An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold.

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.

Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis.

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors.

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Surface Characteristics, Biodegradability and Biocompatibility of Porous Silicon for Microfabricated Neural Electrode.

Porous Si (PSi) used for microfabrication of a novel neural electrode was prepared on Si wafers by an anodization process. Surface morphology and porous structure of the PSi were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). 3D inter-connected and nano sized pores were homogeneously formed across the surface. Wettability of the PSi was determined using a sessile drop method. Although Si-Hx functional groups on the PSi surface had negative effect on wettability, water contact angle of the PSi reduced to 34.5 ± 0.5° due to the enhanced surface roughness and the capillary force generated by nano sized pores. Moreover, in vitro biocompatibility of the PSi was assessed by seeding a breast cancer cell line (MCF-7). After 5 days of culture, cell morphology was observed using a fluorescence microscope. Although more than 99% of the cells under the microscope were living for both Si and PSi samples, morphology of the cells attached on their surfaces was different. MTT assay was also used to quantitatively evaluate in vitro biocompatibility, and revealed false positive results due to the spontaneous reduction of MTT on the PSi surface. Therefore, MTT assay was not suitable for in vitro quantitatively study of PSi.

Cavity-agnostic acoustofluidic manipulations enabled by guided flexural waves on a membrane acoustic waveguide actuator.

This article presents an in-depth exploration of the acoustofluidic capabilities of guided flexural waves (GFWs) generated by a membrane acoustic waveguide actuator (MAWA). By harnessing the potential of GFWs, cavity-agnostic advanced particle manipulation functions are achieved, unlocking new avenues for microfluidic systems and lab-on-a-chip development. The localized acoustofluidic effects of GFWs arising from the evanescent nature of the acoustic fields they induce inside a liquid medium are numerically investigated to highlight their unique and promising characteristics. Unlike traditional acoustofluidic technologies, the GFWs propagating on the MAWA's membrane waveguide allow for cavity-agnostic particle manipulation, irrespective of the resonant properties of the fluidic chamber. Moreover, the acoustofluidic functions enabled by the device depend on the flexural mode populating the active region of the membrane waveguide. Experimental demonstrations using two types of particles include in-sessile-droplet particle transport, mixing, and spatial separation based on particle diameter, along with streaming-induced counter-flow virtual channel generation in microfluidic PDMS channels. These experiments emphasize the versatility and potential applications of the MAWA as a microfluidic platform targeted at lab-on-a-chip development and showcase the MAWA's compatibility with existing microfluidic systems.

Microfabricated acoustofluidic membrane acoustic waveguide actuator for highly localized in-droplet dynamic particle manipulation.

Precision manipulation techniques in microfluidics often rely on ultrasonic actuators to generate displacement and pressure fields in a liquid. However, strategies to enhance and confine the acoustofluidic forces often work against miniaturization and reproducibility in fabrication. This study presents microfabricated piezoelectric thin film membranes made via silicon diffusion for guided flexural wave generation as promising acoustofluidic actuators with low frequency, voltage, and power requirements. The guided wave propagation can be dynamically controlled to tune and confine the induced acoustofluidic radiation force and streaming. This provides for highly localized dynamic particle manipulation functionalities such as multidirectional transport, patterning, and trapping. The device combines the advantages of microfabrication and advanced acoustofluidic capabilities into a miniature "drop-and-actuate" chip that is mechanically robust and features a high degree of reproducibility for large-scale production. The membrane acoustic waveguide actuators offer a promising pathway for acoustofluidic applications such as biosensing, organoid production, and in situ analyte transport.

Characterization of polymerized liposomes using a combination of dc and cyclical electrical field-flow fractionation.

Characterization of polymerized liposomes (PolyPIPosomes) was carried out using a combination of normal dc electrical field-flow fractionation and cyclical electrical field-flow fractionation (CyElFFF) as an analytical technique. The constant nature of the carrier fluid and channel configuration for this technique eliminates many variables associated with multidimensional analysis. CyElFFF uses an oscillating field to induce separation and is performed in the same channel as standard dc electrical field-flow fractionation separation. Theory and experimental methods to characterize nanoparticles in terms of their sizes and electrophoretic mobilities are discussed in this paper. Polystyrene nanoparticles are used for system calibration and characterization of the separation performance, whereas polymerized liposomes are used to demonstrate the applicability of the system to biomedical samples. This paper is also the first to report separation and a higher effective field when CyElFFF is operated at very low applied voltages. The technique is shown to have the ability to quantify both particle size and electrophoretic mobility distributions for colloidal polystyrene nanoparticles and PolyPIPosomes.

A novel method for effective field measurements in electrical field-flow fractionation.

The electric field that drives separation and retention in electrical field flow fractionation (ElFFF) and cyclical electrical field-flow fractionation (CyElFFF) is a complex function of many parameters such as carrier ionic strength and pH, voltage, channel dimensions, flowrate, and electrode material. Currently there is no accurate or in situ method to measure the field during system operation. This paper introduces a technique to measure the effective electric field during ElFFF and CyElFFF operation using transient electrical spikes. With this technique we can determine the relationship between changes in carrier conductivity and flowrate during a run and their combined effect on effective field and retention in ElFFF. This technique can also be used to measure the voltage drop due to double layer capacitance in CyElFFF and the variation in effective field with frequency of the applied field. The measured effective fields for the CyElFFF and DC ElFFF techniques are also tested with a high ionic-strength buffer solution as carrier. For a high ionic-strength buffer, DC ElFFF generates a near-zero effective field (0.2% in 100 s), whereas CyElFFF can sustain much higher effective fields (~8%) even at relatively high voltages. The ability to measure the effective field allows for experiments to provide better data and for tuning and optimization of the separation run.

Development of niosomes for encapsulating captopril-quercetin prodrug to combat hypertension.

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery.

Mutational analysis of the eyeless gene and phenotypic rescue reveal that an intact Eyeless protein is necessary for normal eye and brain development in Drosophila.

Pax6 genes encode evolutionarily highly conserved transcription factors that are required for eye and brain development. Despite the characterization of mutations in Pax6 homologs in a range of organisms, and despite functional studies, it remains unclear what the relative importance is of the various parts of the Pax6 protein. To address this, we have studied the Drosophila Pax6 homolog eyeless. Specifically, we have generated new eyeless alleles, each with single missense mutations in one of the four domains of the protein. We show that these alleles result in abnormal eye and brain development while maintaining the OK107 eyeless GAL4 activity from which they were derived. We performed in vivo functional rescue experiments by expressing in an eyeless-specific pattern Eyeless proteins in which either the paired domain, the homeodomain, or the C-terminal domain was deleted. Rescue of the eye and brain phenotypes was only observed when full-length Eyeless was expressed, while all deletion constructs failed to rescue. These data, along with the phenotypes observed in the four newly characterized eyeless alleles, demonstrate the requirement for an intact Eyeless protein for normal Drosophila eye and brain development. They also suggest that some endogenous functions may be obscured in ectopic expression experiments.

Vitamin D status before Roux-en-Y and efficacy of prophylactic and therapeutic doses of vitamin D in patients after Roux-en-Y gastric bypass surgery.

BACKGROUND: Literature regarding the effect of Roux-en-Y gastric bypass (RYGBP) on vitamin D level shows contradictory findings. Our goal was to determine preoperatively vitamin D levels, to evaluate the efficacy of therapeutic and prophylactic doses of vitamin D and to assess the relationship of 25-OH vitamin D level and body mass index (BMI). METHODS: We conducted a retrospective cross-sectional study of 72 patients who underwent RYGBP from April 2007 to October 2007 in Bariatric Surgery Department at Saint Vincent Charity Hospital. RESULTS: Our study demonstrated that 80% of the obese patients undergoing RYGBP had serum 25-OH vitamin D levels of less than 32 ng/ml. Postoperative data show that 45% of these patients continue being vitamin D insufficient despite the treatment. We demonstrated that a statistically significant inverse correlation between BMI and 25-OH vitamin D levels (r = 0.464, p = 0.01) exists. CONCLUSION: Our finding strongly supports the need for aggressive monitoring of vitamin D levels for long-term prevention of complications of vitamin D deficiency in gastric bypass patients. Identifying the factors that predict patient's responses to vitamin D supplementation requires larger-scale studies and further analysis of these tendencies suggested by our findings.

Telescoping intestine in an adult.

Protrusion of a bowel segment into another (intussusception) produces severe abdominal pain and culminates in intestinal obstruction. In adults, intestinal obstruction due to intussusception is relatively rare phenomenon, as it accounts for minority of intestinal obstructions in this population demographic. Organic lesion is usually identifiable as the cause of adult intussusceptions, neoplasms account for the majority. Therefore, surgical resection without reduction is almost always necessary and is advocated as the best treatment of adult intussusception. Here, we describe a rare case of a 44-year-old male with a diffuse large B-cell lymphoma involving the terminal ileum, which had caused ileocolic intussusception and subsequently developed intestinal obstruction requiring surgical intervention. This case emphasizes the importance of recognizing intussusception as the initial presentation for bowel malignancy.

Diffusion Split-Flow Thin Cell (SPLITT) system for protein separations.

A diffusion Split-Flow Thin Cell (SPLITT) system was used to partially remove small peptides such as ß2 microglobulin (ß2M) and parathyroid hormone (PTH) in a continuous manner from an input flow stream while preserving most (over 97%) of the larger protein in the sample, such as albumin. To help determine the operating conditions for this work, a two-dimensional numerical model based on the Navier-Stokes equation and convection-diffusion equations was developed for diffusional SPLITT using COMSOL multiphysics software (COMSOL Inc., MA). These simulations were used to obtain the relationship between important operational parameters and the purification efficiency for proteins of interest. The diffusion-based SPLITT system was fabricated using xurography and was used to demonstrate protein purification based on the differences in size or diffusion coefficient of the sample. The results obtained from the experiments are compared with the mathematical model and show good agreement, while the variations between these results are discussed. The results show that significant portions of small peptides (>25%) can be removed while preserving larger proteins (up to 95%) in the carrier stream. A potential application of this technique is to be used as an additional step in kidney dialysis to remove toxins that are not effectively removed by current dialysis protocols.

Plasma-assisted atomic layer deposition of Al(2)O(3) and parylene C bi-layer encapsulation for chronic implantable electronics.

Encapsulation of biomedical implants with complex three dimensional geometries is one of the greatest challenges achieving long-term functionality and stability. This report presents an encapsulation scheme that combines Al(2)O(3) by atomic layer deposition with parylene C for implantable electronic systems. The Al(2)O(3)-parylene C bi-layer was used to encapsulate interdigitated electrodes, which were tested invitro by soak testing in phosphate buffered saline solution at body temperature (37 °C) and elevated temperatures (57 °C and 67 °C) for accelerated lifetime testing up to 5 months. Leakage current and electrochemical impedance spectroscopy were measured for evaluating the integrity and insulation performance of the coating. Leakage current was stably about 15 pA at 5 V dc, and impedance was constantly about 3.5 MΩ at 1 kHz by using electrochemical impedance spectroscopy for samples under 67 °C about 5 months (approximately equivalent to 40 months at 37 °C). Alumina and parylene coating lasted at least 3 times longer than parylene coated samples tested at 80 °C. The excellent insulation performance of the encapsulation shows its potential usefulness for chronic implants.

Interaction of silver nanoparticles with an environmentally beneficial bacterium, Pseudomonas chlororaphis.

This study explores the potential antimicrobial mechanisms of commercial silver nanoparticles (Ag NPs) in the environmental bacterium, Pseudomonas chlororaphis O6. The 10nm size NPs aggregated in water, as demonstrated by atomic force microscopy. Solubility of the NPs at 10mg/L was 0.28 mg/L (pH 6) and 2.3mg/L (pH 7); release from 10mg/L bulk Ag was below detection. The NPs eliminated cell culturability at 3mg/L, whereas no effect was observed at 10mg/L bulk Ag. Zeta potential measurements revealed that the NPs were negatively charged; unlike Ag ions, their addition to the negatively charged cells did not change cell charge at pH 6, but showed a trend to reduce cell charge at pH 7. Isolated extracellular polymeric substances (EPS) from PcO6 was polydisperse, with negative charge that was neutralized by Ag ions, but not by the NPs. Addition of EPS eliminated Ag NP's toxicity in cells lacking EPS. Intracellular accumulation of OH was not detected in NP-treated cells; however, the use of scavengers suggested the NPs caused extracellular H(2)O(2) production. No evidence was found for loss of membrane integrity upon treatment with the NPs. Our findings indicate that growth of environmental bacteria could be impaired by Ag NPs, depending on the extent of EPS production.

Improved theory of cyclical electrical field flow fractionation.

Previously reported theories for cyclical electrical field flow fractionation (CyElFFF) are severely limited in that they do not account for diffusion, steric, or electric double layer effects. Experiments have shown that these theories overpredict the retention of particles in CyElFFF. In this work, we present a model for prediction of steric, diffusion, and electrical effects. The electrical double layer effects are treated using a lumped electrical circuit model that accounts for the field shielding by the electrical double layer formed at the electrode-carrier interface. The electrical effects are shown to dominate retention times and outweigh the contributions of diffusion and particle size. Detailed results from the simulations are presented in this work, and a comparison between the theoretical and experimental results obtained from the retentions of polystyrene particle standards is presented in this paper. The models are shown to correctly predict the retention of the polystyrene standards in CyElFFF with a reasonable error, while existing models are shown to have significant failings.