Neuromorphic responses of nanofluidic memristors in symmetric and asymmetric ionic solutions.

We show that ionic conduction properties of a multipore nanofluidic memristor can be controlled not only by the amplitude and frequency of an external driving signal but also by chemical gating based on the electrolyte concentration, presence of divalent and trivalent cations, and multi-ionic systems in single and mixed electrolytes. In addition, we describe the modulation of current rectification and hysteresis phenomena, together with neuromorphic conductance responses to voltage pulses, in symmetric and asymmetric external solutions. In our case, memristor conical pores act as nanofluidic diodes modulated by ionic solution characteristics due to the surface charge-regulated ionic transport. The above facts suggest potential sensing and actuating applications based on the conversion between ionic and electronic signals in bioelectrochemical hybrid circuits.

Efficacy of Allopurinol in Improving Endothelial Dysfunction: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endothelial dysfunction has been implicated in various cardiovascular disorders as the initial pathology. Allopurinol has been shown to improve endothelial dysfunction in patients with gout, but its effect on cardiovascular patients is unclear. AIMS: We aim to assess allopurinol efficacy in improving endothelial dysfunction overall and in different disease states including but not limited to heart failure, chronic kidney disease, ischemic heart disease METHODS: We conducted a literature search of PubMed, Cochrane's Central Library, and Scopus until December 2022, including randomized controlled trials and double-arm observational studies. The primary outcome measure was endothelial function assessed by change in flow mediated dilation (FMD) RESULTS: Our meta-analysis included 22 studies with a total of 1472 patients. Our pooled analysis shows that allopurinol significantly improved FMD (WMD = 1.46%, 95% CI [0.70, 2.22], p < 0.01) compared to control. However, there was no significant difference between allopurinol and control for endothelial-independent vasodilation measured by forearm blood flow (WMD = 0.10%, 95% CI [- 0.89, 0.69], p = 0.80). Subgroup analysis indicated that the effect of allopurinol on FMD was more significant in diabetic and congestive heart failure patients. CONCLUSION: While allopurinol may improve endothelial function in various patient populations, further high-quality randomized controlled trials are needed to determine its efficacy in preventing cardiovascular disease exacerbation.

Comprehensive multi-level expression profiling of key biomarkers in breast cancer patients.

OBJECTIVES: In this comprehensive breast cancer (BC) study, we aimed to identify, validate, and characterize key biomarkers with significant implications in BC diagnosis, prognosis, and as therapeutic targets. METHODS: Our research strategy involved a multi-level methodology, combining bioinformatic analysis with experimental validation. RESULTS: Initially, we conducted an extensive literature search to identify BC biomarkers, selecting those with reported accuracies exceeding 20% in specificity and sensitivity. This yielded nine candidate biomarkers, which we subsequently analyzed using Cytoscape to identify a few key biomarkers. Based on the degree method, we denoted four key biomarkers, including progesterone receptor (PGR), epidermal growth factor receptor (EGFR), estrogen receptor 1 (ESR1), and Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2). Expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that PGR and EGFR exhibited significant (p-value < 0.05) down-regulation in BC samples when compared to controls, while ESR1 and ERBB2 showed up-regulation. To strengthen our findings, we collected clinical BC tissue samples from Pakistani patients and performed expression verification using real-time quantitative polymerase chain reaction (RT-qPCR). The results aligned with our initial TCGA dataset analysis, further validating the differential expression of these key biomarkers in BC. Furthermore, we utilized receiver operating characteristic (ROC) curves to demonstrate the diagnostic use of these biomarkers. Our analysis underscored their accuracy and sensitivity as diagnostic markers for BC. Survival analysis using the Kaplan-Meier Plotter tool revealed a prognostic significance of PGR, ESR1, EGFR, and ERBB2. Their expression levels were associated with poor overall survival (OS) of BC patients, shedding light on their roles as prognostic indicators in BC. Lastly, we explored DrugBank to identify drugs that may reverse the expression patterns , and estradiol, decitabine, and carbamazepine were singled out. CONCLUSION: Our study gives valuable insight into BC biomarkers, for diagnosis and prognosis. These findings have implications for BC management using personalized and targeted therapeutic approaches for BC patients.

Developing tiny-sized particles, different modification behaviors of gold atoms, and nucleating distorted particles.

The study of tiny-sized particles is beneficial in many ways. This has been the subject of many studies. The development of a tiny-sized particle depends on the attained dynamics of the atoms. In the development process of a tiny-sized particle, gold atoms must deal with different modification behaviors. Photons traveling along the air-solution interface also alter the characteristics of a developing tiny-sized particle. The electronic structures, modification behaviors, and attained dynamics of the atoms mainly contribute toward the development of tiny-sized particles. Energy under the supplied source and the local resulting forces collectively bind gold atoms. Both internally and externally driven dynamics influence the development process of different tiny-sized particles. Atoms in such developed tiny-sized particles do not experience the collective oscillations upon photons traveling along the air-solution interface. In the study of binding atoms, it is essential to consider the roles of both energy and force. Here, the development of tiny particles having different sizes presents a convincing discussion. Nucleating a distorted particle from the non-uniform amalgamation of tiny-sized particles is also discussed.

A Rare Case of Huge Schistosomiasis-Associated Cecal Polyp Mimicking Colon Carcinoma.

Schistosomiasis is a parasitic infection caused by Schistosoma species, commonly found in tropical and subtropical regions. It affects millions of people worldwide and can lead to different clinical presentations like abdominal pain, weight loss, anemia, and chronic colonic schistosomiasis. In rare cases, chronic infection can result in the development of polyps, which can mimic colon carcinoma, posing a diagnostic challenge. Here, we present a rare case of a huge Schistosomiasis-associated cecal polyp in a patient initially suspected to have colon cancer. The patient's clinical history and the histopathological analysis confirmed the diagnosis, emphasizing the importance of considering parasitic infections in the differential diagnosis of gastrointestinal polyps in Schistosomiasis-endemic areas. This case report highlights the need for increased awareness among healthcare professionals of the potential for Schistosomiasis-associated polyps and the importance of multidisciplinary management in such cases.

Cation pumping against a concentration gradient in conical nanopores characterized by load capacitors.

We study the cation transport against an external concentration gradient (cation pumping) that occurs in conical nanopores when zero-average oscillatory and white noise potentials are externally applied. This pumping, based on the electrically asymmetric nanostructure, is characterized here by a load capacitor arrangement. In the case of white noise signals, the conical nanopore acts as an electrical valve that allows extraction of order from chaos. No molecular carriers, specific ion pumps, and competitive ion-binding phenomena are required. The nanopore conductance on/off states mimic those of the voltage-gated ion channels in the cell membrane. These channels allow modulating membrane potentials and ionic concentration gradients along oscillatory pulses in circadian rhythms and the cell cycle. We show that the combination of asymmetric nanostructures with load capacitors can be useful for the understanding of nanofluidic processes based on bioelectrochemical gradients.

Electrical conductance of conical nanopores: Symmetric and asymmetric salts and their mixtures.

We have studied experimentally the electrical conductance-voltage curves of negatively and positively charged conical nanopores bathed in ionic solutions with monovalent, divalent, and trivalent cations at electrochemically and biologically relevant ionic concentrations. To better understand the interaction between the pore surface charge and the mobile ions, both single salts and salt mixtures have been considered. We have paid attention to the effects on the conductance of the cation valency, the pore charge asymmetry, and the pore charge inversion phenomena due to trivalent ions, both in single salts and salt mixtures. In addition, we have described how small concentrations of multivalent ions can tune the nanopore conductance due to monovalent majority ions, together with the effect of these charges on the additivity of ionic conductance and fluoride-induced negative differential conductance phenomena. This compilation and discussion of previously presented experimental data offers significant insights on the interaction between fixed and mobile charges confined in nanoscale volumes and should be useful in establishing and checking new models for describing ionic transport in the vicinity of charged surfaces.

Fluoride-Induced Negative Differential Resistance in Nanopores: Experimental and Theoretical Characterization.

We describe experimentally and theoretically the fluoride-induced negative differential resistance (NDR) phenomena observed in conical nanopores operating in aqueous electrolyte solutions. The threshold voltage switching occurs around 1 V and leads to sharp current drops in the nA range with a peak-to-valley ratio close to 10. The experimental characterization of the NDR effect with single pore and multipore samples concern different pore radii, charge concentrations, scan rates, salt concentrations, solvents, and cations. The experimental fact that the effective radius of the pore tip zone is of the same order of magnitude as the Debye length for the low salt concentrations used here is suggestive of a mixed pore surface and bulk conduction regime. Thus, we propose a two-region conductance model where the mobile cations in the vicinity of the negative pore charges are responsible for the surface conductance, while the bulk solution conductance is assumed for the pore center region.

Enhancement of heavy ion track-etching in polyimide membranes with organic solvents.

The effect of organic solvents on the ion track-etching of polyimide (PI) membranes is studied to enhance the nanopore fabrication process and the control over pore diameter growth. To this end, two approaches are employed to investigate the influence of organic solvents on the nanopore fabrication in PI membranes. In the first approach, the heavy ion irradiated PI samples are pretreated with organic solvents and then chemically etched with sodium hypochlorite (NaOCl) solution, resulting up to ∼4.4 times larger pore size compared to untreated ones. The second approach is based on a single-step track-etching process where the etchant (NaOCl) solution contains varying amounts of organic solvent (by vol%). The experimental data shows that a significant increase in both the bulk-etch and track-etch rates is observed by using the etchant mixture, which leads to ∼47% decrease in the nanopore fabrication time. This enhancement of nanopore fabrication process in PI membranes would open up new opportunities for their implementation in various potential applications.

Ultrasensitive and Selective Protein Recognition with Nanobody-Functionalized Synthetic Nanopores.

The development of flexible and reconfigurable sensors that can be readily tailored toward different molecular analytes constitutes a key goal and formidable challenge in biosensing. In this regard, synthetic nanopores have emerged as potent physical transducers to convert molecular interactions into electrical signals. Yet, systematic strategies to functionalize their surfaces with receptor proteins for the selective detection of molecular analytes remain scarce. Addressing these limitations, a general strategy is presented to immobilize nanobodies in a directional fashion onto the surface of track-etched nanopores exploiting copper-free click reactions and site-specific protein conjugation systems. The functional immobilization of three different nanobodies is demonstrated in ligand binding experiments with green fluorescent protein, mCherry, and α-amylase (α-Amy) serving as molecular analytes. Ligand binding is resolved using a combination of optical and electrical recordings displaying quantitative dose-response curves. Furthermore, a change in surface charge density is identified as the predominant molecular factor that underlies quantitative dose-responses for the three different protein analytes in nanoconfined geometries. The devised strategy should pave the way for the systematic functionalization of nanopore surfaces with biological receptors and their ability to detect a variety of analytes for diagnostic purposes.

Selective detection of preferential activity of Lanthanum ion at zinc oxide functionalized nanochannel.

A significant increase of rare earth transition metals concentration in water reservoirs caused by the dumping of household materials and petrol-producing industries is a potential threat to human and aquatic life. Here, we demonstrate a model nanofluidic channel for the Lanthanum (La3+) ions recognition. To this end, a single conical nanochannel is first modified with poly allylamine hydrochloride followed by immobilization of synthesized ZnO nanoparticles on the channel surface through electrostatic adsorption. A significant change in the nanopore electrical readout is noticed when the functionalized nanochannel is exposed to an electrolyte solution having La3+cations. The distinctive response by the nanofluidic system towards La3+ions is assumed to be due to ionic radii, hexagonal crystal structure, and associated basal plane interaction between anchored ZnO nanoparticles and La3+ions. We anticipate that this nanofluidic system can be used as a model to design highly sensitive metal ion detection devices.

A Mixed-Methods Study to Explore the Impact of Hospital Accreditation.

There are several hospital accreditors globally but there is limited understanding of how accreditation impacts on hospital performance and the health system objectives. The objective of the study were to explore the impact of hospital accreditation and inform policy decision-making. We adopted a mixed-methods approach to include an online survey and 3 focus groups. We report 27 of 36 private hospitals who responded to the survey. Key reasons for accreditation were to improve quality (n = 23), implement evidence-based practice (n = 17), continuity of accreditation (n = 15), and popularity (n = 11). Reported improvements include quality of care (27), patient care (26), organizational processes (21), and patient satisfaction (19) among others. Average stakeholder satisfaction rate was 74%. Participants from the 3 focus group discussions felt that staff hours and stress levels were high during the accreditation process, and some standards were useful while others were deemed non-essential. There was support for a local accreditation body with an emphasis on best practice. The findings from the study suggest accreditation to have an impact on structure and process measures, but the gains in key areas were short-lived. There is a need to strengthen governance and develop performance measures to evidence outcome improvement, assure alignment with regulation and the health system objectives.

Comparative transcriptomics reveals desynchronisation of gene expression during the floral transition between Arabidopsis and Brassica rapa cultivars.

Comparative transcriptomics can be used to translate an understanding of gene regulatory networks from model systems to less studied species. Here, we use RNA-Seq to determine and compare gene expression dynamics through the floral transition in the model species Arabidopsis thaliana and the closely related crop Brassica rapa. We find that different curve registration functions are required for different genes, indicating that there is no single common 'developmental time' between Arabidopsis and B. rapa. A detailed comparison between Arabidopsis and B. rapa and between two B. rapa accessions reveals different modes of regulation of the key floral integrator SOC1, and that the floral transition in the B. rapa accessions is triggered by different pathways. Our study adds to the mechanistic understanding of the regulatory network of flowering time in rapid cycling B. rapa and highlights the importance of registration methods for the comparison of developmental gene expression data.

Highly Efficient Permeation and Separation of Gases with Metal-Organic Frameworks Confined in Polymeric Nanochannels.

This work demonstrates the confinement of porous metal-organic framework (HKUST-1) on the surface and walls of track-etched nanochannel in polyethylene terephthalate (np-PET) membrane using a liquid-phase epitaxy (LPE) technique. The composite membrane (HKUST-1/np-PET) exhibits defect-free MOF growth continuity, strong attachment of MOF to the support, and a high degree of flexibility. The high flexibility and the strong confinement of the MOF in composite membrane results from (i) the flexible np-PET support, (ii) coordination attachment between HKUST-1 and the support, and (iii) the growth of HKUST-1 crystal in nanoconfined geometries. The MOF has a preferred growth orientation with a window size of 3.5 Å, resulting in a clear cut-off of CO2 from natural gas and olefins. The experimental results and DFT calculations show that the restricted diffusion of gases only takes place through the nanoporous MOF confined in the np-PET substrate. This research thereby provides a new perspective to grow other porous MOFs in artificially prepared nanochannels for the realization of continuous, flexible, and defect-free membranes for various applications.

Impact of Surface Charge Directionality on Membrane Potential in Multi-ionic Systems.

The membrane potential (Vmem), defined as the electric potential difference across a membrane flanked by two different salt solutions, is central to electrochemical energy harvesting and conversion. Also, Vmem and the ionic concentrations that establish it are important to biophysical chemistry because they regulate crucial cell processes. We study experimentally and theoretically the salt dependence of Vmem in single conical nanopores for the case of multi-ionic systems of different ionic charge numbers. The major advances of this work are (i) to measure Vmem using a series of ions (Na+, K+, Ca2+, Cl-, and SO42-) that are of interest to both energy conversion and cell biochemistry, (ii) to describe the physicochemical effects resulting from the nanostructure asymmetry, (iii) to develop a theoretical model for multi-ionic systems, and (iv) to quantify the contributions of the liquid junction potentials established in the salt bridges to the total cell membrane potential.

Phosphoprotein Detection with a Single Nanofluidic Diode Decorated with Zinc Chelates.

We report a nanofluidic device for the label-free detection of phosphoprotein (PPn) analytes. To achieve this goal, a metal ion chelator, namely 4-[bis(2-pyridylmethyl)aminomethyl]aniline (DPA-NH2 ) compound was synthesized. Single asymmetric nanofluidic channels were fabricated in polyethylene terephthalate (PET) membranes. The chelator (DPA-NH2 ) molecules are subsequently immobilized on the nanochannel surface, followed by the zinc ion complexation to afford DPA-Zn2+ chelates, which act as ligand moieties for the specific binding of phosphoproteins. The success of the chemical reaction and biomolecular recognition process that occur in a confined geometry can be monitored from the changes in electrical readout of the nanochannel. The nanofluidic sensor has the ability to sensitively and specifically detect lower concentrations (≥1 nM) of phosphoprotein (albumin and α-casein) in the surrounding environment as evidenced from the significant decrease in ion current flowing through the nanochannels. However, dephosphoproteins such as lysozyme and dephospho-α-casein even at higher concentration (>1 µM) could not induce any significant change in the transmembrane ion flux. This observation indicated the sensitivity and specificity of the proposed nanofluidic sensor towards PPn proteins, and has potential for use in differentiating between phosphoproteins and dephosphoproteins.

Aflatoxin Contamination of Milk Produced in Peri-urban Farms of Pakistan: Prevalence and Contributory Factors.

Aflatoxin M1 contamination of milk in Pakistan, like many developing countries, is poorly understood. The present study was therefore conducted to determine AFM1 contamination of milk and its contributory factors in Pakistan. We sampled milk and feedstuffs from 450 peri-urban dairy farms in seven major cities following a cross-sectional study design. Analysis of milk using ELISA revealed high contamination with an overall average of 3164.5 ng of AFM1/L, and significant differences (p < 0.001) between cities. The milk sampled from Gilgit, in northern hilly areas, had an average AFM1 level of 92.5 ng/L. Milk from other cities had 3529.7 ng/L average contamination, with only 5.7% samples qualifying the maximum tolerable limit of 500 ng of AFM1/L. Heavy mean aflatoxin contamination was found in bakery waste (724.6 µg/kg), and cottonseed cake (600.8 µg/kg). Rest of the other feedstuffs had moderate to low mean aflatoxin contamination, ranging from 66.0 µg/kg in maize stover to 3.4 µg/kg in wheat bran. The mean aflatoxin level in commercial dairy concentrates was 32.7 µg/kg. About 80% of the total aflatoxin intake of dairy animals was contributed by cottonseed cake alone due to its high aflatoxin contamination and proportion in dairy rations. On-farm storage time of oilseed cakes varied (p < 0.01) in different cities but was not associated with aflatoxin contamination. The exceptionally high AFM1 contamination suggests that milk from peri-urban dairy farms is a serious public health threat in Pakistan. This situation can be mitigated by reducing aflatoxin contamination in cottonseed cake and promoting the use of commercial concentrates and other feedstuffs with low contamination.

Ultrasensitive and Selective Copper(II) Detection: Introducing a Bioinspired and Robust Sensor.

A nanopore-based CuII -sensing system is reported that allows for an ultrasensitive and selective detection of CuII with the possibility for a broad range of applications, for example in medical diagnostics. A fluorescent ATCUN-like peptide 5/6-FAM-Dap-ß-Ala-His is employed to selectively bind CuII ions in the presence of NiII and ZnII and was crafted into ion track-etched nanopores. Upon CuII binding the fluorescence of the peptide sensor is quenched, permitting the detection of CuII in solution. The ion transport characteristics of peptide-modified nanopore are shown to be extremely sensitive and selective towards CuII allowing to sense femtomolar CuII concentrations in human urine mimics. Washing with EDTA fully restores the CuII -binding properties of the sensor, enabling multiple repetitive measurements. The robustness of the system clearly has the potential to be further developed into an easy-to-use, lab-on-chip CuII -sensing device, which will be of great importance for bedside diagnosis and monitor of CuII levels in patients with copper-dysfunctional homeostasis.

Ionic circuitry with nanofluidic diodes.

Ionic circuits composed of nanopores functionalized with polyelectrolyte chains can operate in aqueous solutions, thus allowing the control of electrical signals and information processing in physiological environments. We demonstrate experimentally and theoretically that different orientations of single-pore membranes with the same and opposite surface charges can operate reliably in series, parallel, and mixed series-parallel arrangements of two, three, and four nanofluidic diodes using schemes similar to those of solid-state electronics. We consider also different experimental procedures to externally tune the fixed charges of the molecular chains functionalized on the pore surface, showing that single-pore membranes can be used efficiently in ionic circuitry with distinct ionic environments.