Ultra-sensitive pressure sensing capabilities of defective one-dimensional photonic crystal.

Present research work deals with the extremely sensitive pressure-sensing capabilities of defective one-dimensional photonic crystal structure (GaP/SiO2)N/Al2O3/(GaP/SiO2)N. The proposed structure is realized by putting a defective layer of material Al2O3 in the middle of a structure consisting of alternating layers of GaP and SiO2. The transfer matrix method has been employed to examine the transmission characteristics of the proposed defective one-dimensional photonic crystal in addition to MATLAB software. An external application of the hydrostatic pressure on the proposed structure is responsible for the change in the position and intensity of defect mode inside the photonic band gap of the structure due to pressure-dependent refractive index properties of the materials being used in the design of the sructure. Additionally, the dependence of the transmission properties of the structure on other parameters like incident angle and defect layer thickness has also studied. The theoretical obtained numeric values of the quality factor and sensitivity are 17,870 and 72 nm/GPa respectively. These results are enough to support our claim that the present design can be used as an ultra-sensitive pressure sensor.

Ultra-high sensitive cancerous cells detection and sensing capabilities of photonic biosensor.

The ultra-high sensitive cancer cell detection capabilities of one-dimensional photonic crystal with defect have been theoretically examined in this work. The simulations of the work have been carried out with MATLAB programming and transfer matrix method. The performance of the proposed biosensor loaded separately with samples containing different cancer cells has been studied by changing the period number, defect layer thickness, and incident angle corresponding to s polarized light only to identify the parameters under which the proposed design becomes ultra-sensitive. The working principle of the proposed biosensor is to sense the minute change in the refractive index of the analytes containing different cancer cells of human. This sensing is done shifting the respective defect mode inside photonic band gap of the structure from one position to other near by position due to change in the refractive index of sample under consideration. Our structure under optimum conditions yields maximum shifting in the position of defect mode from 1538 to 1648 nm corresponding to the samples containing normal and Glioblastoma cells of refractive indices 1.350 and 1.4470 respectively which results a ultra-high sensitivity of 4270.525928 nm/RIU.

Nasopharyngeal carriage of Streptococcus pneumoniae serotypes among sick and healthy children in northern India: A case-control study.

BACKGROUND: Streptococcus pneumoniae is leading bacterial cause of community acquired pneumonia and according to World Health Organization, responsible for 14 % death in children. There is effective vaccine available against Streptococcus pneumoniae. Hence the primary objective was to isolate Streptococcus pneumoniae from nasopharyngeal swabs in children aged 2-59 months with and without community acquired pneumonia and to assess their serotypes. METHODS: This case-control study was conducted in tertiary teaching institutes in northern India. Hospitalized children, aged 2-59 months, with World Health Organization-defined community acquired pneumonia were included as cases. Age matched healthy controls were recruited from immunization clinic. All enrolments were done after written informed parental consent. Nasopharyngeal swabs were taken from both cases and controls, and were cultured on 5 % sheep blood agar with gentamycin plate for growth of Streptococcus pneumoniae and incubated in a jar at 370 for 18-24 hrs. Quellung reaction test was used for serotyping. RESULTS: From March 2017 to December 2022, 2693 children (1910 cases and 783 controls), were recruited. The median age of cases was 7 months and controls 10 months. Almost all the cases had received antibiotics prior to hospitalization. Streptococcus pneumoniae positivity in nasopharyngeal swab was 8.1 % in cases, of which 56.8 % were vaccine serotypes and 23.6 % in controls, of which 37.8 % were vaccine serotypes. Adjusted odds ratio of isolating vaccine serotypes among cases as compared to controls was 1.77 (95 % CI, 1.09-2.88). CONCLUSION: Streptococcus pneumoniae isolation from nasopharyngeal was found to be in lower proportion in cases as compared to control, though colonization with vaccine serotypes was higher in cases as compared to control. Therefore, pneumococcal vaccine coverage must be increased to prevent community acquired pneumonia.

MATLAB simulation based study on poliovirus sensing through one-dimensional photonic crystal with defect.

The present work, theoretically examined the poliovirus sensor model composed of one-dimensional photonic crystal with defect. The transfer matrix method with the help of MATLAB software has been used to detect poliovirus present in the water sample. The main objective of the present work is to design an efficient sensor by identifying the minute variation in the refractive index of water sample due to change in the poliovirus concentration present in the sample. The alternate layers of aluminum nitride and gallium nitride has been taken to realize Bragg reflector having defect layer of air at center of the Bragg reflector. The effect of change in thickness of defect layer region, period number and incident angle corresponding to transverse electric wave has been examined to optimize the structure which correspond maximum performance of the proposed poliovirus sensing structure. The maximum performance of the structure has been obtained with optimum value of defect layer thickness 1200 nm, period number 10 and incident angle 40°. Under optimum condition maximum sensitivity of 1189.65517 nm/RIU has been obtained when the structure is loaded with waters sample of poliovirus concentration C = 0.005 g/ml whereas figure of merit, quality factor, signal to noise ratio, dynamic range, limit of detection and resolution values become 2618.28446 per RIU, 3102.06475, 2.27791, 2090.99500, 1.91E-05 and 0.24656 respectively.

Biophotonic sensor for swift detection of malignant brain tissues by using nanocomposite YBa2Cu3O7/dielectric material as a 1D defective photonic crystal.

In the present research work we have theoretically examined the biosensing capabilities of proposed one dimensional defective photonic crystal for swift detection of malignant brain tissues. The transfer matrix formulation and MATLAB computational tool have been used to examine the transmission properties of proposed structure. The identical buffer layers of nanocomposite superconducting material have been used either side of cavity region to enhance the interaction between incident light and different brain tissue samples poured into the cavity region. All the investigations have been carried out under normal incidence to suppress the experimental liabilities involved. We have investigated the biosensing performance of the proposed design by changing the values of two internal parameters (1) the cavity layer thickness (d4) and (2) volume fraction (η) of nanocomposite buffer layers one by one to get the optimum biosensing performance from the structure. It has been found that the sensitivity of the proposed design becomes 1.42607 µm/RIU when the cavity region of thickness 15dd is loaded with lymphoma brain tissue. This value of sensitivity can be further increased to 2.66136 µm/RIU with η = 0.8. The findings of this work are very beneficial for designing of various bio-sensing structures composed of nanocomposite materials of diversified biomedical applications.

Exploring the overlap between alopecia areata and major depressive disorder: Epidemiological and genetic perspectives.

BACKGROUND: Research suggests that Alopecia areata (AA) and Major Depressive Disorder (MDD) show substantial comorbidity. To date, no study has investigated the hypothesis that this is attributable to shared genetic aetiology. OBJECTIVES: To investigate AA-MDD comorbidity on the epidemiological and molecular genetic levels. METHODS: First, epidemiological analyses were performed using data from a cohort of adult German health insurance beneficiaries (n = 1.855 million) to determine the population-based prevalence of AA-MDD comorbidity. Second, analyses were performed to determine the prevalence of MDD in a clinical AA case-control sample with data on psychiatric phenotypes, stratifying for demographic factors to identify possible contributing factors to AA-MDD comorbidity. Third, the genetic overlap between AA and MDD was investigated using a polygenic risk score (PRS) approach and linkage disequilibrium score (LDSC) regression. For PRS, summary statistics from a large MDD GWAS meta-analysis (PGC-MD2) were used as the training sample, while a Central European AA cohort, including the above-mentioned AA patients, and an independent replication US-AA cohort were used as target samples. LDSC was performed using summary statistics of PGC-MD2 and the largest AA meta-analysis to date. RESULTS: High levels of AA-MDD comorbidity were reported in the population-based (MDD in 24% of AA patients), and clinical samples (MDD in 44% of AA patients). MDD-PRS explained a modest proportion of variance in AA case-control status (R2  = 1%). This signal was limited to the major histocompatibility complex (MHC) region on chromosome 6. LDSC regression (excluding MHC) revealed no significant genetic correlation between AA and MDD. CONCLUSIONS: As in previous research, AA patients showed an increased prevalence of MDD. The present analyses suggest that genetic overlap may be confined to the MHC region, which is implicated in immune function. More detailed investigation is required to refine understanding of how the MHC is involved in the development of AA and MDD comorbidity.

Nasopharyngeal Carriage of Streptococcus pneumoniae Serotypes Among Healthy Children in Northern India.

Streptococcus pneumoniae (SP) infections cause morbidity and mortality among children worldwide. Hence India introduced 13-valent pneumococcal conjugate vaccine (PCV-13) in 2017 in a phased manner. The primary objective of this study was to assess the proportion of healthy children having nasopharyngeal colonization (NP) with SP. Secondary objective was to determine prevalent serotype of SP among the PCV13 vaccinated and non-vaccinated children. This cross-sectional study was conducted in 4 hospitals of Lucknow District, Northern India. Three hundred healthy children (2-59 months) were recruited between July and August 2019 from vaccination-clinics of hospitals. NP specimen was cultured using 5% sheep blood agar plate containing gentamicin. Pneumococcal isolates were identified by optochin sensitivity and bile-solubility tests. Serotyping was done using Quellung Method. Of the 300 healthy children, 56.7% (170/300) were males and 59.3% (181/300) had received at least one dose of PCV13 vaccine. The NP carriage rate of SP among healthy children was 37.7% (113/300). Vaccine serotypes were found in 33.3% (22/66) in PCV vaccinated children and 48.9% (23/47) in non-vaccinated children (p 0.09). Common vaccine serotypes that isolated were: 18C, 19A, 19F, 23F, 3, 4, 6A, 6B, 9 V. Thus more than one-third of healthy children had NP colonization with SP. Adjusting for age, there was a trend for significant reduction in vaccine serotypes in the NP with one doses versus two or more doses (ptrend = 0.04).

Bio-Alcohol Sensor Based on One-Dimensional Photonic Crystals for Detection of Organic Materials in Wastewater.

In this work, we have explored a novel application of one-dimensional (1D) photonic crystals (PCs) as a biomarker for the detection of organic materials in wastewater. The high concentration of organic materials may lead to adverse impact on human life. In order to save human life from these adverse effects, we have investigated the bio-alcohol sensing properties of a 1D multilayer periodic structure (AB)N/C/(AB)N capable of detecting organic materials in wastewater. The proposed structure works on the principle to detect a very small change in the refractive index of the wastewater sample under investigation by means of producing a shift in the position of the defect mode inside the photonic band gap (PBG) of the proposed structure. The transfer matrix method (TMM) has been used to investigate the transmission properties of the proposed design with the help of MATLAB software. We have also studied the effect of changes in the defect layer's thickness, the volume fraction of the nanocomposite material and the incident angle on the sensitivity of our proposed bio-alcohol sensing design. Our bio-alcohol sensor shows a high sensitivity value of 500 nm/RIU and a low detection limit value of 1 × 10-5 RIU. The figure of merit and quality factor values of our bio-alcohol sensor are 5 × 103 and 5.236 × 103, respectively. The damping rate of the design is ξ=95.4927×10-5.

Externally tunable multichannel filtering applications of organic material based 1D magnetic cold-plasma photonic crystals.

In the present research work, we employed the transfer matrix method (TMM) in addition to MATLAB software to examine the transmission properties of various organic-based one-dimensional (1D) magnetic cold-plasma photonic crystals (MCPPhCs). The proposed structures were found to be made up of periodic layers of organic materials and magnetic cold-plasma (MCP) at normal incidence. An external magnetic field (B) polarized in right-hand (RH) and left-hand (LH) configurations was applied on 1D MCPPhCs. In this study, four organic materials, namely pentane, hexane, heptane, and octane, were chosen to design four 1D photonic crystals (PCs), named as PC1 (pentane-MCP), PC2 (hexane-MCP), PC3 (heptane-MCP), and PC4 (octane-MCP). Our results indicated that the central frequency of the resonant peaks of unit transmission inside the photonic band-gap (PBG) of the respective organic PCs could be tuned towards the higher or lower frequency side by applying B polarized in RH and LH configurations, respectively. We also studied the effect of the period number N to produce closely spaced N-1 transmission channels of unit transmission inside the PBG of all four organic PCs. By increasing the period number N we could increase the number of transmission channels inside the PBG as per our desire. These multiple resonant peaks of unit transmission inside PBG could be easily modulated inside the PBG to accommodate new frequencies by applying B polarized in either RH or LH configurations, respectively. Moreover, our results showed that under the RH configuration, increasing B resulted in a shifting of the resonant peak towards the higher frequency side with a reduction in its full width half maximum (FWHM), whereas the findings were the opposite in the case of increasing B under the LH configuration. These findings may be beneficial for designing externally tuneable organic chemical sensors in the microwave frequency region.

Piperine, an active ingredient of white pepper, suppresses the growth of multidrug-resistant toxigenic Vibrio cholerae and other pathogenic bacteria.

Emergence and rapid spread of multidrug-resistant (MDR) bacteria including Vibrio cholerae are a global public health issue. Much attention has been paid to natural compounds, such as spices and herbs to find novel antimicrobial compounds as they are considered to be cheaper alternatives to develop as a drug. Here, we show that methanol extract of white pepper could inhibit the growth of V. cholerae O1 El Tor variant, responsible for the recent outbreaks/epidemics. Furthermore, we demonstrate for the first time that piperine, the major component of white pepper, showed a dose-dependent bactericidal effect on V. cholerae growth irrespective of their biotypes and serogroups in the presence of 200 and 300 µg ml-1 of piperine, respectively. Piperine also inhibited the growth of MDR strains of Pseudomonas aeruginosa, Escherichia coli isolated from poultry and enterohemorrhagic/enteroaggregative E. coli O104 in the presence of 200 µg ml-1 . Interestingly, we did not observe any significant inhibitory effect of piperine on E. coli strains isolated from healthy person even up to 200 µg ml-1 . Our data suggest that piperine could be a novel antimicrobial agent in therapeutic and preventive applications against infections caused by pathogenic bacteria including MDR strains.

Study on a one-dimensional defective photonic crystal suitable for organic compound sensing applications.

Organic-compound-based sensors have important applications, such as applications in geothermal power stations, the shoe industry, the extraction of vegetable oil, azeotropic calibration and medical science. Herein, a 1D photonic crystal (PC) with a defect has been used to develop a photonic-technology-based organic compound sensor with optimum performance. The structure of the proposed organic compound sensor consists of a water cavity sandwiched between two symmetric sub-PCs, which are composed of alternate layers of SiO2 and ZnO. The proposed air/(SiO2/ZnO)5/cavity/(SiO2/ZnO)5/glass structure with the optimized structural parameters achieves a quality factor that varies between a minimum value of 4968.2 and a maximum value of 6418.5. The FOM and sensitivity values of the proposed sensing design are on the order of 102 and 103, respectively. The LOD value of the proposed sensor is on the order of 10-5, which is very low, as is always expected for chemical sensing designs. Thus, the simple design and excellent performance make our design highly efficient and suitable for sensing applications in the industrial and biomedical fields.

Soil quality parameters vis-a-vis growth and yield attributes of sugarcane as influenced by integration of microbial consortium with NPK fertilizers.

Intensive agriculture involving high crop intensity, unavailability of organics, and higher use of straight fertilizers causes imbalanced use and deficiencies of several other macro and micronutrients. Nutrients supply through the integration of microbial consortium containing Gluconacetobater diazotrophicus, Trichoderma harzianum, and Pseudomonas fluorescens can reduce the requirements on the one hand and can also increase the response of chemical fertilizers. Thus we had planned the present experiment with the objectives (i) to determine the effect of integrated application of microbial consortium (MC) and NPK fertilizer on soil quality parameters and crop growth and yield attributes and (ii) to assess the effect of integration on agronomic efficiency of N, P and K and find out the possibilities for reduction in applied doses of NPK, if any. Five treatments viz., T1; N0P0K0; T2: N75P13K25; T3: N150P26K50; T4: N75P13K25 + microbial consortium and T5: N150P26K50 + microbial consortium containing new strains of Trichoderma harzianum, Gluconcetobacter diazotrophicus, and Pseudomonas fluorescens (CFU 109-10 per ml liquid culture) were evaluated under four replications in a randomized block design (RBD). Experimental results indicated that integrating microbial consortium and NPK fertilizers' application proved effective in improving soil organic carbon, soil microbial population, microbial biomass carbon, microbial biomass nitrogen, and soil respiration. Integrated use of microbial consortium with NPK also improved the cation exchange capacity of soil and roots. However, the growth and yield attributes, nutrients uptake, sugarcane, and sugar yields also revealed a positive effect of microbial consortium's integrated application with NPK. The integration of MC and NPK also improved the agronomic efficiency of applied nutrients (NPK). Reduction of 50% NPK with these microbial consortia (Trichoderma harzianum, Gluconcetobacter diazotrophicus, and Pseudomonas fluorescens) was found better than the application of full NPK through chemical fertilizers. Thus application of N150P26K50 with microbial consortium can sustain soil fertility besides improving sugarcane and sugar yields in subtropical Indian conditions.

Refractive Error Prevalence among School Children in Dadeldhura District of Nepal.

Background Uncorrected refractive error is the major cause of visual impairment worldwide. There is no data on refractive error prevalence among school children in hilly region of Far West Nepal. Objective The prevalence of refractive error has been found to vary among children of different caste/ethnic groups and geographical regions. The purpose of this study is to determine the prevalence of refractive error among school children from different caste/ethnic groups in Dadeldhura district of Far West Nepal. Method This is a cross sectional study of refractive error among secondary school children from 2 schools in Dadeldhura district. All children underwent a vision screening consisting of visual acuity, ocular examination and refraction. Myopia was diagnosed for an eye with spherical equivalent refraction (SER) ≤ -0.5 D whereas an eye with SER ≥ +2.0 D was diagnosed as hyperopic. Ethnicity was reported through self administered questionnaire. Result Among children aged 12 to 16 years (14.07 ± 1.4) prevalence of myopia was 3.5%, hyperopia 0.33% and astigmatism 1%. All except three children had spherical equivalent refraction (SER) within ±2 D. Caste/ethnicity was not associated significantly with myopia in either eye (χ2 = 0.27, df= 2, p= 0.87). Conclusion The prevalence of refractive error among secondary school children in Dadeldhura district of Far West Nepal is very low in comparison to myopia prevalence reported in studies from other parts of the world, but slightly lower than myopia prevalence found in other, eastern parts of Nepal.

Rapid analysis of pharmaceutical drugs using LIBS coupled with multivariate analysis.

Type 2 diabetes drug tablets containing voglibose having dose strengths of 0.2 and 0.3 mg of various brands have been examined, using laser-induced breakdown spectroscopy (LIBS) technique. The statistical methods such as the principal component analysis (PCA) and the partial least square regression analysis (PLSR) have been employed on LIBS spectral data for classifying and developing the calibration models of drug samples. We have developed the ratio-based calibration model applying PLSR in which relative spectral intensity ratios H/C, H/N and O/N are used. Further, the developed model has been employed to predict the relative concentration of element in unknown drug samples. The experiment has been performed in air and argon atmosphere, respectively, and the obtained results have been compared. The present model provides rapid spectroscopic method for drug analysis with high statistical significance for online control and measurement process in a wide variety of pharmaceutical industrial applications.

Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Virulence of acute hepatopancreatic necrosis disease PirAB-like relies on secreted proteins not on gene copy number.

AIMS: To investigate the virulence of the Vp_PirAB-like genes in Vibrio parahaemolyticus- acute hepatopancreatic necrosis disease (AHPND)-causing strain and the factors that are associated with the virulence level. METHODS AND RESULTS: The virulence of Vp_PirAB-like was examined using a non-virulent strain FP11 of V. parahaemolyticus transformed with a plasmid harbouring Vp_PirAB-like genes and then it was used to challenge shrimp Litopenaeus vannamei and Marsupenaeus japonicus. Both species experienced 100% mortality at 10 days post infection. Analysis of a mutant strain (E1M), that was originally identified as virulent strain (E1) but lost its virulence to L. vannamei, revealed that it lacked a part of the Vp_PirA-like gene and all of the Vp_PirB-like gene. The copy numbers of Vp_PirA-like and Vp_PirB-like genes varied among virulent strains and were not correlated with their virulence. In Western blotting, Vp_PirA-like and Vp_PirB-like proteins were detected in both the cell lysate and the culture supernatant. The strongest intensity of detecting band in the culture supernatant was observed in the strain that caused the highest mortality. The V. parahaemolyticus AHPND-causing strain, unlike the human tdh-positive strain, did not show any enterotoxicity. CONCLUSION: Vibrio parahaemolyticus AHPND-causing strains secrete the Vp_PirA-like and Vp_PirB-like proteins during the growing phase. The amount of secreted proteins affects the shrimp mortality. SIGNIFICANCE AND IMPACT OF THE STUDY: The secreted proteins of Vp_PirAB-like are key factors of virulence in the V. parahaemolyticus AHPND-causing strain, but not gene copy.

Polymorphisms in host genes encoding NOSII, C-reactive protein, and adhesion molecules thrombospondin and E-selectin are risk factors for Plasmodium falciparum malaria in India.

Cytoadherence of Plasmodium falciparum-infected red blood cells (RBCs) in host microvasculature and complex regulation of the immune response are important contributors to the clinical outcome of disease. We tested the association of 23 single nucleotide polymorphisms (SNPs) and a microsatellite repeat in adhesion molecule genes THBS1 and ESEL, and immune regulatory molecule genes NOSII, CRP, and MBL2 with falciparum malaria in populations residing in a malaria-endemic and a non-endemic region of India. The THBS1 haplotype CCCCA (rs1478604, rs7170682, rs2664141, rs12912082, rs3743125) was a risk factor in the endemic region (relative risk = 3.78) and an ESEL SNP (rs5368, His468Tyr) associated with cerebral malaria (CM) [CM vs. non-cerebral malaria (NCM), odds ratio (OR) = 2.23, p = 0.03]. In the non-endemic region, an ESEL 3'UTR SNP (rs5359) associated with enhanced risk of disease (OR = 3.62, p = 1 × 10(-4)) and the CT genotype of the CRP promoter SNP (C/T/A) strongly associated with protection (severe vs. control, OR = 0.29, p = 6 × 10(-5)). Long repeat alleles of the NOSII promoter microsatellite (CCTTT)n exhibited strong association with protection and the NOSII ATG haplotype (rs3729508, rs2297520, rs9282801) was strongly protective against severe malaria in both regions (endemic, severe vs. control, OR = 0.05, p = 0.0001; non-endemic, severe vs. control, OR = 0.3, p = 1 × 10(-5)). Our results suggest differential contribution of variants of the investigated genes in determining the outcome of malaria in Indian populations.

Antidyslipidemic and antioxidant activity of an unusual amino acid (2-amino-5-hydroxyhexanoic acid) isolated from the seeds of Crotalaria juncea.

In continuation of our drug discovery programme on Indian medicinal plants, we isolated an unusual amino acid, i.e. 2-amino-5-hydroxyhexanoic acid (1) from the seeds of Crotalaria juncea. The 2-amino-5-hydroxyhexanoic acid (1) showed dose dependent lipid lowering activity in the in vivo experiments and also showed good in vitro antioxidant activity. The cyclized compound, 3-amino-6-methyltetrahydro-2H-pyran-2-one (2) showed better lipid lowering and antioxidant profile than the parent compound 1.

Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer.

BACKGROUND: EBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2-overexpressing breast cancer cells. METHODS: Effects of EBP1 on ErbB2 levels were measured by western blotting. Effects of EBP1 and IPA-3 on tamoxifen sensitivity were measured using a tetrazolium based cell viability assay. RESULTS: Transient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1, tamoxifen sensitive. IPA-3, a specific small MW PAK1 inhibitor, sensitised cells to tamoxifen only when EBP1 was ectopically expressed. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels only in EBP1-overexpressing cells. CONCLUSION: These studies suggest that phosphorylation of EBP1 may be one mechanism of PAK1-induced hormone resistance and that PAK1 inhibitors may be useful in cells in which EBP1 is overexpressed.