Multiomics data identifies RSPO2 as a prognostic biomarker in human tumors associated with pan-cancer.

RSPO2 protein may provide valuable insights into the mechanism underlying various types of tumorigenesis. The role of RSPO2 in pan-cancer has not been reported so far. Therefore, this study aimed to provide a comprehensive analysis of RSPO2 from a pan-cancer perspective employing multiomics data. The expression profile and function of RSPO2 across different tumors were investigated using various web-based tools UALCAN, GEPIA, TIMER, Human Protein Atlas, cBioPortal, TISIDB, STRING, and Metascape to interpret the expression profile, promoter methylation status, genomic alterations, survival analysis, protein-protein interaction, correlation with immune cell subtypes, tumor immune microenvironment and enrichment analysis. Comprehensive pan-cancer analysis indicated that RSPO2 was significantly downregulated in eleven and upregulated in five tumor types compared to normal tissues, validation results further suggest RSPO2 was downregulated in most of the tumors. The protein level expression of RSPO2 was mostly low in malignant tissues. We found that RSPO2 was significantly related to individual pathological stages in BLCA, COAD, LUAD and LUSC. Prognostic analysis indicates that the high RSPO2 expression was significantly correlated with the poor prognosis in BRCA, KICH, KIRP, READ, and UCES. Furthermore, RSPO2 is frequently amplified, exhibits hypermethylated promoter in most cancers, and is associated with immune subtypes, molecular subtypes and immune cell infiltration. Finally, enrichment analysis showed that RSPO2 is involved in the regulation of the canonical Wnt pathway and neuronal development. The overall comprehensive pan-cancer analysis affirms that RSPO2 could be a promising diagnostic and prognostic biomarker and latent therapy target in the future.

Unravelling a novel CTNND1-RAB6A fusion transcript: Implications in colon cancer cell migration.

The interchange of DNA sequences between genes may occur because of chromosomal rearrangements leading to the formation of chimeric genes. These chimeric genes have been linked to various cancers, accumulated significant interest in recent times. We used paired-end RNA-seq. data of four CRC and one normal sample generated from our previous study. The STAR-Fusion pipeline was utilized to identify the fusion genes unique to CRC. The in-silico identified fusion gene(s) were explored for their diagnostic, prognostic and therapeutic biomarker potential using TCGA-datasets, then validated through PCR and DNA sequencing. Further, cell line-based studies were performed to gain functional insights of the novel fusion transcript CTNND1-RAB6A, which was amplified in one sample. Sequencing revealed that there was a total loss of the CTNND1 gene, whereas RAB6A retained its coding sequence. Further, RAB6A was functionally characterized for its oncogenic potential in HCT116 cell line. RAB6A under-expression was found to be significantly associated with increased cell migration and is proposed to be regulated via the RAB6A-ECR1-Liprin-α axis. We conclude that RAB6A gene may play significant role in CRC oncogenesis, and could be used as a potential biomarker and therapeutic target in future for better management of a subset of CRCs harbouring this fusion.

Microbial exopolysaccharides in the biomedical and pharmaceutical industries.

The most significant and renewable class of polymeric materials are extracellular exopolysaccharides (EPSs) produced by microorganisms. Because of their diverse chemical and structural makeup, EPSs play a variety of functions in a variety of industries, including the agricultural industry, dairy industry, biofilms, cosmetics, and others, demonstrating their biotechnological significance. EPSs are typically utilized in high-value applications, and current research has focused heavily on them because of their biocompatibility, biodegradability, and compatibility with both people and the environment. Due to their high production costs, only a few microbial EPSs have been commercially successful. The emergence of financial barriers and the growing significance of microbial EPSs in industrial and medical biotechnology has increased interest in exopolysaccharides. Since exopolysaccharides can be altered in a variety of ways, their use is expected to increase across a wide range of industries in the coming years. This review introduces some significant EPSs and their composites while concentrating on their biomedical uses.

HIF-1α regulates the expression of the non-conventional isoform of the cd5 gene in T cells under the hypoxic condition: A potential mechanism for CD5neg/low phenotype of infiltrating cells in solid tumors.

CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., anon-conventional formofthe cd5gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1α onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.

Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer.

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.

A deep-learning model of prescient ideas demonstrates that they emerge from the periphery.

Where do prescient ideas-those that initially challenge conventional assumptions but later achieve widespread acceptance-come from? Although their outcomes in the form of technical innovation are readily observed, the underlying ideas that eventually change the world are often obscured. Here, we develop a novel method that uses deep learning to unearth the markers of prescient ideas from the language used by individuals and groups. Our language-based measure identifies prescient actors and documents that prevailing methods would fail to detect. Applying our model to corpora spanning the disparate worlds of politics, law, and business, we demonstrate that it reliably detects prescient ideas in each domain. Moreover, counter to many prevailing intuitions, prescient ideas emanate from each domain's periphery rather than its core. These findings suggest that the propensity to generate far-sighted ideas may be as much a property of contexts as of individuals.

Carbon dioxide fixation and lipid storage of Scenedesmus sp. ASK22: A sustainable approach for biofuel production and waste remediation.

In this study, an airlift reactor (ALR) has been employed to evaluate the carbon dioxide fixation rate (Rc) and lipid yield (LY) of unicellular green microalgae Scenedesmus sp. ASK22, using dairy effluent as a biofuel feedstock. Independent process parameters (PPs) such as light intensity, CO2 concentration, and aeration rate and their effect on Rc and LY were revealed. The central composite design (CCD) was used to optimize the PPs. The best-operating conditions were measured as light intensity -6.24 Klux, CO2 concentration -14.03% (v v-1), and aeration rate -1.02 liter per minute (LPM). Under these conditions, LY and Rc were found to be 4.22 gL-1 and 1.27 gL-1d-1 which were 2.24- and 1.94-fold higher than the value obtained in the control experiment (1.88 gL-1 and 0.656 gL-1d-1) at the end of 12th day. The corresponding values for bioremediation of nitrate, phosphate, as well as chemical oxygen demand (COD), remained within 98-100%. The biochemical, CHN, thermogravimetric, and fatty acid analysis of Scenedesmus sp. ASK22 biomass and lipid confirmed their potential as a clean biofuel feedstock. Furthermore, a comprehensive analysis of lipid-extracted microalgae biomass (LEMB) was carried out suggesting that LEMB could be used as a high-quality cattle and fish feed, fertilizers, and a sustainable source for biogas, bioethanol, and bio-oils. In addition to improving the developed system's efficiency, a semi-continuous regime was implemented which resulted in biomass productivity of 1.89 gL-1d-1 which was 2.6-fold higher than the batch cultivation without hampering lipid productivity (0.377 gL-1d-1). The present results suggest that Scenedesmus sp. ASK22 is a potential candidate for CO2 sequestration from atmosphere/flue gas, biofuel production (biodiesel, bioethanol, biogas, biobutanol, etc.), and waste remediation.

Integrated Analysis Identifies Novel Fusion Transcripts in Laterally Spreading Tumors Suggestive of Distinct Etiology Than Colorectal Cancers.

BACKGROUND: Laterally spreading tumors (LSTs) of the colon and rectum are a class of abnormality which spreads laterally and appears ulcerated. They are a subclass of colorectal cancer (CRCs) with higher invasive potential than CRCs. Moreover, the etiology of LST still remains obscure. METHODS: This study aimed to identify unique fusion transcript(s) in LSTs and evaluate their role in LST development and progression. RNA-Seq data for LST samples from the EMBL-EBI database were used to identify fusion transcripts. An integrated approach using Gene Ontology, pathway analysis, hub gene, and co-expression network analysis functionally characterized fusion transcripts to shed light upon the etiology of LSTs. RESULT: We identified 48 unique fusion genes in LSTs. GO terms were enriched in mRNA metabolic (p ≤ 2.06E-06), mRNA stabilization (p ≤ 1.60E-05), in cytosol (1.20E-05), RBP (p ≤ 2.30E-04), and RNA binding activity (p ≤ 3.51E-08) processes. Pathway analysis revealed an inflammatory phenotype of LSTs suggesting a distinct etiology than CRCs as pathways were enriched in salmonella infection (p ≤ 4.41 e-03), proteoglycans in cancer (p ≤ 1.18 e-02), and insulin signaling (p ≤ 2.13 e-02). Our exclusion and inclusion criteria and hub gene analysis finally identified 9 hub genes. Co-expression analysis of hub genes identified the most significant transcription factors (NELFE, MYC, TAF1, MAX) and kinases (MAPK14, CSNK2A1, CDK1, MAPK1) which were implicated in various cancer pathways. Furthermore, an overall survival analysis of hub genes was performed. Our predefined criterion resulted in the enrichment of NPM1-PTMA (NPM1: p ≤ 0.005) and HIST1H2BO-YBX1 (YBX1: p ≤ 0.02) fusion transcripts, significantly associated with the patient's overall survival. CONCLUSION: Our systematic analysis resulted in novel fusion genes in LSTs suggesting a different etiology than CRCs. Fusion transcripts were observed more frequently in non-granular LSTs suggestive of genetically more unstable than granular LST. We hypothesize that NPM1-PTMA and HIST1H2BO-YBX1 could be implicated in LST development and progression and may also serve as a prognostic or diagnostic biomarker in future for better management of LSTs.

Thuja occidentalis: An Unexplored Phytomedicine with Therapeutic Applications.

BACKGROUND: The recent outbreak of SARS-CoV-2 has received global attention. Due to a lack of recommended treatment regimens, the world faced various limitations resulting in improper management of the disease. Phytomedicines have played a prominent role in the prevention of various epidemics and pandemics in the past. OBJECTIVE: Here, we attempt to focus on safe and feasible use of Thuja occidentalis to manage and alleviate the panic of viral respiratory infections, including COVID-19, by strengthening an individual's immunity. The relevant information was collected from the web-based databases PubMed, Google Scholar, and MEDLINE, as well as other internet sources to review the applicability of T. occidentalis as a phytomedicine in managing respiratory infections and strengthening immunity. CONCLUSION: As important phytomedicine, and antipsychotic, T. occidentalis possesses a plethora of immunological properties that can be used effectively in the management of viral respiratory infections and has the potential to prevent further progression of the disease. Importantly, this could be only a part of the approach for treatment during the current outbreak that should be considered along with other measures.

Tandem synthesis of N-methylated tertiary amines via three-component coupling of carbonyl compounds, amines, and methanol.

An Ir-catalyzed tandem synthesis of various N-methylated tertiary amines from three-component coupling of carbonyl compounds, amines, and methanol following reductive amination/N-methylation is reported for the first time. A wide array of substrates with tolerance of different functional groups was demonstrated. The protocol was extended to the synthesis of N-methyl containing pharmaceutically important drug molecules. A probable catalytic cycle was proposed based on various control experiments and different analytical techniques such as NMR, IR and ESI-MS.

Mesoporous nanosilica: A thromboprotective nanomaterial for biomedical applications.

Nanosilica is widely employed in various biomedical applications because of their tailorable physiochemical properties and excellent biocompatibility. In the present study, we have evaluated interaction of nanosilica with important coagulation components, such as platelets, a highly sensitive cell found in the blood, and coagulation proteins. Mesoporous silica nanoparticles (MSNs) were prepared using sol-gel process and characterized by FESEM and TEM to find out the size and shape of the particles. Different platelet functional parameters including platelet adhesion, aggregation, activation, secretion, clot formation and clot retraction-based studies have been carried out to investigate the impact of synthesized nanosilica on the blood coagulation system. Besides, ROS generation and increase in intracellular calcium was also monitored as they play a pivotal role in regulating platelet functions. The complete detailed study revealed that MSNs neither has stimulatory action towards platelets nor do they show any effective interaction with coagulation proteins.

Experts' Consensus on Use of Long-Acting Nitroglycerine in the Management of Angina and Chronic Coronary Syndrome in India.

AIM: To address the existing gaps in knowledge about long-acting nitroglycerine (LA-NTG) and provide recommendations to address these issues. METHODOLOGY: Approved LA-NTG questionnaire that included 17 questions related to the role of LA-NTG in the management of angina and chronic coronary syndrome (CCS) was shared with 150 expert cardiologists from different regions from India. Results of these survey questionnaires were further discussed in 12 regional level meetings. The opinions and suggestions from all the meetings were compiled and analyzed. Further, recommendations were made with the help of attending national cardiology experts and a consensus statement was derived. RESULTS: This is the first consensus on LA-NTG, summarizing the clinical evidence from India and suggesting recommendations based on these data. The experts recommended early use of LA-NTG as a first-line antianginal therapy in combination with beta-blocker since it improves exercise tolerance in patients with CCS. A strong consensus was observed for using LA-NTG in patients with co-morbid hypertension, diabetes, chronic kidney disease and post-percutaneous coronary intervention angina. As a part of cardiac rehabilitation, LA-NTG allows patients with angina to exercise to a greater functional capacity. CONCLUSIONS: A national consensus was observed for several aspects of LA-NTG in the management of angina and CCS. The clinical experience of the experts confirmed an extremely satisfied patient perception about the efficacy of LA-NTG.

Regio-Selective C3- and N-Alkylation of Indolines in Water under Air Using Alcohols.

We disclosed a regio-selective C-H and N-H bond functionalization of indolines using alcohols in water via tandem dehydrogenation of N-heterocycles and alcohols. A diverse range of N- and C3-alkylated indolines/indoles were accessed utilizing a new cooperative iridium catalyst. The practical applicability of this methodology was demonstrated by the preparative-scale synthesis and synthesis of a psychoactive drug, N,N-dimethyltryptamine. A catalytic cycle is proposed based on several kinetic experiments, series of control experiments and density functional theory calculations.

Validation of the OPtimal Treatment of Angina (OPTA) Questionnaire in Indian Patients with Chronic Stable Angina.

BACKGROUND: A rising burden of coronary artery disease (CAD) in India is a major cause of concern, with angina being the leading manifestation. Hence a questionnaire to sensitize the clinicians about stable angina management and to assist in risk stratification is imperative. OBJECTIVE: To evaluate the content and face validity of a modified questionnaire adapted from the 7-item Seattle Angina Questionnaire (SAQ). MATERIALS AND METHODS: A panel of six experts in the field of evidence-based practice reviewed and rated the modified instrument for content clarity and relevance based on the 4-point ordinal scale. Face validity was assessed based on the trichotomous rating of "disagreed", "agree" or "neutral". Items on which ≥75% of patients "disagreed" were subjected to further review and revision. RESULTS: A total of six experts and 51 patients participated in the content and face validity, respectively. As no question received a score ≤2 by two or more experts for either content clarity or relevance, no modification in the questionnaire was required post content validation. During face validation, all patients agreed that the questions correctly measured the specific area of cardiovascular health status and response options correctly captured the answers provided. Demographic and baseline data of the patients were collected. CONCLUSION: The newly developed 5-item questionnaire demonstrated content and face validity, suggesting it to be a potential instrument to improve management decision and care of angina patients in India.

Transcriptomic landscape of early age onset of colorectal cancer identifies novel genes and pathways in Indian CRC patients.

Past decades of the current millennium have witnessed an unprecedented rise in Early age Onset of Colo Rectal Cancer (EOCRC) cases in India as well as across the globe. Unfortunately, EOCRCs are diagnosed at a more advanced stage of cancer. Moreover, the aetiology of EOCRC is not fully explored and still remains obscure. This study is aimed towards the identification of genes and pathways implicated in the EOCRC. In the present study, we performed high throughput RNA sequencing of colorectal tumor tissues for four EOCRC (median age 43.5 years) samples with adjacent mucosa and performed subsequent bioinformatics analysis to identify novel deregulated pathways and genes. Our integrated analysis identifies 17 hub genes (INSR, TNS1, IL1RAP, CD22, FCRLA, CXCL3, HGF, MS4A1, CD79B, CXCR2, IL1A, PTPN11, IRS1, IL1B, MET, TCL1A, and IL1R1). Pathway analysis of identified genes revealed that they were involved in the MAPK signaling pathway, hematopoietic cell lineage, cytokine-cytokine receptor pathway and PI3K-Akt signaling pathway. Survival and stage plot analysis identified four genes CXCL3, IL1B, MET and TNS1 genes (p = 0.015, 0.038, 0.049 and 0.011 respectively), significantly associated with overall survival. Further, differential expression of TNS1 and MET were confirmed on the validation cohort of the 5 EOCRCs (median age < 50 years and sporadic origin). This is the first approach to find early age onset biomarkers in Indian CRC patients. Among these TNS1 and MET are novel for EOCRC and may serve as potential biomarkers and novel therapeutic targets in future.

Molecular subtypes of colorectal cancer: An emerging therapeutic opportunity for personalized medicine.

Molecular subtypes-based therapies offer new potential framework for desired and precise outcome in clinical settings. Current treatment strategies in colorectal cancer are largely 'one drug fit all' model for patients that display same pathological conditions. However, CRC is a very heterogenous set of malignancy that does not support for above criteria. Each subtype displays different pathological and genetic signatures. Based on these features, therapeutic stratification for individual patients may be designed, which may ultimately lead to improved therapeutic outcomes. In this comprehensive review, we have attempted to briefly outline major CRC pathways. A detailed overview of molecular subtypes and their clinical significance has been discussed. Present and future methods, governing CRC subtyping in the era of personalized therapy with a special emphasis on CMS subtypes of CRC has been reviewed. Together, discovery and validation of new CRC patient stratification methods, screening for novel therapeutic targets, and enhanced diagnosis of CRC may improve the treatment outcome.

Meta-Analytic Use of Balanced Identity Theory to Validate the Implicit Association Test.

This meta-analysis evaluated theoretical predictions from balanced identity theory (BIT) and evaluated the validity of zero points of Implicit Association Test (IAT) and self-report measures used to test these predictions. Twenty-one researchers contributed individual subject data from 36 experiments (total N = 12,773) that used both explicit and implicit measures of the social-cognitive constructs. The meta-analysis confirmed predictions of BIT's balance-congruity principle and simultaneously validated interpretation of the IAT's zero point as indicating absence of preference between two attitude objects. Statistical power afforded by the sample size enabled the first confirmations of balance-congruity predictions with self-report measures. Beyond these empirical results, the meta-analysis introduced a within-study statistical test of the balance-congruity principle, finding that it had greater efficiency than the previous best method. The meta-analysis's full data set has been publicly archived to enable further studies of interrelations among attitudes, stereotypes, and identities.

Structural insight of two 4-Coumarate CoA ligase (4CL) isoforms in Leucaena suggests targeted genetic manipulations could lead to better lignin extractability from the pulp.

4-Coumarate: coenzyme A ligase (4CL) is a key enzyme involved in the early steps of the monolignol biosynthetic pathway. It is hypothesized to modulate S and G monolignol content in the plant. Lignin removal is imperative to the paper industry and higher S/G ratio governs better extractability of lignin and economics of the pulping process. This background prompted us to predict 3D structure of two isoforms of 4CL in Leucaena leucocephala and evaluate their substrate preferences. The 3D structure of Ll4CL1 and Ll4CL2 protein were created by homology modeling and further refined by loop refinement. Molecular docking studies suggested differential substrate preferences of both the isoforms. Ll4CL1 preferred sinapic acid (- 4.91 kcal/mole), ferulic acid (- 4.84 kcal/mole), hydroxyferulic acid (- 4.72 kcal/mole), and caffeic acid (- 4.71 kcal/mole), in their decreasing order. Similarly, Ll4CL2 preferred caffeic acid (- 6.56 kcal/mole, 4 H bonds), hydroxyferulic acid (- 6.56 kcal/mole, 3 H bonds), and ferulic acid (- 6.32 kcal/mole) and sinapic acid (- 5.00 kcal/mole) in their decreasing order. Further, active site residues were identified in both the isoforms and in silico mutation and docking analysis was performed. Our analysis suggested that ASP228, TYR262, and PRO326 for Ll4CL1 and SER165, LYS247 and PRO315 for Ll4CL2 were important for their functional activity. Based on differential substrate preferences of the two isoforms, as a first step towards genetically modified Leuaena having the desired phenotype, it can be proposed that over-expression of Ll4CL1 gene and/or down-regulation of Ll4CL2 gene could yield higher S/G ratio leading to better extractability of lignin.

Development and cost-benefit analysis of a novel process for biofuel production from microalgae using pre-treated high-strength fresh cheese whey wastewater.

In this study, a novel two-step integrated process is proposed to facilitate the microalgae biofuel production as well as fresh cheese whey wastewater (FCWW) treatment simultaneously. The pre- and post-treatment of high-strength FCWW were performed by means of coagulation and algal cultivation, respectively. The pre-treatment of FCWW for maximum removal of chemical oxygen demand (COD), turbidity (TUR) and total solids (TS) as responses was obtained by statistical optimization of coagulation parameters. The maximum removal of COD, TUR and TS at the optimum level of variables was obtained as 68.09%, 47.80% and 73.63%, respectively. The pre-treated FCWW was further treated by Chlorella pyrenoidosa and observed a significant reduction in the above-mentioned responses (87-94%). The maximum algal biomass yield and lipid productivity were observed as 2.44 g L-1 and 77.41 mg L-1 day-1, respectively. Based on promising results of FCWW treatment and its use as a third-generation biodiesel feedstock, a cost-benefit analysis of the developed process was assessed for microalgal oil production. The total profit earned by the integrated process model was $9.59 million year-1. Accordingly, the estimated production cost of algal oil (TAG) from the developed system was estimated to be $79.03 per barrel.