Nuclear SRP9/SRP14 heterodimer transcriptionally regulates 7SL and BC200 RNA expression.

The SRP9/SRP14 heterodimer is a central component of signal recognition particle (SRP) RNA (7SL) processing and Alu retrotransposition. In this study, we sought to establish the role of nuclear SRP9/SRP14 in the transcriptional regulation of 7SL and BC200 RNA. 7SL and BC200 RNA steady-state levels, rate of decay, and transcriptional activity were evaluated under SRP9/SRP14 knockdown conditions. Immunofluorescent imaging, and subcellular fractionation of MCF-7 cells, revealed a distinct nuclear localization for SRP9/SRP14. The relationship between this localization and transcriptional activity at 7SL and BC200 genes was also examined. These findings demonstrate a novel nuclear function of SRP9/SRP14 establishing that this heterodimer transcriptionally regulates 7SL and BC200 RNA expression. We describe a model in which SRP9/SRP14 cotranscriptionally regulate 7SL and BC200 RNA expression. Our model is also a plausible pathway for regulating Alu RNA transcription and is consistent with the hypothesized roles of SRP9/SRP14 transporting 7SL RNA into the nucleolus for posttranscriptional processing, and trafficking of Alu RNA for retrotransposition.

Functional Meta-Analysis of the Proteomic Responses of Arabidopsis Seedlings to the Spaceflight Environment Reveals Multi-Dimensional Sources of Variability across Spaceflight Experiments.

The human quest for sustainable habitation of extraterrestrial environments necessitates a robust understanding of life's adaptability to the unique conditions of spaceflight. This study provides a comprehensive proteomic dissection of the Arabidopsis plant's responses to the spaceflight environment through a meta-analysis of proteomics data from four separate spaceflight experiments conducted on the International Space Station (ISS) in different hardware configurations. Raw proteomics LC/MS spectra were analyzed for differential expression in MaxQuant and Perseus software. The analysis of dissimilarities among the datasets reveals the multidimensional nature of plant proteomic responses to spaceflight, impacted by variables such as spaceflight hardware, seedling age, lighting conditions, and proteomic quantification techniques. By contrasting datasets that varied in light exposure, we elucidated proteins involved in photomorphogenesis and skotomorphogenesis in plant spaceflight responses. Additionally, with data from an onboard 1 g control experiment, we isolated proteins that specifically respond to the microgravity environment and those that respond to other spaceflight conditions. This study identified proteins and associated metabolic pathways that are consistently impacted across the datasets. Notably, these shared proteins were associated with critical metabolic functions, including carbon metabolism, glycolysis, gluconeogenesis, and amino acid biosynthesis, underscoring their potential significance in Arabidopsis' spaceflight adaptation mechanisms and informing strategies for successful space farming.

Dimerization of the ETO1 family proteins plays a crucial role in regulating ethylene biosynthesis in Arabidopsis thaliana.

ETHYLENE OVERPRODUCER1 (ETO1), ETO1-LIKE1 (EOL1), and EOL2 are members of the Broad complex, Tramtrack, Bric-a-brac (BTB) protein family that collectively regulate type-2 1-aminocyclopropane-1-carboxylic acid synthase (ACS) activity in Arabidopsis thaliana. Although ETO1 and EOL1/EOL2 encode structurally related proteins, genetic studies suggest that they do not play an equivalent role in regulating ethylene biosynthesis. The mechanistic details underlying the genetic analysis remain elusive. In this study, we reveal that ETO1 collaborates with EOL1/2 to play a key role in the regulation of type-2 ACS activity via protein-protein interactions. ETO1, EOL1, and EOL2 exhibit overlapping but distinct tissue-specific expression patterns. Nevertheless, neither EOL1 nor EOL2 can fully complement the eto1 phenotype under control of the ETO1 promoter, which suggests differential functions of ETO1 and EOL1/EOL2. ETO1 forms homodimers with itself and heterodimers with EOLs. Furthermore, CULLIN3 (CUL3) interacts preferentially with ETO1. The BTB domain of ETO1 is sufficient for interaction with CUL3 and is required for homodimerization. However, domain-swapping analysis in transgenic Arabidopsis suggests that the BTB domain of ETO1 is essential but not sufficient for a full spectrum of ETO1 function. The missense mutation in eto1-5 generates a substitution of phenylalanine with an isoleucine in ETO1F466I that impairs its dimerization and interaction with EOLs but does not affect binding to CUL3 or ACS5. Overexpression of ETO1F466I in Arabidopsis results in a constitutive triple response phenotype in dark-grown seedlings. Our findings reveal the mechanistic role of protein-protein interactions of ETO1 and EOL1/EOL2 that is crucial for their biological function in ethylene biosynthesis.

Doublesex controls specification and maintenance of the gonad stem cell niches in Drosophila.

Sex-specific development of the gonads is a key aspect of sexual dimorphism that is regulated by Doublesex/Mab3-related transcription factors (DMRTs) in diverse animal species. We find that in mutants for Drosophila dsx, important components of the male and female gonad stem cell niches (hubs and terminal filaments/cap cells, respectively) still form. Initially, gonads in all dsx mutants (both XX and XY) initiate the male program of development, but later half of these gonads switch to form female stem cell niche structures. One individual can have both male-type and female-type gonad niches; however, male and female niches are usually not observed in the same gonad, indicating that cells make a 'group decision' about which program to follow. We conclude that dsx does not act in an instructive manner to regulate male versus female niche formation, as these structures form in the absence of dsx function. Instead, dsx acts to 'tip the balance' between the male or female programs, which are then executed independently of dsx We show that bric a brac acts downstream of dsx to control the male versus female niche decision. These results indicate that, in both flies and mammals, the sexual fate of the somatic gonad is remarkably plastic and is controlled by a combination of autonomous and non-autonomous cues.

Emerging market dynamics in H1N1 and COVID-19 pandemics.

The spread of COVID-19 increased general interest in the effects of pandemics on stock markets. We believe it is interesting to analyze emerging countries due to their role in future economies. The announcement of the H1N1 and COVID-19 pandemics instigated observable effects on the stock market. Our goal is to measure and compare the effects of these announcements, specifically for the BRIC bloc, using the event study method. We find evidence that these stock markets exhibited more negative abnormal returns at the announcement of COVID-19 than at the announcement of H1N1. However, Russia and China seem to cope better with COVID-19, having already experienced H1N1. Due to the possibility of a new pandemic and for the sake of the future participation of emerging countries, it is recommended to deepen this line of research.

The Health Impact Fund: making the case for engagement with pharmaceutical laboratories in Brazil, Russia, India, and China.

Despite progress in global health, the general disease burden still disproportionately falls on low- and middle-income countries. The health needs of these countries' populations are unmet because there is a shortage in drug research and development, as well as a lack of access to essential drugs. This health disparity is especially problematic for diseases associated with poverty, namely neglected tropical diseases and microbial infections. Currently, the pharmaceutical landscape focuses on innovations determined by profit margins and intellectual property protection. To expand drug accessibility and catalyze research and development for neglected diseases, a team of researchers proposed the Health Impact Fund as a potential solution. However, the fund is predominantly considering partnerships with pharmaceutical giants in high-income countries. This commentary explores the limitations and benefits in partnering with pharmaceutical companies based in Brazil, Russia, India, and China (BRIC), with the goal of expanding the Health Impact Fund's vision to incorporate long-term, local partnerships. Identified limitations to a BRIC country partnership include lower levels of drug development expertise compared to their high-income pharmaceutical counterparts, and whether the Health Impact Fund and the participating stakeholders have the financial capability to assist in bringing a new drug to market. However, potential benefits include the creation of new incentives to fuel competitive local innovation, more equitable routes to drug discovery and development, and a product pipeline that could involve stakeholders in lower- and middle-income countries. Our commentary explores how partnership with pharmaceutical firms in BRIC countries might be advantageous for all: The Health Impact Fund, pharmaceutical companies in BRIC economies, and stakeholders in low- and middle- income countries.

The Bile Salt Export Pump: Molecular Structure, Study Models and Small-Molecule Drugs for the Treatment of Inherited BSEP Deficiencies.

The bile salt export pump (BSEP/ABCB11) is responsible for the transport of bile salts from hepatocytes into bile canaliculi. Malfunction of this transporter results in progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2) and intrahepatic cholestasis of pregnancy (ICP). Over the past few years, several small molecular weight compounds have been identified, which hold the potential to treat these genetic diseases (chaperones and potentiators). As the treatment response is mutation-specific, genetic analysis of the patients and their families is required. Furthermore, some of the mutations are refractory to therapy, with the only remaining treatment option being liver transplantation. In this review, we will focus on the molecular structure of ABCB11, reported mutations involved in cholestasis and current treatment options for inherited BSEP deficiencies.

Does corruption matter for stock markets? The role of heterogeneous institutions.

In examining the role of institutions in resisting corruption and its impact on growth, most studies concentrate on the aggregate level and conclude that sound institutions enhance growth. We focus instead on varying dimensions of heterogeneous institutions in the presence of corruption and their interactive effect on stock returns in four emerging economies: Brazil, Russia, India, and China (BRIC). We pay particular attention to democratic accountability, bureaucratic quality, and law and order. Using monthly data for the first time in this literature, we find that corruption and other weaker institutions lower stock returns during the period 1995-2014. However, interaction effects show interesting mixed results: Bureaucratic quality can mitigate the ill effects of corruption and increase returns by reducing red tape, whereas corruption distorts law and order and lowers stock returns. Our findings suggest that policies to enhance bureaucratic efficiency can abate the adverse effects of corruption, but a restrictive law and order environment tends to lower stock returns.

Variation in the transcriptome of different ecotypes of Arabidopsis thaliana reveals signatures of oxidative stress in plant responses to spaceflight.

PREMISE OF THE STUDY: Spaceflight provides a unique environment in which to dissect plant stress response behaviors and to reveal potentially novel pathways triggered in space. We therefore analyzed the transcriptomes of Arabidopsis thaliana plants grown on board the International Space Station to find the molecular fingerprints of these space-related response networks. METHODS: Four ecotypes (Col-0, Ws-2, Ler-0 and Cvi-0) were grown on orbit and then their patterns of transcript abundance compared to ground-based controls using RNA sequencing. KEY RESULTS: Transcripts from heat-shock proteins were upregulated in all ecotypes in spaceflight, whereas peroxidase transcripts were downregulated. Among the shared and ecotype-specific changes, gene classes related to oxidative stress and hypoxia were detected. These spaceflight transcriptional response signatures could be partly mimicked on Earth by a low oxygen environment and more fully by oxidative stress (H2 O2 ) treatments. CONCLUSIONS: These results suggest that the spaceflight environment is associated with oxidative stress potentially triggered, in part, by hypoxic response. Further, a shared spaceflight response may be through the induction of molecular chaperones (such as heat shock proteins) that help protect cellular machinery from the effects of oxidative damage. In addition, this research emphasizes the importance of considering the effects of natural variation when designing and interpreting changes associated with spaceflight experiments.

Transcriptome stability profiling using 5'-bromouridine IP chase (BRIC-seq) identifies novel and functional microRNA targets in human melanoma cells.

RNA half-life is closely related to its cellular physiological function, so stability determinants may have regulatory functions. Micro(mi)RNAs have primarily been studied with respect to post-transcriptional mRNA regulation and target degradation. Here we study the impact of the tumour suppressive melanoma miRNA miR-211 on transcriptome stability and phenotype in the non-pigmented melanoma cell line, A375. Using 5'-bromouridine IP chase (BRIC)-seq, transcriptome-wide RNA stability profiles revealed highly regulated genes and pathways important in this melanoma cell line. By combining BRIC-seq, RNA-seq and in silico predictions, we identified both existing and novel direct miR-211 targets. We validated DUSP3 as one such novel miR-211 target, which itself sustains colony formation and invasion in A375 cells via MAPK/PI3K signalling. miRNAs have the capacity to control RNA turnover as a gene expression mechanism, and RNA stability profiling is an excellent tool for interrogating functionally relevant gene regulatory pathways and miRNA targets when combined with other high-throughput and in silico approaches.

Discovery of a Nitric Oxide-Responsive Protein in Arabidopsis thaliana.

In plants, much like in animals, nitric oxide (NO) has been established as an important gaseous signaling molecule. However, contrary to animal systems, NO-sensitive or NO-responsive proteins that bind NO in the form of a sensor or participating in redox reactions have remained elusive. Here, we applied a search term constructed based on conserved and functionally annotated amino acids at the centers of Heme Nitric Oxide/Oxygen (H-NOX) domains in annotated and experimentally-tested gas-binding proteins from lower and higher eukaryotes, in order to identify candidate NO-binding proteins in Arabidopsis thaliana. The selection of candidate NO-binding proteins identified from the motif search was supported by structural modeling. This approach identified AtLRB3 (At4g01160), a member of the Light Response Bric-a-Brac/Tramtrack/Broad Complex (BTB) family, as a candidate NO-binding protein. AtLRB3 was heterologously expressed and purified, and then tested for NO-response. Spectroscopic data confirmed that AtLRB3 contains a histidine-ligated heme cofactor and importantly, the addition of NO to AtLRB3 yielded absorption characteristics reminiscent of canonical H-NOX proteins. Furthermore, substitution of the heme iron-coordinating histidine at the H-NOX center with a leucine strongly impaired the NO-response. Our finding therefore established AtLRB3 as a NO-interacting protein and future characterizations will focus on resolving the nature of this response.

Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants.

BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.

Experimental and Computational Considerations in the Study of RNA-Binding Protein-RNA Interactions.

After an RNA is transcribed, it undergoes a variety of processing steps that can change the encoded protein sequence (through alternative splicing and RNA editing), regulate the stability of the RNA, and control subcellular localization, timing, and rate of translation. The recent explosion in genomics techniques has enabled transcriptome-wide profiling of RNA processing in an unbiased manner. However, it has also brought with it both experimental challenges in developing improved methods to probe distinct processing steps, as well as computational challenges in data storage, processing, and analysis tools to enable large-scale interpretation in the genomics era. In this chapter we review experimental techniques and challenges in profiling various aspects of RNA processing, as well as recent efforts to develop analyses integrating multiple data sources and techniques to infer RNA regulatory networks.

Morphometric analyses of petioles of seedlings grown in a spaceflight experiment.

Gravity is a constant unidirectional stimulus on Earth, and gravitropism in plants involves three phases: perception, transduction, and response. In shoots, perception takes place within the endodermis. To investigate the cellular machinery of perception in microgravity, we conducted a spaceflight study with Arabidopsis thaliana seedlings, which were grown in microgravity in darkness using the Biological Research in Canisters (BRIC) hardware during space shuttle mission STS-131. In the 14-day-old etiolated plants, we studied seedling development and the morphological parameters of the endodermal cells in the petiole. Seedlings from the spaceflight experiment (FL) were compared to a ground control (GC), which both were in the BRIC flight hardware. In addition, to assay any potential effects from growth in spaceflight hardware, we performed another control by growing seedlings in Petri dishes in standard laboratory conditions (termed the hardware control, HC). Seed germination was significantly lower in samples grown in flight hardware (FL, GC) compared to the HC. In terms of cellular parameters of endodermal cells, the greatest differences also were between seedlings grown in spaceflight hardware (FL, GC) compared to those grown outside of this hardware (HC). Specifically, the endodermal cells were significantly smaller in seedlings grown in the BRIC system compared to those in the HC. However, a change in the shape of the cell, suggesting alterations in the cell wall, was one parameter that appears to be a true microgravity effect. Taken together, our results suggest that caution must be taken when interpreting results from the increasingly utilized BRIC spaceflight hardware system and that it is important to perform additional ground controls to aid in the analysis of spaceflight experiments.

Evaluation of DAMAGE Algorithm in Frontal Crashes.

With the current trend of including the evaluation of the risk of brain injuries in vehicle crashes due to rotational kinematics of the head, two injury criteria have been introduced since 2013 - BrIC and DAMAGE. BrIC was developed by NHTSA in 2013 and was suggested for inclusion in the US NCAP for frontal and side crashes. DAMAGE has been developed by UVa under the sponsorship of JAMA and JARI and has been accepted tentatively by the EuroNCAP. Although BrIC in US crash testing is known and reported, DAMAGE in tests of the US fleet is relatively unknown. The current paper will report on DAMAGE in NCAP-like tests and potential future frontal crash tests involving substantial rotation about the three axes of occupant heads. Distribution of DAMAGE of three-point belted occupants without airbags will also be discussed. Prediction of brain injury risks from the tests have been compared to the risks in the real world. Although DAMAGE correlates well with MPS in the human brain model across several test scenarios, the predicted risk of AIS2+ brain injuries are too high compared to real-world experience. The prediction of AIS4+ brain injury risk in lower velocity crashes is good, but too high in NCAP-like and high speed angular frontal crashes.

A novel case report of benign recurrent intrahepatic cholestasis-associated USP53 genetic mutation in a Pakistani girl.

Benign recurrent intrahepatic cholestasis is an autosomal recessive disorder presenting with intermittent episodes of cholestatic jaundice. The initial episode of benign recurrent intrahepatic cholestasis tends to occur within the first two decades of a patient's life. Episodes can occur unprompted but can often be precipitated by infections or pregnancy. We report an interesting case of a 13-year-old girl presented with recurrent intrahepatic cholestasis. The patient has a unique homozygous USP53 genetic mutation, the first patient to present with this mutation within the South Asian region. The patient was initially misdiagnosed as a case of autoimmune hepatitis, and when presenting to our set-up was diagnosed as a case of benign recurrent intrahepatic cholestasis. The patient has since been managed on medication and remains regular in follow-up, responding well to treatment.

Evaluation of Brain Rotational Injury Criteria (BrIC) in vehicle frontal crashes.

OBJECTIVE: The objective of this study was to estimate strains in the human brain in regulatory, research, and due care frontal crashes by simulating those impacts. In addition, brain strain simulations were estimated for belted human volunteer tests and in impacts between two players in National Football League (NFL), some with no injury and some with mild Traumatic Brain Injuries (mTBI). METHODS: The brain strain responses were determined using version 5 of the Global Human Body Modeling Consortium (GHBMC) 50th percentile human brain model. One hundred and sixty simulations with the brain model were conducted using rotational velocities and accelerations of Anthropomorphic Test Devices (ATD's) or those of human volunteers in sled or crash tests, as inputs to the model and strain related responses like Maximum Principal Strains (MPS) and Cumulative Strain Damage Measure (CSDM) in various regions of the brain were monitored. The simulated vehicle tests ranged from sled tests at 24 and 32 kph delta-V with three-point belts without airbags to full scale crash and sled tests at 56 kph and a series of Research Mobile Deformable Barrier (RMDB) tests described in Prasad et al. RESULTS: The severity of rotational input into the model as represented by BrIC, averaged between 0.5 and 1.2 for the various test conditions, and as high as 1.5 for an individual case. The MPS responses for the various test conditions averaged between 0.28 and 0.86 and as high as 1.3 in one test condition. The MPS responses in the brain for volunteers, low velocity sled, and NCAP tests were similar to those in the no-mTBI group in the NFL cases and consistent with real world accident data. The MPS responses of the brain in angular crash and sled tests were similar to those in the mTBI group. CONCLUSIONS: The brain strain estimations do not indicate the likelihood of severe-to-fatal brain injuries in the crash environments studied in this paper. However, using the risk functions associated with BrIC, severe-to-fatal brain injuries (AIS4+) are predicted in several environments in which they are not observed or expected.

A novel mutation within a transmembrane helix of the bile salt export pump (BSEP, ABCB11) with delayed development of cirrhosis.

BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11) is essential for bile salt secretion at the canalicular membrane of liver cells. Clinical phenotypes associated with BSEP mutations are commonly categorized as benign recurrent intrahepatic cholestasis (BRIC-2) or progressive familial intrahepatic cholestasis (PFIC-2). METHODS: The molecular basis of BSEP-associated liver disease in a sibling pair was characterized by immunostaining, gene sequencing, bile salt analysis and recombinant expression in mammalian cells and yeast for localization and in vitro activity studies respectively. RESULTS: Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood. Gene sequencing of ABCB11 identified the novel missense mutation p.G374S, which is localized in the putative sixth transmembrane helix of BSEP. Liver fibrosis was present in the brother at the age of 18 with progression to cirrhosis within 3 years. Immunofluorescence of liver tissue showed clear canalicular BSEP expression; however, biliary concentration of bile salts was drastically reduced. In line with these in vivo findings, HEK293 cells showed regular membrane targeting of human BSEP(G374S), whereas in vitro transport measurements revealed a strongly reduced transport activity. CONCLUSIONS: The novel mutation p.G374S impairs transport function without disabling membrane localization of BSEP. While all other known BSEP mutations within transmembrane helices are associated with PFIC-2, the new p.G374S mutation causes a transitional phenotype between BRIC-2 and PFIC-2.

Integrative bioinformatics and RNA sequencing based methodology results in the exploration of breast invasive carcinoma biomarkers.

BACKGROUND: Previously reported breast invasive carcinoma (BRIC) biomarkers have compromised utility because of their heterogeneity-specific behaviors. The goal of this study was to find BRIC biomarkers that could be used in spite of the heterogeneity barrier. METHODS: Previously reported BRIC-linked hub genes were obtained from the literature via a search technique. A protein-protein interaction (PPI) network of the extracted hub genes was constructed, visualized, and analyzed to explore the top six real hub genes. Following this, real hub genes' expression profiling was carried out using various TCGA data sources and RNA sequencing (RNA-seq) of BT 20 and HMEC cell lines to uncover the tumor-driver roles of the real hub genes. RESULTS: In total, 124 BRIC-linked hub genes were collected from the literature via the search technique. From these collected hub genes, a total of 6 genes, including Centrosomal protein of 55 kDa (CEP55), Kinesin Family Member 2C (KIF2C), kinesin family member 20A (KIF20A), Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), Aurora A Kinase (AURKA), and Protein Regulator of cytokinesis 1 (PRC1) were determined to be the real hub genes. Via expression profiling and validation analyses, we documented the overexpression of CEP55, KIF2C, KIF20A, RRM2, AURKA, and PRC1 real hub genes in BRIC patients with different clinical variables. Further correlational analyses showed diverse associations among real hub genes' expression and other important parameters, including promoter methylation status, genetic alteration, overall survival (OS), relapse-free survival (RFS), tumor purity, CD8+ T, CD4+ T immune cell infiltration, and different mutant genes across BRIC samples. Finally, in this work, we investigated several transcription factors (TFS), microRNAs, and therapeutic medicines related to the real hub genes that have great therapeutic potential. CONCLUSION: In conclusion, we discovered six real hub genes, which may be employed as novel potential biomarkers for BRIC patients with different clinical parameters.

The influencing factors of carbon emissions in the railway transportation industry based on extended LMDI decomposition method: evidence from the BRIC countries.

In the twenty-first century, global warming and other environmental issues have become the focus of international attention. The total generation of carbon emissions for the railway transportation industry in the BRIC countries (Brazil, Russia, Indian and China) accounted for 25.73% of the global carbon emissions in this industry during 2017. Therefore, it is necessary to identify the influencing factors of carbon emission in the railway transportation industry for the BRIC, in order to better control and reduce carbon emissions and to achieve the global goal of "net-zero emission." The logarithmic mean divisia index (LMDI) decomposition method was used to examine the factors that influenced carbon emissions from the railway transportation industry in the BRIC from 1997 to 2017. According to the findings, the total carbon emissions of the railway transportation industry in BRIC were 60.92 million tons in 2017, increased by 98.62% compared to 1997. The factor of economic output effect has contributed positively to the increase in carbon emissions in all identified countries. However, the effect of population size effect, energy structure, and transportation intensity effect for carbon emission demonstrated heterogeneity in BRIC. In addition, policy suggestions are put forward for the reduction of carbon emissions from the railway transportation industry in BRIC.