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Secondary metabolites play crucial roles in plant defense, development, and ecological interactions, making them valuable for medicinal and agricultural applications. However, the regulatory mechanisms governing their biosynthesis remain incompletely understood. Here, we conduct a meta-analysis of publicly available Rauvolfia serpentina transcriptome data from different plant tissues to investigate secondary metabolite biosynthesis and root system development. Our analysis points to the involvement of distinct biosynthetic routes and associated co-expression networks that may collectively contribute to metabolite production in R. serpentina . The co-expression analysis revealed two putative modules—plum1 and steelblue—that showed a coordinated transcriptional pattern with genes implicated in secondary metabolism. Within these modules, hub-gene analysis identified three key candidates, STR1 , ABI3/VP1 , and WRKY25 , which appear to be linked not only to secondary metabolite biosynthesis but also to aspects of root system development. Subsequent promoter analysis and qRT-PCR validation revealed tissue-specific regulation of WRKY25 , STR1 , and ABI3/VP1 , with significant stress-responsive expression detected primarily in roots, particularly under salicylic acid and drought treatments. This induction pattern reinforces their potential involvement in both metabolite production and broader stress-tolerance mechanisms. Overall, this study provides a useful set of candidate genes and regulatory elements that can be pursued in future functional assays. It also offers preliminary insights into the tissue-specific regulation of secondary metabolite biosynthesis in R. serpentina .

ObjectivesOur objective was to compare prostate cancer detection rates between patients undergoing serum prostate-specific antigen (PSA) vs magnetic resonance imaging (MRI) for prostate cancer screening.DesignPhase III open-label randomised controlled trial.SettingSingle tertiary cancer centre in Toronto, Canada.ParticipantsMen 50 years of age and older with no history of PSA screening for ≥3 years, a negative digital rectal exam and no prior prostate biopsy.InterventionsPatients were recommended to undergo a prostate biopsy if their PSA was ≥2.6 ng/mL (PSA arm) or if they had a PIRADS score of 4 or 5 (MRI arm). Patients underwent an end-of-study PSA in the MRI arm.Primary and secondary outcome measuresAdenocarcinoma on prostate biopsy. Prostate biopsy rates and the presence of clinically significant prostate cancer were also compared.ResultsA total of 525 patients were randomised, with 266 in the PSA arm and 248 in the MRI arm. Due to challenges with accrual and study execution during the COVID-19 pandemic, the study was terminated early. In the PSA arm, 48 patients had an abnormal PSA and 28 (58%) agreed to undergo a prostate biopsy. In the MRI arm, 25 patients had a PIRADS score of 4 or 5 and 24 (96%) agreed to undergo a biopsy. The relative risk for MRI to recommend a prostate biopsy was 0.52 (95% CI 0.33 to 0.82, p=0.005), compared with PSA. The cancer detection rate for patients in the PSA arm was 29% (8 of 28) vs 63% (15 of 24, p=0.019) in the MRI arm, with a higher proportion of clinically significant cancer detected in the MRI arm (73% vs 50%). The relative risk for detecting cancer and clinically significant with MRI compared with PSA was 1.89 (95% CI 0.82 to 4.38, p=0.14) and 2.77 (95% CI 0.89 to 8.59, p=0.07), respectively.ConclusionsProstate MRI as a stand-alone screening test reduced the rate of prostate biopsy. The number of clinically significant cancers detected was higher in the MRI arm, but this did not reach statistical significance. Due to early termination, the study was underpowered. More patients were willing to follow recommendations for prostate biopsy based on MRI results.Trial registration numberNCT02799303.

Autoimmune hypothyroidism is known to be caused by immune responses related to the thyroid gland and its immunological feature includes presence of autoimmune antibodies. Therefore the aim was to analyze presence of anti-TPO antibodies in hypothyroidism patients in Gujarat. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) is one of the susceptibility genes for various autoimmune diseases. Hence, exon1 +49A/G and 3'UTR CT60A/G single nucleotide polymorphisms (SNPs) in CTLA4 and its mRNA expression levels were investigated in autoimmune hypothyroidism patients. Thyroglobulin (TG) is known to be associated with autoimmune thyroid disorders and thus exon 33 (E33) SNP in TG was investigated. We analyzed the presence of anti-TPO antibodies in the plasma samples of 84 hypothyroidism patients and 62 controls by ELISA. PCR-RFLP technique was used for genotyping of polymorphisms. sCTLA4 and flCTLA4 mRNA expression levels were assessed by real time PCR. 59.52% of hypothyroid patients had anti-TPO antibodies in their circulation. The genotype and allele frequencies differed significantly for +49A/G (p = 0.0004 for +49AG, p = 0.0019 for +49GG & p = 0.0004 for allele), CT60 (p = 0.0110 for CT60AG, p = 0.0005 for CT60GG & p<0.0001 for allele) and TG E33 (p = 0.0003 for E33TC p<0.0001 for E33CC& p<0.0001 for allele) SNPs between patients and controls. Patients had significantly decreased mRNA levels of both sCTLA4 (p = 0.0017) and flCTLA4 (p<0.0001) compared to controls. +49A/G and CT60 polymorphisms of CTLA4 were in moderate linkage disequilibrium. Logistic regression analysis indicated significant association of CT49A/G, CT60A/G and TG exon 33 polymorphisms with susceptibility to autoimmune hypothyroidism when adjusted for age and gender. Our results suggest +49A/G and CT60 polymorphism of CTLA4 and E33 polymorphism of TG may be genetic risk factors for autoimmune hypothyroidism susceptibility and down regulation of both forms of CTLA4 advocates the crucial role of CTLA4 in pathogenesis of autoimmune hypothyroidism.

Vitiligo is a depigmenting disorder resulting from loss of functional melanocytes in the skin. NPY plays an important role in induction of immune response by acting on a variety of immune cells. NPY synthesis and release is governed by IL1B. Moreover, genetic variability in IL1B is reported to be associated with elevated NPY levels. Aim of the present study was to explore NPY promoter -399T/C (rs16147) and exon2 +1128T/C (rs16139) polymorphisms as well as IL1B promoter -511C/T (rs16944) polymorphism and to correlate IL1B transcript levels with vitiligo. PCR-RFLP method was used to genotype NPY -399T/C SNP in 454 patients and 1226 controls; +1128T/C SNP in 575 patients and 1279 controls and IL1B -511C/T SNP in 448 patients and 785 controls from Gujarat. IL1B transcript levels in blood were also assessed in 105 controls and 95 patients using real-time PCR. Genotype and allele frequencies for NPY -399T/C, +1128T/C and IL1B -511C/T SNPs differed significantly (p<0.0001, p<0.0001; p = 0.0161, p = 0.0035 and p<0.0001, p<0.0001) between patients and controls. 'TC' haplotype containing minor alleles of NPY polymorphisms was significantly higher in patients and increased the risk of vitiligo by 2.3 fold (p<0.0001). Transcript levels of IL1B were significantly higher, in patients compared to controls (p = 0.0029), in patients with active than stable vitiligo (p = 0.015), also in female patients than male patients (p = 0.026). Genotype-phenotype correlation showed moderate association of IL1B -511C/T polymorphism with higher IL1B transcript levels. Trend analysis revealed significant difference between patients and controls for IL1B transcript levels with respect to different genotypes. Our results suggest that NPY -399T/C, +1128T/C and IL1B -511C/T polymorphisms are associated with vitiligo and IL1B -511C/T SNP influences its transcript levels leading to increased risk for vitiligo in Gujarat population. Up-regulation of IL1B transcript in patients advocates its possible role in autoimmune pathogenesis of vitiligo.

Autoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo. To explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat. PSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis. The frequency of 'TT' genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively). PSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype 'CC' advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.

The potential for plant-origin essential oils to modulate rumen functions for reducing bio-hydrogenation of fatty acids and methane production has been a significant area of research in recent times. This study investigated the effects supplementation of garlic (Allium sativum) essential oils have on in vitro bio-hydrogenation of fatty acids, methanogenesis and fermentation characteristics of total mixed ration in buffalo with the aim of enhancing conjugated linoleic acid (CLA) content in animal products as well as reducing environmental pollution. Allium sativum (AS) essential oils were examined at four levels [0 (Control), 33.33 µL (AS-1), 83.33 µL (AS-2) and 166.66 µL (AS-3) per litre of buffered rumen fluid] in a radio-frequency based automatic gas production system (ANKOM-RF). Two bottles per treatment per run over two incubation runs were undertaken to gain representative results. Oats hay and concentrate mixture (1:1) was used as a substrate (500 ± 5 mg) and incubated with 60 mL of buffered rumen fluid in 250 mL ANKOM bottles fitted with automatic an gas recording system at 39 °C for 24 h, following standard in vitro gas production protocols. The results demonstrated a reduction (p < 0.01) in lipid bio-hydrogenation, measured by lowered saturated fatty acids and enhanced unsaturated fatty acids on the supplementation of AS essential oils, irrespective of the dose levels. Moreover, the increased (p < 0.01) production of trans vaccenic (trans C18:1) acid (TVA) following graded dose supplementations of the AS essential oils increased the production of conjugated linoleic acids (CLA) in animal products. Although, reduced methane production (p < 0.01) was evidenced, the decrease in total gas production and feed digestibility (TDDM) demonstrated the strong antimicrobial properties of AS at all dose levels. The study reveals that the Allium sativam (Garlic) essential oils have the potential to be an agent for the reduction of the rumen biohydrogenation of fatty acids and methanogenesis. However, in vivo examination is necessary to validate the findings and confirm its suitability for use as an additive to enhance nutraceutical and organoleptic properties in animal products.

Subclinical hypothyroidism (SCH) remains largely unnoticed as a major cause of infertility due to asymptomatic. Polymorphisms of phosphodiesterase 8B gene have been linked with various diseases, including female infertility. Hence, we aimed to study prevalence of SCH, in infertile females, explore association of rs4704397 A/G and rs6885099 G/A polymorphisms with infertility in females suffering from SCH and genotype-phenotype correlation of the polymorphisms with thyroid stimulating hormone (TSH) levels in Gujarat population. In this retrospective study, TSH level was estimated from plasma of 230 infertile and 100 control females by enzyme-linked fluorescence immunoassay (ELFA) to find out the prevalence of SCH. Further, based on TSH levels, thyroid function test (TFT) was performed in controls and infertile females with subclinical hypothyroidism (IF-SCH). PDE8B rs4704397 and rs6885099 polymorphisms were genotyped by PCR-RFLP and ARMS-PCR, respectively in 74 controls and 60 IF-SCH females. We observed i. significantly high prevalence of SCH (32%) in the infertile females, ii. significantly lower frequency of 'G' allele (P=0.006), while the frequency of 'A' allele (P<0.0001) was higher in IFSCH females, compared to the controls, for rs4704397 A/G SNP, iii. no significant difference in the genotype (P=0.214; OR=2.51; CI=0.74-8.42) and the allele frequency (P=0.129; OR=1.51; CI=0.92-2.47) of rs6885099 G/A SNP, iv) low linkage disequilibrium for the polymorphisms, v. significantly higher frequency of 'AA' haplotype (P=0.0001; OR=3.84; CI=1.86-8.01),while the 'GG' haplotype (P=0.0023; OR=0.33; CI=0.16-0.69) was significantly lower in IF-SCH females and vi. no significant difference in the TSH level of IF-SCH females with respect to the genotypes. The present study reports an association of rs4704397 polymorphism with infertility in SCH females. The study categorically shows a higher prevalence of SCH in infertile females of Gujarat and advocates the importance of screening for SCH in infertility management.

Background Tobacco’s PR-1a gene is induced by pathogen attack or exogenous application of salicylic acid (SA). Nucleosome mapping and chromatin immunoprecipitation assay were used to delineate the histone modifications on the PR-1a promoter. However, the epigenetic modifications of the inducible promoter of the PR-1a gene are not fully understood yet. Methods and results Southern approach was used to scan the promoter of PR-1a to identify presence of nucleosomes, ChIP assays were performed using anti-histones antibodies of repressive chromatin by di- methylated at H3K9 and H4K20 or active chromatin by acetylated H3K9/14 and H4K16 to find epigenetic malleability of nucleosome over core promoter in uninduced or induced state post SA treatment. Class I and II mammalian histone deacetylase (HDAC) inhibitor TSA treatment was used to enhance the expression of PR-1a by facilitating the histone acetylation post SA treatment. Here, we report correlated consequences of the epigenetic modifications correspond to disassembly of the nucleosome (spans from − 102 to + 55 bp, masks TATA and transcription initiation) and repressor complex from core promoter, eventually initiates the transcription of PR-1a gene post SA treatment. While active chromatin marks di and trimethylation of H3K4, acetylation of H3K9 and H4K16 are increased which are associated to the transcription initiation of PR-1a following SA treatment. However, in uninduced state constitutive expression of a negative regulator ( SNI1 ) of AtPR1, suppresses AtPR1 expression by six-fold in Arabidopsis thaliana . Further, we report 50-to-1000-fold increased expression of AtPR1 in uninduced lsd1 mutant plants, up to threefold increased expression of AtPR1 in uninduced histone acetyl transferases ( HATs) mutant plants, SNI1 dependent negative regulation of AtPR1 , all together our results suggest that inactive state of PR-1a is indeed maintained by a repressive complex. Conclusion The study aimed to reveal the mechanism of transcription initiation of tobacco PR-1a gene in presence or absence of SA. This is the first study that reports nucleosome and repressor complex over core promoter region maintains the inactivation of gene in uninduced state, and upon induction disassembling of both initiates the downstream gene activation process.

The present study was conducted to examine the plant bioactive compounds individually and in association for modulation of rumen fermentation in buffalo (Bubalus bubalis) with the aim to develop phytogenic feed additive for enteric methane mitigation from ruminants. The extracts of Sapindus mukorossi (SMF) fruits (aqueous and ethanolic) as a source of saponins, Ficus bengalensis (FBL) leaves (aqueous and acetonic) as a source of tannins and Eucalyptus globulus oils (ECO) as a source of essential oils were prepared and evaluated individually and in association for their effect on feed fermentation and methanogenesis by four separate in vitro experiments. Each experiment was conducted as a completely randomized design using a control and various treatment groups with different concentrations of plant bioactive compounds and their blends. Rumen fluid inoculum was collected from four rumen fistulated Murrah (B. bubalis) buffalo steers. The in vitro incubations were carried out for a period of 24 h with five replicates for each treatment. For SMF and FBL extracts, a concentration of 0, 0.5, 1.0, 2.0 and 4.0 mL were tested, whereas, ECO was tested at the levels of 0, 20, 40, 80 and 120 µL per 40 mL buffered rumen fluid with 0.4 g of oats hay as substrate. Both aqueous or ethanol extracts of SMF, acetonic extract of FBL, and ECO showed linear decrease (p < 0.001) in methane production with increasing concentrations of plant compound. Out of four blends tested, blend-1 (ECO, 125 µL; SMF aqueous extract and FBL acetonic extract, 6.25 mL each per L rumen fluid) showed reduced methane production without affecting negatively to rumen fermentation at much lower individual doses, representing positive associative effect. It is implied that the extracts from S. mukorossi fruits, F. bengalensis leaves and E. globulus essential oils and their blends have the potential to act as anti methanogenic agents. A positive associative effect in reducing enteric methanogenesis in their blends signifies their application as the phytogenic feed additive in ruminants.

The potential for plant-origin essential oils to modulate rumen functions for reducing bio-hydrogenation of fatty acids and methane production has been a significant area of research in recent times. This study investigated the effects supplementation of garlic (Allium sativum) essential oils have on in vitro bio-hydrogenation of fatty acids, methanogenesis and fermentation characteristics of total mixed ration in buffalo with the aim of enhancing conjugated linoleic acid (CLA) content in animal products as well as reducing environmental pollution. Allium sativum (AS) essential oils were examined at four levels [0 (Control), 33.33 µL (AS-1), 83.33 µL (AS-2) and 166.66 µL (AS-3) per litre of buffered rumen fluid] in a radio-frequency based automatic gas production system (ANKOM-RF). Two bottles per treatment per run over two incubation runs were undertaken to gain representative results. Oats hay and concentrate mixture (1:1) was used as a substrate (500 ± 5 mg) and incubated with 60 mL of buffered rumen fluid in 250 mL ANKOM bottles fitted with automatic an gas recording system at 39 °C for 24 h, following standard in vitro gas production protocols. The results demonstrated a reduction (p < 0.01) in lipid bio-hydrogenation, measured by lowered saturated fatty acids and enhanced unsaturated fatty acids on the supplementation of AS essential oils, irrespective of the dose levels. Moreover, the increased (p < 0.01) production of trans vaccenic (trans C18:1) acid (TVA) following graded dose supplementations of the AS essential oils increased the production of conjugated linoleic acids (CLA) in animal products. Although, reduced methane production (p < 0.01) was evidenced, the decrease in total gas production and feed digestibility (TDDM) demonstrated the strong antimicrobial properties of AS at all dose levels. The study reveals that the Allium sativam (Garlic) essential oils have the potential to be an agent for the reduction of the rumen biohydrogenation of fatty acids and methanogenesis. However, in vivo examination is necessary to validate the findings and confirm its suitability for use as an additive to enhance nutraceutical and organoleptic properties in animal products.