Secondary Pathways Research Articles

Cold-stress induced metabolomic and transcriptomic changes in leaves of three mango varieties with different cold tolerance

BackgroundMango (Mangifera indica L.) is grown in Hainan, Guangdong, Yunnan, Sichuan, and Fujian provinces and Guanxi autonomous region of China. However, trees growing in these areas suffer severe cold stress during winter, which affects the yield. To this regard, data on global metabolome and transcriptome profiles of leaves are limited. Here, we used combined metabolome and transcriptome analyses of leaves of three mango cultivars with different cold stress tolerance, i.e. Jinhuang (J)—tolerant, Tainung (T) and Guiremang No. 82 (G)—susceptible, after 24 (LF), 48 (MF) and 72 (HF) hours of cold.ResultsA total of 1,323 metabolites belonging to 12 compound classes were detected. Of these, amino acids and derivatives, nucleotides and derivatives, and lipids accumulated in higher quantities after cold stress exposure in the three cultivars. Notably, Jinhuang leaves showed increasing accumulation trends of flavonoids, terpenoids, lignans and coumarins, and alkaloids with exposure time. Among the phytohormones, jasmonic acid and abscisic acid levels decreased, while N6-isopentenyladenine increased with cold stress time. Transcriptome analysis led to the identification of 22,526 differentially expressed genes. Many genes enriched in photosynthesis, antenna proteins, flavonoid, terpenoid (di- and sesquiterpenoids) and alkaloid biosynthesis pathways were upregulated in Jihuang leaves. Moreover, expression changes related to phytohormones, MAPK (including calcium and H2O2), and the ICE-CBF-COR signalling cascade indicate involvement of these pathways in cold stress responses.ConclusionCold stress tolerance in mango leaves is associated with regulation of primary and secondary metabolite biosynthesis pathways. Jasmonic acid, abscisic acid, and cytokinins are potential regulators of cold stress responses in mango leaves.

Biochemical dynamics during postharvest: Highlighting the interplay of stress during storage and maturation of fresh produce.

The lifecycle of fresh produce involves a sequence of biochemical events during their ontology, and these events are particularly significant for climacteric fruits. A high demand during ripening is observed in these plant products, which is reflected in a high rate of respiration and ethylene production. Increased respiratory demand triggers the activation of secondary pathways such as alternate oxidase, which do not experience critical increases in energy consumption in non-climacteric fruit. In addition, biochemical events produced by external factors lead to compensatory responses in fresh produce to counteract the oxidative stress caused by the former. The dynamics of these responses are accompanied by signaling, where reactive oxygen species play a pivotal role in fresh product cell perception. This review aims to describe the protection mechanisms of fresh produce against environmental challenges and how controlled doses of abiotic stressors can be used to improve quality and prolong their shelf-life through the interaction of stress and defense mechanisms.

Weather and the City: Machine Learning for Predicting and Attributing Fine Scale Air Quality to Meteorological and Urban Determinants.

Urban air quality persists as a global concern, with critical health implications. This study employs a combination of machine learning (gradient boosting regression, GBR) and spatial analysis to better understand the key drivers behind air pollution and its prediction and mitigation strategies. Focusing on New York City as a representative urban area, we investigate the interplay between urban characteristics and weather factors, showing that urban features, including traffic-related parameters and urban morphology, emerge as crucial predictors for pollutants closely associated with vehicular emissions, such as elemental carbon (EC) and nitrogen oxides (NOx). Conversely, pollutants with secondary formation pathways (e.g., PM2.5) or stemming from nontraffic sources (e.g., sulfur dioxide, SO2) are predominantly influenced by meteorological conditions, particularly wind speed and maximum daily temperature. Urban characteristics are shown to act over spatial scales of 500 × 500 m2, which is thus the footprint needed to effectively capture the impact of urban form, fabric, and function. Our spatial predictive model, needing only meteorological and urban inputs, achieves promising results with mean absolute errors ranging from 8 to 32% when using full-year data. Our approach also yields good performance when applied to the temporal mapping of spatial pollutant variability. Our findings highlight the interacting roles of urban characteristics and weather conditions and can inform urban planning, design, and policy.

Abstract 6500: Dependence of EGFR-mutant NSCLC on MET as demonstrated by vebreltinib, a novel and selective brain-penetrating MET kinase inhibitor

Abstract Background: Although EGFR inhibitors (EGFRi), preferably osimertinib, have offered substantial benefit for the classical plus T790M EGFR-mutant NSCLC patients, drug resistance develops and poses a critical challenge for long-term survival. The resistance is rooted to either on-target secondary EGFR mutations or compensatory oncogenic pathways bypassing EGFRi intervention, one of which appears to be treatment-acquired MET amplification (METamp). In this study we set out to understand the conditions when the tumor cells become dependent on MET. Methods: NSCLC patient-derived tumor models (PDX) carrying classical and T790M EGFR driver mutations were selected based on EGFRi history and concurrent MET gene copy numbers or RNA expression levels: Type 1) resistant to osimertinib with METamp; Type 2) partially resistant to osimertinib with METamp; and Type 3) sensitive to osimertinib with low MET expression, no METamp. These PDX xenograft mice were treated with vebreltinib (APL-101) at clinically relevant doses as single agent or in combination with osimertinib. The pharmacodynamic effects on EGFR and MET phosphor (P)- and total proteins were analyzed from tumor samples harvested during and at the end of treatments. Results: Vebreltinib single agent inhibited tumor growth of the type-1 PDX. One such PDX was resistant to chemotherapies, BRAF inhibitor and EGFRi including osimertinib, was inhibited by vebreltinib with ED50 of 3 mg/kg (p.o/q.d.). Another such PDX tumor appeared to be eradicated by vebreltinib treatment at 10 mg/kg (p.o/q.d.) and the mice became tumor-free on Day 18 and remained so after dosing stop on day 21 with last observation at study end (Day 70). In comparison, reference METi savolitinib showed only partial tumor size reduction against the same PDX tumor, not as durable as vebreltinib, and did not eradicate tumor growth at the same dose as vebreltinib or in combo with Osimertinib. Re-grown tumor after savolitinib osimertinib combo dosing stop was inhibited completely by vebreltinib follow-on treatment. In the type-2 PDX, tumor growth was partially inhibited by vebreltinib but was completely inhibited by combo of vebreltinib and osimertinib. The anti-tumor activity of vebreltinib in type-1 and type-2 PDX was associated with pharmacodynamic inhibition of P-MET and P-EGFR and MET protein degradation. In the type-3 PDX, tumor growth appeared to be eradicated by osimertinib and not inhibited by vebreltinib. However, addition of vebreltinib suppressed tumor re-growth after osimertinib dosing stop. Conclusion: EGFR-mutant NSCLC resistance to EGFRi may be dependent on MET pathway regardless of acquired METamp, whereas METamp may dictate the degree of MET dependence. Our data supports the hypothesis that adding vebreltinib to EGFRi overcome MET dependent resistance with durable effect or preventing MET dependent resistance to maximize therapeutic benefits. Citation Format: Xiaoling Zhang, Elaine Liu, Yan Song, Peony Yu, Sanjeev Redkar, Guo-Liang Yu. Dependence of EGFR-mutant NSCLC on MET as demonstrated by vebreltinib, a novel and selective brain-penetrating MET kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6500.

Streptomyces sungeiensis SD3 as a Microbial Chassis for the Heterologous Production of Secondary Metabolites.

We present the newly isolated Streptomyces sungeiensis SD3 strain as a promising microbial chassis for heterologous production of secondary metabolites. S. sungeiensis SD3 exhibits several advantageous traits as a microbial chassis, including genetic tractability, rapid growth, susceptibility to antibiotics, and metabolic capability supporting secondary metabolism. Genomic and transcriptomic sequencing unveiled the primary metabolic capabilities and secondary biosynthetic pathways of S. sungeiensis SD3, including a previously unknown pathway responsible for the biosynthesis of streptazone B1. The unique placement of S. sungeiensis SD3 in the phylogenetic tree designates it as a type strain, setting it apart from other frequently employed Streptomyces chassis. This distinction makes it the preferred chassis for expressing biosynthetic gene clusters (BGCs) derived from strains within the same phylogenetic or neighboring phylogenetic clade. The successful expression of secondary biosynthetic pathways from a closely related yet slow-growing strain underscores the utility of S. sungeiensis SD3 as a heterologous expression chassis. Validation of CRISPR/Cas9-assisted genetic tools for chromosomal deletion and insertion paved the way for further strain improvement and BGC refactoring through rational genome editing. The addition of S. sungeiensis SD3 to the heterologous chassis toolkit will facilitate the discovery and production of secondary metabolites.

Unravelling the impact of plant ontogenic factors on the content and phytotoxic potential of Cistus ladanifer L. (rockrose) essential oils

In recent years, research has focused on the development of next-generation herbicides based on allelochemicals, with a particular emphasis on plant essential oils, such as Cistus ladanifer L. (rockrose) essential oil. This study has evaluated how plant ontogenic factors influence the yield, chemical composition, and phytotoxic activity of C. ladanifer essential oil. The essential oils were extracted by hydrodistillation and analysed by gas chromatography coupled with mass spectrometry (GC–MS). The results revealed that the content of essential oil varied significantly, with higher yields observed during the fruit maturation stage compared to the flowering stage. C. ladanifer essential oils were characterized by their richness in terpene-oxygenated compounds. The most significant finding was that C. ladanifer essential oil displayed potent dose-dependent phytotoxic activity on Raphanus sativus (radish) seedlings, indicating their potential use as a natural bioherbicide in agriculture. Notably, essential oil samples from the fruit maturation stage, which contained higher levels of monoterpenes and sesquiterpenes (both hydrocarbons and oxygenated forms), exhibited greater phytotoxic activity on seed germination and early growth compared to the samples from the flowering stage, which were richer in diterpenes and the group labelled ``others''. Multivariate analyses (PCA and Heatmaps combined with cluster analysis) revealed concordance between modifications in secondary metabolism biosynthetic pathways and their enzymes implicated as responses to diverse plant-specific ecological functions. Finally, by exploring sustainable natural products like plant essential oils, this research contributes to the development of next-generation herbicides that promote crop protection while reducing environmental impact.

Peribacillus frigoritolerans T7-IITJ, a potential biofertilizer, induces plant growth-promoting genes of Arabidopsis thaliana.

This study aimed to isolate plant growth and drought tolerance-promoting bacteria from the nutrient-poor rhizosphere soil of Thar desert plants and unravel their molecular mechanisms of plant growth promotion. Among our rhizobacterial isolates, Enterobacter cloacae C1P-IITJ, Kalamiella piersonii J4-IITJ, and Peribacillus frigoritolerans T7-IITJ, significantly enhanced root and shoot growth (4-5-fold) in Arabidopsis thaliana under PEG-induced drought stress. Whole genome sequencing and biochemical analyses of the non-pathogenic bacterium T7-IITJ revealed its plant growth-promoting traits, viz., solubilization of phosphate (40-73µg/ml), iron (24±0.58mm halo on chrome azurol S media), and nitrate (1.58±0.01µg/ml nitrite), along with production of exopolysaccharides (125±20µg/ml) and auxin-like compounds (42.6±0.05µg/ml). Transcriptome analysis of A. thaliana inoculated with T7-IITJ and exposure to drought revealed the induction of 445 plant genes (log2fold-change>1, FDR<0.05) for photosynthesis, auxin and jasmonate signalling, nutrient uptake, redox homeostasis, and secondary metabolite biosynthesis pathways related to beneficial bacteria-plant interaction, but repression of 503 genes (log2fold-change < -1) including many stress-responsive genes. T7-IITJ enhanced proline 2.5-fold, chlorophyll 2.5-2.8-fold, iron 2-fold, phosphate 1.6-fold, and nitrogen 4-fold, and reduced reactive oxygen species 2-4.7-fold in plant tissues under drought. T7-IITJ also improved the germination and seedling growth of Tephrosia purpurea, Triticum aestivum, and Setaria italica under drought and inhibited the growth of two plant pathogenic fungi, Fusarium oxysporum, and Rhizoctonia solani. P. frigoritolerans T7-IITJ is a potent biofertilizer that regulates plant genes to promote growth and drought tolerance.

The GaKAN2, a KANADI transcription factor, modulates stem trichomes in Gossypium arboreum.

GaKAN2, a member of the KANADI family, was found to be widely expressed in the cotton tissues and regulates trichome development through complex pathways. Cotton trichomes are believed to be the defense barrier against insect pests. Cotton fiber and trichomes are single-cell epidermal extensions with shared regulatory mechanisms. Despite several studies underlying mechanism of trichome development remains elusive. The KANADI is one of the key transcription factors (TFs) family, regulating Arabidopsis trichomes growth. However, the function of KANADI genes in cotton remains unknown. In the current study genome-wide scanning, transcriptomic analysis, gene silencing, subcellular localization, and yeast two-hybrid techniques were employed to decipher the function of KANADI TFs family genes in cotton crop. A total of 7 GaKAN genes were found in the Gossypium arboreum. Transcriptomic data revealed that these genes were significantly expressed in stem and root. Moreover, GaKAN2 was widely expressed in other tissues also. Subsequently, we selected GaKAN2 to validate the function of KANADI genes. Silencing of GaKAN2 resulted in a 24.99% decrease in single-cell trichomes and an 11.33% reduction in internodal distance, indicating its potential role in regulating trichomes and plant growth. RNA-Seq analysis elucidated that GaSuS and GaERS were the downstream genes of GaKAN2. The transcriptional activation and similarity in silencing phenotype between GaKAN2 and GaERS suggested that GaKAN2 regulates trichomes development through GaERS. Moreover, KEGG analysis revealed that a significant number of genes were enriched in the biosynthesis of secondary metabolites and plant hormone signal transduction pathways, thereby suggesting that GaKAN2 regulates the stem trichomes and plant growth. The GFP subcellular localization and yeast transcriptional activation analysis elucidated that GaKAN2 was located in the nucleus and capable of regulating the transcription of downstream genes. This study elucidated the function and characteristics of the KANADI gene family in cotton, providing a fundamental basis for further research on GaKAN2 gene in cotton plant trichomes and plant developmental processes.

Evaluation of a pilot of a community virtual triage for breast symptoms outside of usual primary or secondary care pathways.

Both primary and secondary care services in the NHS have been overwhelmed with an increase in referrals on the suspected cancer pathways. The years 2020/2021 saw 551,770 symptomatic breast referrals made in England alone. The Wessex Rapid investigations service in conjunction with the local district general hospital and primary care networks instigated a virtual triage for new breast symptoms. Over the course of a year, 664 people were assessed by either telephone or video using specially trained nurses. Appointments were given within 1-2 working days. The service was highly valued by patients and general practitioners. We were unable to confirm a reduction in referral to secondary care as the evaluation occurred during a postpandemic peak in referrals. We found that 10% of patients with new breast symptoms can safely self-manage. This percentage varied with the experience of the triage clinician. A specialist community face-to-face service could reduce further the need for full secondary care evaluation. Better integration and use of information technology systems would improve the service. The rapid responsiveness and length of consultations is valued by patients. Representation with the same symptoms was rare. This pathway utilises staff outside of the usual primary and secondary care providers and thus reduces the pressure on stretched systems.

Unraveling Hidden Cell Signaling Pathways Using Biophysical Methods: Application to the Gαq/Phospholipase Cβ Signaling System.

The success of pharmaceutical therapies relies on how well cells respond to a particular drug, but accurately predicting responses can be difficult due to the complex and numerous potential molecular interactions that are possible in cells, and the responses of individuals can be variable due to cryptic and unexpected interactions. With the advancement of proteomics and fluorescence imaging methods, it is now possible to elucidate novel secondary signaling pathways and predict unexpected responses that might otherwise be missed, allowing for the development of better therapeutics. The Gαq/PLCβ signaling pathway is activated by agents that mediate allergic responses, neurotransmission, and heart rate, as well as other functions that are critical for survival. This Review describes the factors that must be considered in delineating signaling pathways and describes the novel translational role that we have uncovered for this signaling pathway.

Integrated full-length transcriptome and metabolome analysis reveals the defence response of melon to gummy stem blight.

Gummy stem blight (GSB), a widespread disease causing great loss to cucurbit production, has become a major threat to melon cultivation. However, the melon-GSB interaction remains largely unknown. Here, full-length transcriptome and widely targeted metabolome were used to investigate the defence responses of resistant (PI511089) and susceptible (Payzawat) melon accessions to GSB pathogen infection at 24 h. The biosynthesis of secondary metabolites and MAPK signalling pathway were specifically enriched for differentially expressed genes in PI511890, while carbohydrate metabolism and amino acid metabolism were specifically enriched in Payzawat. More than 1000 novel genes were identified and MAPK signalling pathway was specifically enriched for them in PI511890. There were 11 793 alternative splicing events involving in the defence response to GSB. Totally, 910 metabolites were identified in Payzawat and PI511890, and flavonoids were the dominant metabolites. Integrated full-length transcriptome and metabolome analysis showed eriodictyol and oxalic acid were the potential marker metabolites for GSB resistance in melon. Moreover, posttranscription regulation was widely involved in the defence response of melon to GSB pathogen infection. These results not only improve our understanding on the interaction between melon and GSB, but also facilitate the genetic improvement of melon with GSB resistance.

Genome-wide identification of Uncaria rhynchophylla bHLH transcription factors and in-vitro validation of UrbHLH1 through interaction with terpenoid indole alkaloid synthesis pathway members

Uncaria rhynchophylla (Gouteng), as an evergreen woody vine belong to Rubiaceae family, is a traditional medicinal herb in China. Its terpenoid indole alkaloids (TIAs), which have good antidepressant and combined therapeutic effects on Alzheimer's disease, have attracted widespread attention. However, the content of TIAs is relatively low in U.rhynchophylla, which is unable to meet the growing market demand. The basic helix loop-helix (bHLH) transcription factor family exists in all three eukaryotic kingdoms and can participate in regulating secondary metabolite pathways. So far, there has been no comprehensive analysis of the bHLH gene in U. rhynchophylla, and their role in TIAs is almost unknown. In this study, a total of 171 UrbHLH genes (UrbHLHs) were unevenly distributed on 22 chromosomes and divided into 23 subfamilies. In addition, the physicochemical properties of UrbHLHs were analyzed. Most UrbHLHs in each subgroup had similar gene structures and conserved motifs. Intraspecific collinearity analysis showed that UrbHLH1 may be related to the biosynthesis of TIAs. Subcellular localization experiments revealed that UrbHLH1 is located in the nucleus; Dual luciferase reporter gene analysis (Dual-LUC) showed that UrbHLH1 could activate the expression of UrG10H and Ur10HGO in the TIAs synthesis pathway of U. rhynchophylla. Finally, using yeast one hybrid (Y1H) it was found that the promoter regions of these two genes both have E-box binding elements, which can be bound by UrbHLH1 and produced strong interactions. Therefore, UrbHLH1 may participate in the synthesis of TIAs pathway. In conclusion, this study provides foundation data on the role of UrbHLH transcription factors in regulating TIAs of U. rhynchophylla.

Visible Light Induced Exciton Dynamics and trans-to-cis Isomerization in Azobenzene Aggregates: Insights from Surface Hopping/Semiempirical Configuration Interaction Molecular Dynamics Simulations.

Assemblies of photochromic molecules feature exciton states, which govern photochemical and photophysical processes in multichromophoric systems. Understanding the photoinduced dynamics of the assemblies requires nonadiabatic treatment involving multiple exciton states and numerous nuclear degrees of freedom, thus posing a challenge for simulations. In this work, we address this challenge for aggregates of azobenzene, a prototypical molecular switch, performing on-the-fly surface hopping calculations combined with semiempirical configuration interaction electronic structure and augmented with transition density matrix analysis to characterize exciton evolution. Specifically, we consider excitation of azobenzene tetramers in the nπ* absorption band located in the visible (blue) part of the electromagnetic spectrum, thus extending our recent work on dynamics after ππ* excitation corresponding to the ultraviolet region [Titov, J. Phys. Chem. C2023, 127, 13678-13688]. We find that the nπ* excitons, which are initially strongly localized by ground-state conformational disorder, undergo further (very strong) localization during short-time photodynamics. This excited-state localization process is extremely ultrafast, occurring within the first 10 fs of photodynamics. We observe virtually no exciton transfer of the localized excitons in the nπ* manifold. However, the transfer may occur via secondary pathways involving ππ* states or the ground state. Moreover, we find that the nπ* quantum yields of the trans-to-cis isomerization are reduced in the aggregated state.

Molecular mechanism of salinity and waterlogging tolerance in mangrove Kandelia obovata.

Mangrove forests are colloquially referred to as "Earth's kidneys" and serve many important ecological and commercial functions. Salinity and waterlogging stress are the most important abiotic stressors restricting the growth and development of mangroves. Kandelia obovata (K. obovata) is the greatest latitudinally-distributed salt mangrove species in China.Here, morphology and transcriptomics were used to study the response of K. obovata to salt and waterlogging stress. In addition, weighted gene co-expression network analysis of the combined gene expression and phenotypic datasets was used to identify core salinity- and waterlogging-responsive modules. In this study, we observed that both high salinity and waterlogging significantly inhibited growth and development in K. obovata. Notably, growth was negatively correlated with salt concentration and positively correlated with waterlogging duration, and high salinity was significantly more inhibitive than waterlogging. A total of 7, 591 salt-responsive and 228 waterlogging-responsive differentially expressed genes were identified by RNA sequencing. Long-term salt stress was highly correlated with the measured physiological parameters while long-term waterlogging was poorly correlated with these traits. At the same time, 45 salinity-responsive and 16 waterlogging-responsive core genes were identified. All 61 core genes were mainly involved in metabolic and biosynthesis of secondary metabolites pathways. This study provides valuable insight into the molecular mechanisms of salinity and waterlogging tolerance in K. obovata, as well as a useful genetic resource for the improvement of mangrove stress tolerance using molecular breeding techniques.

Non-target influence of imidacloprid residues on grape global metabolome and berry quality with the identification of metabolite biomarkers.

This paper illustrates the non-target impact of imidacloprid (IM) residues on the grape global metabolome and biomarker identification with high-resolution mass spectrometry. IM was applied at the recommended dose (SD), and ten times SD (10 RD). The global metabolome analysis revealed that 21 metabolites were up- and down-regulated with IM SD treatment. In 10 RD, 9 metabolites were upregulated, and 28 were downregulated. Pathway enrichment analysis revealed the primary and secondary pathway disruption in grapes. Berry quality was affected with decrease in flavonoids by 32.97% in 10 RD; phenols were reduced by 53.93 in SD, 50.8% in 10 RD. The non-target and target study revealed the degradation of IM in grapes to desnitro-IM and IM-urea which were identified as a potential biomarker for IM residues in grapes, which would benefit the authentication of organic product. Overall, imidacloprid showed a significant impact on the grape metabolome and quality.

Treatment pathways, economic burden and clinical outcomes in new users of inhaled corticosteroid/long-acting B2-agonist dual therapy with chronic obstructive pulmonary disease in a primary care setting in England: a retrospective cohort study

ObjectiveManagement of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use,...

Transcriptome and machine learning analysis of the impact of COVID-19 on mitochondria and multiorgan damage.

The effects of coronavirus disease 2019 (COVID-19) primarily concern the respiratory tract and lungs; however, studies have shown that all organs are susceptible to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 may involve multiorgan damage from direct viral invasion through angiotensin-converting enzyme 2 (ACE2), through inflammatory cytokine storms, or through other secondary pathways. This study involved the analysis of publicly accessible transcriptome data from the Gene Expression Omnibus (GEO) database for identifying significant differentially expressed genes related to COVID-19 and an investigation relating to the pathways associated with mitochondrial, cardiac, hepatic, and renal toxicity in COVID-19. Significant differentially expressed genes were identified and ranked by statistical approaches, and the genes derived by biological meaning were ranked by feature importance; both were utilized as machine learning features for verification. Sample set selection for machine learning was based on the performance, sample size, imbalanced data state, and overfitting assessment. Machine learning served as a verification tool by facilitating the testing of biological hypotheses by incorporating gene list adjustment. A subsequent in-depth study for gene and pathway network analysis was conducted to explore whether COVID-19 is associated with cardiac, hepatic, and renal impairments via mitochondrial infection. The analysis showed that potential cardiac, hepatic, and renal impairments in COVID-19 are associated with ACE2, inflammatory cytokine storms, and mitochondrial pathways, suggesting potential medical interventions for COVID-19-induced multiorgan damage.

Myeloid Neoplasms: Better Understanding of their Molecular Pathogenesis with Improvised Genomic Testing: A Ray of Hope for Better Clinical Outcomes

With the increase in incidence and prevalence of myeloid neoplasms in India, it has become a necessity to understand its molecular mechanisms, acquisition of genomic alterations, and understand its primary and secondary resistance pathways which ultimately impact the decision of therapeutics. The objective of this review is to investigate the molecular aspects of this disease type and identify the biomarkers that help with diagnosis, risk assessment, prognosis, and selecting the best line of treatment for a specific myeloid neoplasm. Advancements and innovations in molecular technologies from simplest Real-Time PCR to high throughput next-generation sequencing have played a vital role in screening the most common mutations and fusions to the novel and rare. Molecular technologies have helped to enumerate the genomic landscape of myeloid malignancies. The understanding of both- the mechanisms and the technology is a strong combination as it has helped revolutionize precision oncology and helped in giving better therapeutic choices with better clinical outcomes. The importance of cellular morphology, clinical symptoms, and molecular pathology in assessing the risk of myeloid malignancies is emphasized and summarized in the review. The review concludes that understanding molecular pathogenesis can be improved by using clinical-pathological-molecular strategies for diagnosis and therapy decision-making.

Assessment of Secondary Sulfate Aqueous-Phase Formation Pathways in the Tropical Island City of Haikou: A Chemical Kinetic Perspective.

Sulfate (SO42-) is an essential chemical species in atmospheric aerosols and plays an influential role in their physical-chemical characteristics. The mechanisms of secondary SO42- aerosol have been intensively studied in air-polluted cities. However, few studies have focused on cities with good air quality. One-year PM2.5 samples were collected in the tropical island city of Haikou, and water-soluble inorganic ions, as well as water-soluble Fe and Mn, were analyzed. The results showed that non-sea-salt SO42- (nss-SO42-) was the dominant species of water-soluble inorganic ions, accounting for 40-57% of the total water-soluble inorganic ions in PM2.5 in Haikou. The S(IV)+H2O2 pathway was the main formation pathway for secondary SO42- in wintertime in Haikou, contributing to 57% of secondary SO42- formation. By contrast, 54% of secondary SO42- was produced by the S(IV)+Fe×Mn pathway in summer. In spring and autumn, the S(IV)+H2O2, S(IV)+Fe×Mn, and S(IV)+NO2 pathways contributed equally to secondary SO42- formation. The ionic strength was the controlling parameter for the S(IV)+NO2 pathway, while pH was identified as a key factor that mediates the S(IV)+H2O2 and S(IV)+Fe×Mn pathways to produce secondary SO42-. This study contributes to our understanding of secondary SO42- production under low PM2.5 concentrations but high SO42- percentages.

P202 Streamlining primary and secondary care pathways reduces the time-to-specialist IBD care: the emergence of FIT and the relative decline of calprotectin testing in primary care

Abstract Background Streamlining primary and secondary care pathways reduces the time-to-specialist IBD care. Prior to the COVID-19 pandemic, using an algorithm that screens endoscopy reports for probable IBD, we halved the time to IBD specialist review and treatment. Previous studies report that faecal immunochemical testing (FIT) could be used like calprotectin to test for suspected IBD. We sought to define the changing use of calprotectin and FIT prior to the diagnosis of IBD, and to determine whether their use influenced the time to secondary care treatment. Methods We conducted a retrospective observational cohort study of the time from endoscopic diagnosis of IBD to initiation of treatment. Demographics, stool testing, referral route, disease type, clinical review and treatment data were recorded from our electronic patient record. We sought factors associated with a delay in treatment defined as the upper quartile of time-to-treatment using logistic regression. Results Between 01/07/16 and 01/09/23 there were 805 new diagnoses of IBD (503 UC, 225 Crohn’s disease and 77 IBD-U). Monthly diagnosis rates were stable across the pandemic, except for March 2020 due to endoscopy unit closure. The median time from endoscopy to specialist review was 19.0 days (IQR7.0-44.0) and time to outpatient treatment 5.0 days (IQR 0.0-29.0 days). Overall, the use of pre-IBD diagnosis stool biomarkers has increased over time, but since 2020 there has been a progressive rise in FIT, and a decrease in calprotectin, testing (Fig 1). By 2023, people with a new diagnosis of IBD were more likely to have FIT than calprotectin testing. Whilst stool biomarker testing did not influence the time-to-IBD treatment, FIT testing was associated with a reduced delay from primary referral to endoscopy (OR 0.17 p=0.023). Factors associated with a delay in treatment were a diagnosis of Crohn’s disease versus UC/IBDU, having your index endoscopy undertake by a colorectal surgeon and being managed on a non-emergency pathway. IBD nurse contact prior to medical clinic review was associated with a significant reduction in delay to treatment (OR 0.55 p=0.003) Conclusion In the Southwest of the UK, pre-IBD diagnosis FIT, is now more common than pre-IBD diagnosis calprotectin testing. Factors linked to a delay in treatment were being diagnosed with Crohn’s disease versus UC/IBDU, having your index endoscopy undertaken by a colorectal surgeon and not specialist nurse or gastroenterologist and being managed on a non-emergency pathway. Further studies are needed to understand the influence of FIT versus calprotectin testing in the primary care diagnosis of IBD.