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Undesired coupling to the surrounding environment destroys long-range correlations in quantum processors and hinders coherent evolution in the nominally available computational space. This noise is an outstanding challenge when leveraging the computation power of near-term quantum processors1. It has been shown that benchmarking random circuit sampling with cross-entropy benchmarking can provide an estimate of the effective size of the Hilbert space coherently available2–8. Nevertheless, quantum algorithms’ outputs can be trivialized by noise, making them susceptible to classical computation spoofing. Here, by implementing an algorithm for random circuit sampling, we demonstrate experimentally that two phase transitions are observable with cross-entropy benchmarking, which we explain theoretically with a statistical model. The first is a dynamical transition as a function of the number of cycles and is the continuation of the anti-concentration point in the noiseless case. The second is a quantum phase transition controlled by the error per cycle; to identify it analytically and experimentally, we create a weak-link model, which allows us to vary the strength of the noise versus coherent evolution. Furthermore, by presenting a random circuit sampling experiment in the weak-noise phase with 67 qubits at 32 cycles, we demonstrate that the computational cost of our experiment is beyond the capabilities of existing classical supercomputers. Our experimental and theoretical work establishes the existence of transitions to a stable, computationally complex phase that is reachable with current quantum processors.

Artificial intelligence (AI) in medicine is transforming healthcare by automating system tasks, assisting in diagnostics, predicting patient outcomes and personalising patient care, founded on the ability to analyse vast datasets. In paediatric endocrinology, AI has been developed for diabetes, for insulin dose adjustment, detection of hypoglycaemia and retinopathy screening; bone age assessment and thyroid nodule screening; the identification of growth disorders; the diagnosis of precocious puberty; and the use of facial recognition algorithms in conditions such as Cushing syndrome, acromegaly, congenital adrenal hyperplasia and Turner syndrome. AI can also predict those most at risk from childhood obesity by stratifying future interventions to modify lifestyle. AI will facilitate personalised healthcare by integrating data from ‘omics’ analysis, lifestyle tracking, medical history, laboratory and imaging, therapy response and treatment adherence from multiple sources. As data acquisition and processing becomes fundamental, data privacy and protecting children’s health data is crucial. Minimising algorithmic bias generated by AI analysis for rare conditions seen in paediatric endocrinology is an important determinant of AI validity in clinical practice. AI cannot create the patient–doctor relationship or assess the wider holistic determinants of care. Children have individual needs and vulnerabilities and are considered in the context of family relationships and dynamics. Importantly, whilst AI provides value through augmenting efficiency and accuracy, it must not be used to replace clinical skills.

Three new 2-pyrral amino acid Schiff base palladium (II) complexes were synthesized, characterized and their activity against six bacterial species was investigated. The ligands: Potassium 2-pyrrolidine-L-methioninate (L1), Potassium 2-pyrrolidine-L-histidinate (L2) and Potassium 2-pyrrolidine-L-tryptophanate (L3) were synthesized and reacted with dichloro(1,5-cyclooctadiene)palladium(II) to form new palladium (II) complexes C1, C2 and C3, respectively. 1H NMR, FTIR, UV–Vis, elemental analysis and conductivity measurements were used to characterize the products. The antibacterial activities of the compounds were evaluated against Gram-positive Staphylococcus aureus(S. aureus,ATCC 25923), methicillin-resistant Staphylococcus aureus(MRSA, ATCC 33591), Staphylococcus epidermidis(S. epidermidis, ATCC 12228) and Streptococcus pyogenes(S. pyogenes,ATCC 19615) and, gram-negative Pseudomonas aeruginosa(P. aeruginosa,ATCC 27853) and Klebsiella pneumoniae(K. pneumoniae,ATCC 13883) using the agar well diffusion assay and microtitre plate serial dilution method. The palladium complexes were active against the selected bacteria with the imidazole ring containing complex C2 and indole heterocyclic ring containing complex C3 showing the highest activity.

An important measure of the development of quantum computing platforms has been the simulation of increasingly complex physical systems. Before fault-tolerant quantum computing, robust error-mitigation strategies were necessary to continue this growth. Here, we validate recently introduced error-mitigation strategies that exploit the expectation that the ideal output of a quantum algorithm would be a pure state. We consider the task of simulating electron systems in the seniority-zero subspace where all electrons are paired with their opposite spin. This affords a computational stepping stone to a fully correlated model. We compare the performance of error mitigations on the basis of doubling quantum resources in time or in space on up to 20 qubits of a superconducting qubit quantum processor. We observe a reduction of error by one to two orders of magnitude below less sophisticated techniques such as postselection. We study how the gain from error mitigation scales with the system size and observe a polynomial suppression of error with increased resources. Extrapolation of our results indicates that substantial hardware improvements will be required for classically intractable variational chemistry simulations.

As an important sequela of the burgeoning global obesity problem, metabolic-associated fatty liver disease (MAFLD) has gained increasing prominence recently. The gut–liver axis (GLA) provides a direct conduit to the liver for the gut microbiota and their metabolic by-products (including secondary bile acids, ethanol, and trimethylamine). These GLA-related factors, including the host inflammatory response and integrity of the gut mucosal wall, likely contribute to the pathogenesis of MAFLD. Accordingly, these GLA-related factors are targets for possible preventive and treatment strategies for MAFLD, and include probiotics, prebiotics, bile acids, short-chain fatty acids, fecal microbiota transplantation, carbon nanoparticles, and bacteriophages.

The diversity of the cutaneous manifestations of syphilis and the ability of the spirochete to evade diagnosis have been well documented by medical literature. However, what triggers the onset of secondary syphilis is not yet clear because of difficulties studying the bacterium. Our case describes the onset of a heterogeneous rash (or coexisting rashes) that presented the day after vaccination with the Moderna mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. The potential etiologies of the patient’s rash: A vaccine reaction, reactivation of chronic spontaneous urticaria, or a physical sign of syphilis itself are then reviewed. The potential for the Moderna coronavirus disease 2019 (COVID-19) vaccine to be the catalyst of this patient’s cutaneous manifestations of his immune system responses is also hypothesized.

The plant hormone abscisic acid (ABA) accumulates under abiotic stress to recast water relations and development. To overcome a lack of high-resolution sensitive reporters, we developed ABACUS2s—next-generation Förster resonance energy transfer (FRET) biosensors for ABA with high affinity, signal-to-noise ratio and orthogonality—that reveal endogenous ABA patterns in Arabidopsis thaliana. We mapped stress-induced ABA dynamics in high resolution to reveal the cellular basis for local and systemic ABA functions. At reduced foliar humidity, root cells accumulated ABA in the elongation zone, the site of phloem-transported ABA unloading. Phloem ABA and root ABA signalling were both essential to maintain root growth at low humidity. ABA coordinates a root response to foliar stresses, enabling plants to maintain foraging of deeper soil for water uptake.

The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the KrasG12D-driven mouse LUAD model, we found that loss of Sox9significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8+T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in KrasG12D-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8+T cell and NK cell infiltration and activity. Thus, SOX9 drives KrasG12D-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.

Anomalous origin of the left circumflex coronary artery from the right pulmonary artery is an extremely rare coronary anomaly out of the group of anomalous coronary arteries arising from the pulmonary artery. We present the case of a 27-year-old male, in whom the diagnosis of an anomalous left circumflex coronary artery from the pulmonary artery was made after sudden cardiac arrest. The diagnosis was confirmed by multimodal imaging and the patient underwent successful surgical correction. Abnormal origins of a coronary artery may become symptomatic later in life and may occur as an isolated cardiac malformation. Due to a potentially unfavorable clinical course, surgical correction should be considered as soon as a diagnosis is made.

A tightly regulated actin cytoskeleton attained through balanced activity of RhoGTPases is crucial to maintaining podocyte function. However, how RhoGTPases are regulated by geranylgeranylation, a post-translational modification, has been unexplored. The authors found that loss of the geranylgeranylation enzyme geranylgeranyl transferase type-I (GGTase-I) in podocytes led to progressive albuminuria and foot process effacement in podocyte-specific GGTase-I knockout mice. In cultured podocytes, the absence of geranylgeranylation resulted in altered activity of its downstream substrates Rac1, RhoA, Cdc42, and Rap1, leading to alterations of β1-integrins and actin cytoskeleton structural changes. These findings highlight the importance of geranylgeranylation in the dynamic management of RhoGTPases and Rap1 to control podocyte function, providing new knowledge about podocyte biology and glomerular filtration barrier function.

Extracorporeal membrane oxygenation (ECMO) has been widely used in patients with COVID-19, but uncertainty remains about the determinants of in-hospital mortality and data on post-discharge outcomes are scarce. The aims of this study were to investigate the variables associated with in-hospital outcomes in patients who received ECMO during the first wave of COVID-19 and to describe the status of patients 6 months after ECMO initiation.

Systems of correlated particles appear in many fields of modern science and represent some of the most intractable computational problems in nature. The computational challenge in these systems arises when interactions become comparable to other energy scales, which makes the state of each particle depend on all other particles1. The lack of general solutions for the three-body problem and acceptable theory for strongly correlated electrons shows that our understanding of correlated systems fades when the particle number or the interaction strength increases. One of the hallmarks of interacting systems is the formation of multiparticle bound states2–9. Here we develop a high-fidelity parameterizable fSim gate and implement the periodic quantum circuit of the spin-½ XXZ model in a ring of 24 superconducting qubits. We study the propagation of these excitations and observe their bound nature for up to five photons. We devise a phase-sensitive method for constructing the few-body spectrum of the bound states and extract their pseudo-charge by introducing a synthetic flux. By introducing interactions between the ring and additional qubits, we observe an unexpected resilience of the bound states to integrability breaking. This finding goes against the idea that bound states in non-integrable systems are unstable when their energies overlap with the continuum spectrum. Our work provides experimental evidence for bound states of interacting photons and discovers their stability beyond the integrability limit.

OBJECTIVE--Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate [...]

Neurologic disease of foals is a diagnostic and therapeutic challenge for veterinarians. Disease conditions such as neonatal encephalopathy are seen as well as developmental and congenital defects, bacterial infections, and trauma. Neonatal encephalopathy can be considered a “syndrome” with a variety of causes resulting in a similar clinical presentation. These causes can be categorized as maladaptation, hypoxic/ischemic encephalopathy, and metabolic abnormalities, all leading to signs of cerebral and brainstem disease. Spinal cord signs may occasionally be seen, but these signs are usually overshadowed by cerebral disease. Treatment in most cases involves supportive care and outcome is favorable in most cases.

OBJECTIVE--Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) α--dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS--The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ/activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS--Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA-induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS--The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity., Fibroblast growth factor (FGF)-21 is a recently discovered metabolic regulator of fasting metabolism. FGF-21 activates glucose uptake in adipocytes, protects animals from diet-induced obesity when overexpressed in transgenic mice, and [...]

Metabolic reprogramming is typical in cancerous cells and is required for proliferation and cellular survival. In addition, oncoproteins of high-risk human papillomavirus (HR-HPV) are involved in this process. This study evaluated the relationship between glucose transporter I (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter type 4 (MCT4) expression and cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma (ICC) with HR-HPV infection. The protein expression was evaluated in women with CIN I (n=20), CIN II/III (n=16), or ICC (n=24) by immunohistochemistry. The protein expression was analyzed qualitatively by van Zummeren score and quantitatively by Image ProPlus 6 software. LDHA expression increases in HPV-16 infection. In the CIN I group, GLUT1 immunostaining has a 35% protein expression at the membrane level at more than two thirds of the epithelium, which increased by 21.25% more in CIN II/III in more than two thirds of the epithelium. While LDHA and MCT4 in CIN I mostly do not present immunostaining, or this was only limited to the basal stratum, this expression is increased in CIN II/III and ICC cases. The GLUT1, LDHA, and MCT4 expression increased in ICC. The overexpression in high-grade CIN with HR-HPV infection shows a higher risk for cervical carcinoma progression.

OBJECTIVE--It has been suggested that retinol-binding protein 4 (RBP4) links adiposity, insulin resistance, and type 2 diabetes. However, circulating RBP4 levels are also affected by kidney function. Therefore, the aim of this study was to test whether RBP4 serum levels are primarily associated with kidney function or type 2 diabetes. RESEARCH DESIGN AND METHODS--RBP4 serum concentration was determined by enzyme-linked immunosorbent assay in 126 nondiabetic and 104 type 2 diabetic subjects. The study population was divided according to estimated glomerular filtration rate (eGFR) into the following groups: eGFR >90 ml/min per 1.73 [m.sup.2] (n = 53), 60-90 ml/min per 1.73 [m.sup.2] (n = 90), 30-60 ml/min per 1.73 [m.sup.2] (n = 38), and RESULTS--RBP4 serum concentration was elevated (2.65 vs. 2.01 µmol/l; P < 0.001) and eGFR was reduced (56 vs. 74 ml/min per 1.73 [m.sup.2]; P < 0.001) in type 2 diabetic vs. nondiabetic subjects, respectively. By stratifying for eGFR, no more differences in RBP4 serum concentration were detectable between type 2 diabetic and nondiabetic subjects. A linear regression analysis revealed an influence of eGFR (r = -0.477; P < 0.001) but not A1C (r = 0.093; P = 0.185) on RBP4 serum concentration. CONCLUSIONS--Existing human data showing elevated RBP4 levels in type 2 diabetic patients may be the result of moderate renal insufficiency rather than support for the suggestion that RBP4 links obesity to type 2 diabetes., Retinol-binding protein 4 (RBP4) is a small visceral protein (~21 kDa), mainly synthesized in the liver and catabolized in the kidneys after glomerular filtration (1). To prevent the renal loss [...]

Background: Many laboratories offer glycemic index (GI) services. Objective: We assessed the performance of the method used to measure GI. Design: The GI of cheese-puffs and fruit-leather (centrally provided) was measured in 28 laboratories (n = 311 subjects) by using the FAO/WHO method. The laboratories reported the results of their calculations and sent the raw data for recalculation centrally. Results: Values for the incremental area under the curve (AUC) reported by 54% of the laboratories differed from central calculations. Because of this and other differences in data analysis, 19% of reported food GI values differed by >5 units from those calculated centrally. GI values in individual subjects were unrelated to age, sex, ethnicity, body mass index, or AUC but were negatively related to within-individual variation (P = 0.033) expressed as the CV of the AUC for repeated reference food tests (refCV). The between-laboratory GI values (mean [+ or -] SD) for cheese-puffs and fruit-leather were 74.3 [+ or -] 10.5 and 33.2 [+ or -] 7.2, respectively. The mean laboratory GI was related to refCV (P = 0.003) and the type of restrictions on alcohol consumption before the test (P = 0.006, [r.sup.2] = 0.509 for model). The within-laboratory SD of GI was related to refCV (P < 0.001), the glucose analysis method (P = 0.010), whether glucose measures were duplicated (P = 0.008), and restrictions on dinner the night before (P = 0.013, [r.sup.2] = 0.810 for model). Conclusions: The between-laboratory SD of the GI values is [approximately equal to] 9. Standardized data analysis and low within-subject variation (refCV < 30%) are required for accuracy. The results suggest that common misconceptions exist about which factors do and do not need to be controlled to improve precision. Controlled studies and cost-benefit analyses are needed to optimize GI methodology. The trial was registered at clinicaltrials.gov as NCT00260858. KEY WORDS Clinical trial, humans, dietary carbohydrate, glycemic index, glucose, methodology

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.

OBJECTIVE--Cereal fiber intake is linked to reduced risk of type 2 diabetes in epidemiological observations. The pathogenic background of this phenomenon is unknown. Based on recent findings, we hypothesized that [...]

Adiponectin affects lipid metabolism and insulin sensitivity. However, adiponectin circulates in three different oligomers that may also have distinct biological functions. We aimed to analyze the role of these oligomers in obesity and lipid metabolism after weight reduction. A total of 17 obese volunteers (15 women and 2 men) participated in a weight reduction program. Individuals were characterized before and after 6 months of a balanced diet. Adiponectin was determined by enzyme-linked immunosorbent assay, and oligomers were detected by nondenaturating Western blot. BMI decreased (35.1 ± 1.2 to 32.8 ± 1.1 kg/[m.sup.2], P < 0.001), which was associated with an improved metabolite profile. Total adiponectin increased from 5.3 ± 0.5 to 6.1 ± 0.6 µg/ml (P = 0.076). High (HMW) and medium molecular weight (MMW) adiponectin oligomers significantly increased during weight reduction (HMW: 0.37 ± 0.07 to 0.4 ± 0.08 µg/ml, P = 0.042; MMW: 2.3 ± 0.2 to 2.9 ± 0.3 µg/ml, P = 0.007), while low molecular weight (LMW) did not significantly change. Body weight inversely correlated with HMW (r = -0.695, P = 0.002) and positively with LMW (r = 0 .579, P = 0.015). Interestingly, HDL cholesterol and HMW were strongly correlated (r = 0.665, P = 0.007). Indeed, HMW and free fatty acids before weight reduction predicted ~60% of HDL changes during intervention. In conclusion, weight reduction results in a relative increase of HMW/MMW adiponectin and a reduction of LMW adiponectin. Total adiponectin and especially HMW adiponectin are related to circulating HDL cholesterol., Obesity is associated with dyslipidemia, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease (1,2). Adipose tissue was believed to be a fat-storage organ, but it is now acknowledged to be [...]

Evidence that Line 1 uses at least two distinct mechanisms to link the 5'-end of the nascent L1 copy to its genomic target is provided to analyze the 5' junctions to recent L1 insertions in the human genome by applying bioformatics. The results indicate that a cellular nonhomologous DNA end-joining pathway might resolve intermediates from incomplete L1 retrotransposition events and thus lead to 5' truncations.

Background: 17-Allylamino,17-demethoxygeldanamycin (17AAG) is a novel anticancer drug that inhibits heat shock protein 90 (Hsp90), resulting in proteasomal degradation of several oncogenic proteins. We used phosphorus magnetic resonance spectroscopy ([sup.31]P-MRS) to determine whether 17AAG treatment leads to alterations in phospholipids that could serve as pharmacodynamic markers for tumor response to 17AAG. Methods: HCT116, HT29, and SW620 colon cancer cells were treated with 17AAG, and extracts were examined by [sup.31]P-MRS. HT29 cells were also treated with the active metabolite of 17AAG, 17-amino,17-demethoxygeldanamycin (17AG), or the inactive 17AAG analog NSC683666. MF-1 nude mice carrying HT29 xenografts were examined using in vivo [sup.31]P-MRS before and after 17AAG treatment; xenograft tumor extracts were examined by [sup.31]P-MRS and proton MRS ([sup.1]H-MRS). Hsp90 client protein expression was determined by using western blots. Two-tailed t tests were used to compare metabolite concentrations and ratios, and a Mann-Whitney U test was used to compare proportions. All statistical tests were two-sided. Results: 17AAG treatment led to statistically significantly increased phosphocholine levels in all three cell lines (P = .02). 17AG treatment also increased phosphocholine levels in HT29 cells, whereas NSC683666 had no effect. The phosphomonoester/phosphodiester ratio was statistically significantly increased in the HT29 xenografts after 17AAG treatment relative to the pretreatment ratio (P = .02), whereas no statistically significant change was observed after vehicle treatment (P = .62). Statistically significant increases in phosphocholine, phosphoethanolamine, and valine levels were also observed in tumor extracts treated with 17AAG. Conclusions: Inhibition of Hsp90 by 17AAG resulted in altered phospholipid metabolism in cultured tumor cells and in tumor xenografts. The increases observed in phosphocholine and phosphomonoester levels suggest that these metabolites may have the potential to act as noninvasive pharmacodynamic markers for analyzing tumor response to treatment with 17AAG or other Hsp90 inhibitors.

In this article, we provide formulations of energy flux and radiation stress consistent with the scaling regime of the Korteweg–de Vries (KdV) equation. These quantities can be used to describe the shoaling of cnoidal waves approaching a gently sloping beach. The transformation of these waves along the slope can be described using the shoaling equations, a set of three nonlinear equations in three unknowns: the wave height H, the set-down η¯and the elliptic parameter m. We define a numerical algorithm for the efficient solution of the shoaling equations, and we verify our shoaling formulation by comparing with experimental data from two sets of experiments as well as shoaling curves obtained in previous works.

Schiff bases are organic compounds referred as privileged ligands that are synthesized from the condensation of a primary amine with a carbonyl group. They are regarded as an important class of organic compounds due to their chelating properties and ability to coordinate to a wide range of transition, lanthanide, and actinide ions in different oxidation states using their nitrogen and oxygen atoms to form stable complexes. Tremendous interest has been aroused to explore the potential applications of metal complexes of various Schiff bases in confronting the challenges facing mankind such as antimicrobial resistance and environmental pollution. There has been great interest in Schiff bases and their metal complexes because of their numerous applications in organic, bioinorganic, analytical, material science, and medicinal chemistry. The presence of the azomethine group in the Schiff bases and its ability to coordinate to various metal ions is essential for these applications. This paper covers a wide range of Schiff bases synthesized from the condensation reaction involving the carbonyl group of salicylidene-4-amioantipyrine and the amine group of various organic compounds and their metal complexes which were characterized based on their numerous unique physical, chemical, and spectral properties from which different structures have been proposed. The various information was collected from researches in journals indexed by Scopus, Google Scholar, PubMed published over the years. This review provides an insight into the metal complexes of Schiff bases derived from salicylidene-4-aminoatipyrine and its derivatives and the various research works explored on its biological and analytical applications.

Fueled by the global surge in aging, atherosclerotic cardiovascular disease reached pandemic dimensions putting affected individuals at enhanced risk of myocardial infarction, stroke, and premature death. Atherosclerosis is a systemic disease driven by a wide spectrum of factors, including cholesterol, pressure, and disturbed flow. Although all arterial beds encounter a similar atherogenic milieu, the development of atheromatous lesions occurs discontinuously across the vascular system. Indeed, the internal mammary artery possesses unique biological properties that confer protection to intimal growth and atherosclerotic plaque formation, thus making it a conduit of choice for coronary artery bypass grafting. Its endothelium abundantly expresses nitric oxide synthase and shows accentuated nitric oxide release, while its vascular smooth muscle cells exhibit reduced tissue factor expression, high tPA (tissue-type plasminogen activator) production and blunted migration and proliferation, which may collectively mitigate intimal thickening and ultimately the evolution of atheromatous plaques. We aim here to provide insights into the anatomy, physiology, cellular, and molecular aspects of the internal mammary artery thereby elucidating its remarkable resistance to atherogenesis. We propose a change in perspective from risk to resilience to decipher mechanisms of atheroresistance and eventually identification of novel therapeutic targets presently not addressed by currently available remedies.

A promising approach to study condensed-matter systems is to simulate them on an engineered quantum platform1–4. However, the accuracy needed to outperform classical methods has not been achieved so far. Here, using 18 superconducting qubits, we provide an experimental blueprint for an accurate condensed-matter simulator and demonstrate how to investigate fundamental electronic properties. We benchmark the underlying method by reconstructing the single-particle band structure of a one-dimensional wire. We demonstrate nearly complete mitigation of decoherence and readout errors, and measure the energy eigenvalues of this wire with an error of approximately 0.01 rad, whereas typical energy scales are of the order of 1 rad. Insight into the fidelity of this algorithm is gained by highlighting the robust properties of a Fourier transform, including the ability to resolve eigenenergies with a statistical uncertainty of 10−4rad. We also synthesize magnetic flux and disordered local potentials, which are two key tenets of a condensed-matter system. When sweeping the magnetic flux we observe avoided level crossings in the spectrum, providing a detailed fingerprint of the spatial distribution of local disorder. By combining these methods we reconstruct electronic properties of the eigenstates, observing persistent currents and a strong suppression of conductance with added disorder. Our work describes an accurate method for quantum simulation5,6and paves the way to study new quantum materials with superconducting qubits.

Various cross-sectional studies suggest that a polymorphism (E23K) within the ATP-sensitive [K.sup.+] channel KCNJ11 gene is associated with type 2 diabetes (1). However, only two prospective studies have addressed the [...]

Boundary dynamics are crucial for the transport of energy, mass, and momentum in geospace. The recently discovered plasmapause surface wave (PSW) plays a key role in the inner magnetosphere dynamics. However, a comprehensive investigation of spatial variations of the PSW remains absent. In this study, we elucidate the spatial characteristics of a PSW through observations from multiple spacecrafts in the magnetosphere. Following the initiation of the PSW, quasi‐periodic injections of energetic ions, rather than electrons, are suggested to serve as energy source of the PSW. Based on the distinct wave and particle signatures, we categorize the PSW into four regions: seed region, growth region, stabilization region and decay region, spanning from nightside to afternoon plasmapause. These findings advance our understanding of universal boundary dynamics and contribute to a deeper comprehension of the pivotal roles of surface waves in the energy couplings within the magnetosphere‐plasmasphere‐ionosphere system. Much like the rhythmic beating of a drum, boundaries within the terrestrial system, which delimit distinct plasmas with varying temperatures and densities, can oscillate due to external impulses or internal instabilities, giving rise to surface waves. These surface waves travel along the boundary surface and establish standing wave structures in magnetic field lines. In the terrestrial space environment, two types of surface waves have been identified: the magnetopause surface wave and the plasmapause surface wave (PSW). These waves typically have frequencies ranging from fractions of milli Hertz to a few milli Hertz, with periods spanning from several to tens of minutes. They are believed to play a vital role in mass, energy, and momentum transport within Earth's magnetosphere. However, the exact source that excites the waves and the manner in which the waves evolve along the boundary remain elusive. In this study, we, for the first time, unveil the spatial evolutionary signatures of the PSW during a moderate geomagnetic storm accompanied by substorms, utilizing data from six magnetospheric spacecrafts positioned near the plasmapause. This research contributes to a better understanding of the physical mechanisms underlying the widespread existence of surface waves in the universe, shedding light on the processes of magnetosphere‐plasmasphere‐ionosphere energy couplings and wave‐particle interactions associated with surface waves. Spatial characteristics of plasmapause surface wave (PSW) are elucidate with multiple‐spacecraft observations in the magnetosphereIt is suggested that quasi‐periodic injections of energetic ions rather than electrons sustain the PSW during the substormThe PSW is categorized into seed region, growth region, stabilization region, and decay region with different wave and particle properties Spatial characteristics of plasmapause surface wave (PSW) are elucidate with multiple‐spacecraft observations in the magnetosphere It is suggested that quasi‐periodic injections of energetic ions rather than electrons sustain the PSW during the substorm The PSW is categorized into seed region, growth region, stabilization region, and decay region with different wave and particle properties

The interaction of a solar wind discontinuity with the backstreaming particles of the Earth’s ion foreshock can generate hot, tenuous plasma transients such as foreshock bubbles (FB) and hot flow anomalies (HFA). These transients are known to have strong effects on the magnetosphere, distorting the magnetopause (MP), either locally during HFAs or globally during FBs. However, previous studies on the global impact of FBs have not been able to determine whether the response stems directly from the transverse scale size of the phenomenon or its fast motion over the magnetosphere. Here we present the observation of an FB and its impact on the magnetosphere from different spacecraft scattered over the dayside magnetosphere. We are able to constrain the size of the transverse scale of an FB from direct observations to be about 10 RE. We go on to discuss how the magnetosphere responds to this transient, which seems to have a similar scale across the dayside. The solar wind is a fast plasma flow of charged particles originating from the Sun. Earth’s magnetic field diverts this flow around the planet forming the magnetosphere. The bow shock forms upstream of Earth to decelerate the solar wind and deflect the flow around Earth’s magnetic field. A fraction of the solar wind particles are reflected back into the solar wind stream, forming the foreshock. Discontinuities in the solar wind can concentrate these backstreaming particles forming a bubble of hot and tenuous plasma called a foreshock bubble. These transients structures move with the solar wind, arriving at and modifying the bow shock and leading to an expansion of the magnetosphere due to lower pressure within the transients' core. Such a response was reported before in different studies which conclude that foreshock bubbles have a global impact on the magnetosphere. In our study we report on another foreshock bubble observed by a multi‐spacecraft constellation. The observations allowed us to constrain the size of the foreshock bubble. We observe that the large scale response of the magnetosphere seems to reflect with the size of the FB. Multi satellite observation of a large foreshock bubble (FB) hitting Earth’s magnetosphereThe transverse (y− z) scale size of the FB can be constrained from observations to be at least 8–10 REfitting with simulationsThe magnetospheric response to the FB seems to be visible across almost 10 REof the dayside, matching the FB size Multi satellite observation of a large foreshock bubble (FB) hitting Earth’s magnetosphere The transverse (y− z) scale size of the FB can be constrained from observations to be at least 8–10 REfitting with simulations The magnetospheric response to the FB seems to be visible across almost 10 REof the dayside, matching the FB size

The terms ‘idiopathic short stature’ (ISS) and ‘small for gestational age’ (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term ‘SGA’ was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms ‘SGA’ and ‘ISS’ as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

Modern anti-cancer drugs target DNA specifically for rapid division of malignant cells. One downside of this approach is that they also target other rapidly dividing healthy cells, such as those involved in hair growth leading to serious toxic side effects and hair loss. Therefore, it would be better to develop novel agents that address cellular signaling mechanisms unique to cancerous cells, and new research is now focussing on such approaches. Although the classical chemotherapy area involving DNA as the set target continues to produce important findings, nevertheless, a distinctly discernible emerging trend is the divergence from the cisplatin operation model that uses the metal as the primary active center of the drug. Many successful anti-cancer drugs present are associated with elevated toxicity levels. Cancers also develop immunity against most therapies and the area of cancer research can, therefore, be seen as an area with a high unaddressed need. Hence, ongoing work into cancer pathogenesis is important to create accurate preclinical tests that can contribute to the development of innovative drugs to manage and treat cancer. Some of the emergent frontiers utilizing different approaches include nanoparticles delivery, use of quantum dots, metal complexes, tumor ablation, magnetic hypothermia and hyperthermia by use of Superparamagnetic Iron oxide Nanostructures, pathomics and radiomics, laser surgery and exosomes. This review summarizes these new approaches in good detail, giving critical views with necessary comparisons. It also delves into what they carry for the future, including their advantages and disadvantages.

Purpose: During the COVID-19 pandemic, there have been particular concerns regarding the related impact on specialist tumour services. Neuroendocrine tumour (NET) services are delivered in a highly specialised setting, typically delivered in a small number of centres that fulfil specific criteria as defined by the European Neuroendocrine Tumour Society (ENETS). We aimed to address the COVID-19-related impact on specialist NET tumour services in England and other countries. Methods: Electronic survey addressing patient access and delivery of care distributed to all ENETS Centres of Excellence (CoE) in England and matching number of ENETS CoE elsewhere. Semi-quantitative and qualitative analyses of survey responses were performed. Results: Survey response of ENETS CoE in England was 55% (6/11). Responses from six non-UK ENETS CoE elsewhere were received and analysed in a similar manner. Relevant disruption of various NET services was noted across all responding Centres, which included delayed patient appointments and investigations, reduced availability of treatment modalities including delayed surgical treatment and a major negative impact on research activities. The comparison between English and non-UK ENETS CoE suggested that the former had significantly greater concerns related to future research funding (p?=?0.014), whilst having less disruption to multidisciplinary meetings (p?=?0.01). A trend was also noted towards virtual patient appointments in ENETS CoE in England vs. elsewhere (p?=?0.092). Conclusions: Restoration of highly specialised NET services following COVID-19 and planning for future service delivery and research funding must take account of the severe challenges encountered during the pandemic.

Introduction: Hepatitis A virus infection is more severe in adults than children. Although vaccination can protect adults, current childhood programs cover a large population more successfully. Childhood vaccination is, therefore, a solution to protecting adults if it induces lasting immunity. Fifteen-year protection has been demonstrated in children, but longer-term data are only available for adults. We aimed to predict long term persistence of antibody in children beyond 15 years and assess if immunological mechanisms triggered by vaccination support longer-term protection. Methods: Long-term clinical studies using hepatitis A (HAV) or A/B vaccines (HAB) containing 720 or 1440 Enzyme-linked immunosorbent assay Units (EU) of hepatitis A virus antigen were identified. Duration of persistence of antibodies and possible protection was determined by descriptively comparing antibody geometric mean concentration (GMC) kinetics, as well as GMC (95% confidence interval) at 15 years post-vaccination across studies. Immunological mechanism studies describing hepatitis A vaccination were identified. Results: One study in children 12–15 years (2-dose HAB 720) and four in adults (2-dose HAV 1440 and 3-dose HAB 720) showed comparable GMC kinetics and per year rates of change up to 15 years. At 15 years, the GMC in children [414.7 mEU/ml (336.9; 510.5)] was in the same range as in adults [range 282.6 (217.6; 367.0) to 550.1 (416.0; 727.4)]. Based on these data, mathematical model predictions from adult studies (showing?>?85% protected at 50 years) were deemed likely to also apply to children. Studies identified, both humoral and cell-mediated responses are induced following vaccination. Conclusion: Based on comparable antibody data in adults and children up to 15 years, similar longer-term antibody persistence is expected in children with 2-dose inactivated hepatitis A 720 containing vaccine at least up to 50 years. Accordingly, improving routine childhood hepatitis A vaccination coverage could protect against more severe disease in adulthood. Fig. 1Plain language summary Trial Registration: ClinicalTrials.gov identifiers, NCT00875485, NCT01000324, NCT01037114, NCT00289757, NCT00291876.