = 0.73, p< 0.01). AUROC of the Chinese-CUDOS-M for patients with mixed depression was 0.90 (95%CI: 0.85-0.95), with a cut-off value of 7, sensitivity of 0.95, and specificity of 0.73. Furthermore, AUROC was 0.88 in patients with major depressive disorder (MDD), with a cut-off value of 7, sensitivity of 0.96, and specificity of 0.71. AUROC was 0.92 in bipolar disorder (BD) depression patients, with a cut-off value of 9, sensitivity of 0.89, and specificity of 0.87. CONCLUSION: Our study shows that the Chinese-CUDOS-M can identify mixed features in both MDD and BD depression with satisfactory reliability and validity.

Characterization of full-length transcriptome in Saccharum officinarum and molecular insights into tiller development.

BACKGROUND: Although extensive breeding efforts are ongoing in sugarcane (Saccharum officinarum L.), the average yield is far below the theoretical potential. Tillering is an important component of sugarcane yield, however, the molecular mechanism underlying tiller development is still elusive. The limited genomic data in sugarcane, particularly due to its complex and large genome, has hindered in-depth molecular studies. RESULTS: Herein, we generated full-length (FL) transcriptome from developing leaf and tiller bud samples based on PacBio Iso-Seq. In addition, we performed RNA-seq from tiller bud samples at three developmental stages (T0, T1 and T2) to uncover key genes and biological pathways involved in sugarcane tiller development. In total, 30,360 and 20,088 high-quality non-redundant isoforms were identified in leaf and tiller bud samples, respectively, representing 41,109 unique isoforms in sugarcane. Likewise, we identified 1063 and 1037 alternative splicing events identified in leaf and tiller bud samples, respectively. We predicted the presence of coding sequence for 40,343 isoforms, 98% of which was successfully annotated. Comparison with previous FL transcriptomes in sugarcane revealed 2963 unreported isoforms. In addition, we characterized 14,946 SSRs from 11,700 transcripts and 310 lncRNAs. By integrating RNA-seq with the FL transcriptome, 468 and 57 differentially expressed genes (DEG) were identified in T1vsT0 and T2vsT0, respectively. Strong up-regulation of several pyruvate phosphate dikinase and phosphoenolpyruvate carboxylase genes suggests enhanced carbon fixation and protein synthesis to facilitate tiller growth. Similarly, up-regulation of linoleate 9S-lipoxygenase and lipoxygenase genes in the linoleic acid metabolism pathway suggests high synthesis of key oxylipins involved in tiller growth and development. CONCLUSIONS: Collectively, we have enriched the genomic data available in sugarcane and provided candidate genes for manipulating tiller formation and development, towards productivity enhancement in sugarcane.

Genome-wide identification and expression analyses of R2R3-MYB transcription factor genes from two Orchid species.

MYB transcription factors play important roles in different plant biological processes during plant growth, development and stress response. In this study, 101 (DoMYB1-101) and 99 (PaMYB1-99) R2R3-MYB genes were identified in the genomes of Dendrobium officinale and Phalaenopsis aphrodite, respectively. To classify the isolated candidate genes, the R2R3-MYB genes from A. thaliana were selected as references. As a result, all identified DoMYB and PaMYB genes were classified into 22 subfamilies. Phylogenetic analysis revealed that S21 had the largest number of members of all the subfamilies. The numbers of introns, exons and conserved sequences in all of the identified genes are different. In addition, 20 DoMYB genes from six subfamilies were selected for further analysis of tissue-specific expression and responses to various abiotic stresses treatments. The results showed that all of the DoMYB genes in S4 and S19 subfamilies exhibited the highest relative expression levels in flowers. And five DoMYB genes including DoMYB31, DoMYB40, DoMYB49, DoMYB52 and DoMYB54, responded to the stress response. These results may provide useful information for further studies of the R2R3-MYB gene family.

Safety and Tolerability of Both Arm Ischemic Conditioning in Patients With Major Depression: A Proof of Concept Study.

PURPOSE: A substantial proportion of patients with major depressive disorder (MDD) does not respond or cannot tolerate to currently available treatments. This study was to assess the safety and tolerability of Remote Limb Ischemic Preconditioning (RLIPC) as an adjunctive therapy in patients with MDD. PATIENTS AND METHODS: Enrolled patients underwent RLIPC, five cycles of simultaneous bilateral arm ischemia, 5 min and followed by reperfusion of each cycle, and once daily for eight consecutive weeks. Depression and anxiety severity, and quality of life were assessed every 2 weeks. Descriptive analysis was used for safety and tolerability data. RESULTS: Thirty-seven participants completed at least one RLIPC. Twenty-four of them (64.9%) completed the study. Twelve patients prematurely discontinued the study due to poor adherence, and one due to a mild side effect. The changes in HRSD-17, GAD-7 and QOL-6 total scores from baseline to the endpoint were significant from the end of second week treatment onwards. The responder and remission rates were 59.46% (22/37) and 54.05% (20/37) at the endpoint, respectively. CONCLUSION: RLIPC was safe and well tolerated, and may be effective in reducing depressive symptoms in patients with MDD. Large studies are warranted to test its efficacy and safety as monotherapy or adjunctive therapy in the treatment of MDD.

The effects of Japanese encephalitis virus antibodies on Zika virus infection.

Recently, Zika virus (ZIKV) has become more widespread, thus attracting global attention. The vaccine against Japanese encephalitis virus (JEV) is currently used in China, being included in planned immunisation regimes. Although ZIKV and JEV are closely related mosquito-borne Flaviviruses, and a complex cross-immune response within flaviviruses has been demonstrated, the effect of JEV vaccination on ZIKV infection has not been well described. Thus, this study aimed to explore the impact of different titres of anti-JEV antibodies (Abs) against ZIKV infection using sera from healthy human donors in Guangzhou and anti-JEV rabbit polyclonal antibodies (pAbs) in vitro and vivo. Human anti-JEV Ab titres were tested at decreasing concentrations as the age increased. A neutralising effect on ZIKV infection was observed when anti-JEV Ab titres in human sera or rabbit pAbs were high (the corresponding age was under 30 years). Even though a lower titre in human sera showed no apparent effect, whereas rabbit pAbs had an antibody-dependent enhancement(ADE)effect, we proved an ADE effect in vivo for the first time. This study suggests that individuals over 60 years of age are at high risk for JEV and ZIKV infection, and screening this age group for infection should strengthen. Furthermore, a deep exploration of the relationship between anti-JEV Abs and ZIKV infection is needed.

Biocycle Fermentation Based on Lactic Acid Bacteria and Yeast for the Production of Natural Ethyl Lactate.

Ethyl lactate is widely used in food and pharmaceutical industries, but the complexity of the synthesis process, in particular, involving the addition of organic solvents, hinders its application. Here, we report a natural green strategy to produce ethyl lactate by exploiting the synergistic fermentation of lactic acid bacteria and ester-producing microbes using biomass as a substrate. Interestingly, it is worth noting that the conjugate fermentation has a higher ethyl lactate yield (3.05 g/L) compared to the mixed fermentation (1.32 g/L). The ester production capacity was increased by 2.3 times. These entire processes require only the addition of biomass without introducing any organic solvent. In addition, the obtained catalytic esterification system can reuse the ester-producing microbes by simple centrifugation and maintain over seven cycles of catalysis while it retained a high activity. We firmly believe that the results of this study will provide new ideas for achieving sustainable green production of natural ethyl lactate.

Epidemiological and Evolutionary Analysis of Dengue-1 Virus Detected in Guangdong during 2014: Recycling of Old and Formation of New Lineages.

The incidence of dengue is increasing in Guangdong, China, with the largest outbreak to date in 2014. Widespread awareness of epidemiological and molecular characteristics of the dengue virus (DENV) is required. In 2014, we isolated the virus from patients and sequenced its genome. The sequences of DENV isolated from Guangdong and other countries screened since 2005 were studied to establish molecular evolutionary databases along with epidemiological data to explore its epidemiological, phylogenetic, and molecular characteristics. Causes underlying the occurrence of the dengue epidemic included importation and localization of the virus. The number of indigenous cases significantly exceeded that of imported cases. Dengue virus 1 is the most important serotype and caused the long-term epidemic locally. Based on the data available since 2005, DENV1 was divided into three genotypes (I, IV, and V). Only genotypes I and V were detected in 2014. In 2014, an epidemic involving old lineages of DENV1 genotype V occurred after 2 years of silence. The genotype was previously detected from 2009 to 2011. Genotype I, which caused recent epidemics, demonstrated a continuation of new lineages, and a predictive pattern of molecular evolution since 2005 among the four lineages was present. The DENV isolated from Guangdong was closely related to those causing large-scale epidemics in neighboring countries, suggesting the possibility of its import from these countries. The lack of sufficient epidemiological data and evidence on the local mosquito-borne DENV emphasizes the importance of studying the molecular evolutionary features and establishing a well-established phylogenetic tree for dengue prevention and control in Guangdong.

Research advancements in the neurological presentation of flaviviruses.

Owing to the large-scale epidemic of Zika virus disease and its association with microcephaly, properties that allow flaviviruses to cause nervous system diseases are an important area of investigation. At present, although potential pathogenic mechanisms of flaviviruses in the nervous system have been examined, they have not been completely elucidated. In this paper, we review the possible mechanisms of blood-brain barrier penetration, the pathological effects on neurons, and the association between virus mutations and neurotoxicity. A hypothesis on neurotoxicity caused by the Zika virus is presented. Clarifying the mechanisms of virulence of flaviviruses will be helpful in finding better antiviral drugs and optimizing the treatment of symptoms.

Micro-droplet Digital Polymerase Chain Reaction and Real-Time Quantitative Polymerase Chain Reaction Technologies Provide Highly Sensitive and Accurate Detection of Zika Virus.

The establishment of highly sensitive diagnostic methods is critical in the early diagnosis and control of Zika virus (ZIKV) and in preventing serious neurological complications of ZIKV infection. In this study, we established micro-droplet digital polymerase chain reaction (ddPCR) and real-time quantitative PCR (RT-qPCR) protocols for the detection of ZIKV based on the amplification of the NS5 gene. For the ZIKV standard plasmid, the RT-qPCR results showed that the cycle threshold (Ct) value was linear from 101 to 108 copy/µL, with a standard curve R2 of 0.999 and amplification efficiency of 92.203%; however, a concentration as low as 1 copy/µL could not be detected. In comparison with RT-qPCR, the ddPCR method resulted in a linear range of 101-104 copy/µL and was able to detect concentrations as low as 1 copy/µL. Thus, for detecting ZIKV from clinical samples, RT-qPCR is a better choice for high-concentration samples (above 101 copy/µL), while ddPCR has excellent accuracy and sensitivity for low-concentration samples. These results indicate that the ddPCR method should be of considerable use in the early diagnosis, laboratory study, and monitoring of ZIKV.

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies.

Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 clinical response, suggesting a common efficacy signature between a targeted therapy and immunotherapy. When searching for genes related to lapatinib resistance, CARE identified PRKD3 as the top candidate. PRKD3 inhibition, by both small interfering RNA and compounds, significantly sensitized breast cancer cells to lapatinib. Thus, CARE should enable large-scale inference of response biomarkers and drug combinations for targeted therapies using compound screen data.

Modeling cis-regulation with a compendium of genome-wide histone H3K27ac profiles.

Model-based analysis of regulation of gene expression (MARGE) is a framework for interpreting the relationship between the H3K27ac chromatin environment and differentially expressed gene sets. The framework has three main functions: MARGE-potential, MARGE-express, and MARGE-cistrome. MARGE-potential defines a regulatory potential (RP) for each gene as the sum of H3K27ac ChIP-seq signals weighted by a function of genomic distance from the transcription start site. The MARGE framework includes a compendium of RPs derived from 365 human and 267 mouse H3K27ac ChIP-seq data sets. Relative RPs, scaled using this compendium, are superior to superenhancers in predicting BET (bromodomain and extraterminal domain) -inhibitor repressed genes. MARGE-express, which uses logistic regression to retrieve relevant H3K27ac profiles from the compendium to accurately model a query set of differentially expressed genes, was tested on 671 diverse gene sets from MSigDB. MARGE-cistrome adopts a novel semisupervised learning approach to identify cis-regulatory elements regulating a gene set. MARGE-cistrome exploits information from H3K27ac signal at DNase I hypersensitive sites identified from published human and mouse DNase-seq data. We tested the framework on newly generated RNA-seq and H3K27ac ChIP-seq profiles upon siRNA silencing of multiple transcriptional and epigenetic regulators in a prostate cancer cell line, LNCaP-abl. MARGE-cistrome can predict the binding sites of silenced transcription factors without matched H3K27ac ChIP-seq data. Even when the matching H3K27ac ChIP-seq profiles are available, MARGE leverages public H3K27ac profiles to enhance these data. This study demonstrates the advantage of integrating a large compendium of historical epigenetic data for genomic studies of transcriptional regulation.

Post-transcriptional and translational regulation modulates gene co-expression behavior in more synchronized pace to carry out molecular function in the cell.

MOTIVATION: Biological processes involve much complex interplay between cellular molecules at different molecular levels, and this interplay may exhibit various co-expression patterns explicitly representing the cellular inner regulation mechanism. Whereas, coexpression patterns cannot be necessarily conserved across the different molecular levels for complex regulation processes involved even after transcripts being produced. Investigation of co-expression propagation from transcript level to protein level will reflect inner regulation effects in function states of cells. RESULTS: In this study, we perform a comparative analysis of gene coexpression patterns in Plasmodium falciparum. We investigate coexpression patterns propagation from transcript level to protein level to reveal the underlying biological meaning of post-transcriptional and translational mechanism. Our systems-level approach shows after posttranscriptional and translational regulation gene co-expression pace at protein level is mechanistically adjusted to higher synchronicity. Moreover, co-expression patterns at protein level are more linked to function categories, such as co-expression at the same time point is more related with binding categories, and co-expression delayed by several time points is more related with activity categories. Therefore, posttranscriptional and translational regulation modulates co-expression relationships between molecules for meeting the function demands.