Classical Site Research Articles

Stabilization of High‐Valent Molecular Cobalt Sites through Oxidized Phosphorus in Reduced Graphene Oxide for Enhanced Oxygen Evolution Catalysis

AbstractHeterogeneous molecular cobalt (Co) sites represent one type of classical catalytic sites for electrochemical oxygen evolution reaction (OER) in alkaline solutions. There are dynamic equilibriums between Co2+, Co3+ and Co4+ states coupling with OH−/H+ interaction before and during the OER event. Since the emergence of Co2+ sites is detrimental to the OER cycle, the stabilization of high‐valent Co sites to shift away from the equilibrium becomes critical and is proposed as a new strategy to enhance OER. Herein, phosphorus (P) atoms were doped into reduced graphene oxide to link molecular Co2+ acetylacetonate toward synthesizing a novel heterogeneous molecular catalyst. By increasing the oxidation states of P heteroatoms, the linked Co sites were spontaneously oxidized from 2+ to 3+ states in a KOH solution through OH− ions coupling at an open circuit condition. With excluding the Co2+ sites, the as‐derived Co sites with 3+ initial states exhibited intrinsically high OER activity, validating the effectiveness of the strategy of stabilizing high valence Co sites.

Earliest Ancient Maya salt production in southern Belize: excavations at Jay-yi Nah

Salt works along the Yucatan coasts of Mexico and Belize provide a record of salt production for inland trade during the height of Late Classic Maya civilisation (AD 550–800). At the Paynes Creek Salt Works in Belize, production focused on the creation of salt cakes by boiling brine in pots supported over fires in dedicated salt kitchens. Underwater excavations at the Early Classic (AD 250–550) site of Jay-yi Nah now indicate there was a longer and evolving tradition of salt making in the area, one that initially employed large, incurved bowls to meet local or down-the-line trade needs before inland demand for salt soared.

MRI genicular nerve mapping: a novel approach to sagittal genicular nerve localization

Background and objectivesChronic knee pain, including postarthroplasty knee pain, is a major cause of morbidity. Radiofrequency ablation of genicular nerve branches is a treatment option. The literature to date has...

Integration of Plasmonic Ag(I) Clusters and Fe(II) Porphyrinates into Metal–Organic Frameworks for Efficient Photocatalytic CO2 Reduction Coupling with Photosynthesis of Pure H2O2

AbstractEfficient photocatalytic CO2 reduction coupled with the photosynthesis of pure H2O2 is a challenging and significant task. Herein, using classical CO2 photoreduction site iron porphyrinate as the linker, Ag(I) clusters were spatially separated and evenly distributed within a new metal–organic framework (MOF), namely Ag27TPyP‐Fe. With water as electron donors, Ag27TPyP‐Fe exhibited remarkable performances in artificial photosynthetic overall reaction with CO yield of 36.5 μmol g−1 h−1 and ca. 100 % selectivity, as well as H2O2 evolution rate of 35.9 μmol g−1 h−1. Since H2O2 in the liquid phase can be more readily separated from the gaseous products of CO2 photoreduction, high‐purity H2O2 with a concentration up to 0.1 mM was obtained. Confirmed by theoretical calculations and the established energy level diagram, the reductive iron(II) porphyrinates and oxidative Ag(I) clusters within an integrated framework functioned synergistically to achieve artificial photosynthesis. Furthermore, photoluminescence spectroscopy and photoelectrochemical measurements revealed that the robust connection of Ag(I) clusters and iron porphyrinate ligands facilitated efficient charge separation and rapid electron transfer, thereby enhancing the photocatalytic activity.

Stabilization of High-Valent Molecular Cobalt Sites through Oxidized Phosphorus in Reduced Graphene Oxide for Enhanced Oxygen Evolution Catalysis.

Heterogeneous molecular cobalt (Co) sites represent one type of classical catalytic sites for electrochemical oxygen evolution reaction (OER) in alkaline solutions. There are dynamic equilibriums between Co2+, Co3+ and Co4+ states coupling with OH-/H+ interaction before and during the OER event. Since the emergence of Co2+ sites is detrimental to the OER cycle, the stabilization of high-valent Co sites to shift away from the equilibrium becomes critical and is proposed as a new strategy to enhance OER. Herein, phosphorus (P) atoms were doped into reduced graphene oxide to link molecular Co2+ acetylacetonate toward synthesizing a novel heterogeneous molecular catalyst. By increasing the oxidation states of P heteroatoms, the linked Co sites were spontaneously oxidized from 2+ to 3+ states in a KOH solution through OH- ions coupling at an open circuit condition. With excluding the Co2+ sites, the as-derived Co sites with 3+ initial states exhibited intrinsically high OER activity, validating the effectiveness of the strategy of stabilizing high valence Co sites.

Representing Classical Sites in the Ottoman Aegean: Artifice, Absence, and Heritage in Late Eighteenth- and Early Nineteenth-Century Western European Travelogue Illustrations

Representing Classical Sites in the Ottoman Aegean: Artifice, Absence, and Heritage in Late Eighteenth- and Early Nineteenth-Century Western European Travelogue Illustrations

Prevalence of classic and non-classic pain sites of coronary artery disease: a cross-sectional study

Study objectiveThis study aims to assess the prevalence of both classic and non-classic pain sites in patients with ischemic heart disease, emphasizing the importance of recognizing and not disregarding non-classic symptoms.MethodsThis cross-sectional study included 100 patients diagnosed with coronary artery disease (CAD) who were admitted to two major hospitals in Syria. classic pain was identified as pain located in the precordial area, with or without radiation to the neck, jaw, left shoulder or arm. Patients’ demographics and previous medical history were documented to investigate any potential associations with non-classic pain.Results62% of the patients experienced non-classic pain, while 12% had no precordial pain. For those without precordial pain, the most common pain site was the left chest (66.7%). Non-classic pain was significantly associated with smoking, with 72.2% of smokers experiencing non-classic pain compared to 35.7% non-smokers (p = 0.001). Additionally, patients with previous heart disease were more likely to have non-classic pain (71.7%), compared with patients with no history of heart disease (51.1%) (p = 0.03). Other factors such as age, sex, and diabetes were not statistically significant.ConclusionNon-classic pain is common, affecting 62% of individuals, primarily in the right shoulder, right arm, and back. This type of pain could be associated with smoking and prior heart disease. Misdiagnosing coronary artery disease can have serious consequences, as patients with non-classic symptoms may miss important pre-hospital procedures like ECG.

SIRT1 silencing promotes EMT and Crizotinib resistance by regulating autophagy through AMPK/mTOR/S6K signaling pathway in EML4-ALK L1196M and EML4-ALK G1202R mutant non-small cell lung cancer cells.

Most EML4-ALK rearrangement non-small cell lung cancer (NSCLC) patients inevitably develop acquired drug resistance after treatment. The main mechanism of drug resistance is the acquired secondary mutation of ALK kinase domain. L1196M and G1202R are classical mutation sites. We urgently need to understand the underlying molecular mechanism of drug resistance to study the therapeutic targets of mutant drug-resistant NSCLC cells. The silent information regulator sirtuin1 (SIRT1) can regulate the normal energy metabolism of cells, but its role in cancer is still unclear. In our report, it was found that the SIRT1 in EML4-ALK G1202R and EML4-ALK L1196M mutant drug-resistant cells was downregulated compared with EML4-ALK NSCLC cells. The high expression of SIRT1 was related to the longer survival time of patients with lung cancer. Activation of SIRT1 induced autophagy and suppressed the invasion and migration of mutant cells. Further experiments indicated that the activation of SIRT1 inhibited the phosphorylation level of mTOR and S6K by upregulating the expression of AMPK, thus activating autophagy. SIRT1 can significantly enhanced the sensitivity of mutant cells to crizotinib, improved its ability to promote apoptosis of mutant cells, and inhibited cell proliferation. In conclusion, SIRT1 is a key regulator of drug resistant in EML4-ALK L1196M and G1202R mutant cells. SIRT1 may be a novel therapeutic target for EML4-ALK drug resistant NSCLC.

Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23

Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.

Arbidol, an antiviral drug, identified as a sodium channel blocker with anticonvulsant activity.

Sodium channel blockers (SCBs) have traditionally been utilized as anti-seizure medications by primarily targeting the inactivation process. In a drug discovery project aiming at finding potential anticonvulsants, we have identified arbidol, originally an antiviral drug, as a potent SCB. In order to evaluate its anticonvulsant potential, we have thoroughly examined its biophysical properties as well as its effects on animal seizure models. Patch clamp recording was used to investigate the electrophysiological properties of arbidol, as well as the binding and unbinding kinetics of arbidol, carbamazepine and lacosamide. Furthermore, we evaluated the anticonvulsant effects of arbidol using three different seizure models in male mice. Arbidol effectively suppressed neuronal epileptiform activity by blocking sodium channels. Arbidol demonstrated a distinct mode of action by interacting with both the fast and slow inactivation of Nav1.2 channels compared with carbamazepine and lacosamide. A kinetic study suggested that the binding and unbinding rates might be associated with the specific characteristics of these three drugs. Arbidol targeted the classical binding site of local anaesthetics, effectively inhibited the gain-of-function effects of Nav1.2 epileptic mutations and exhibited varying degrees of anticonvulsant effects in the maximal electroshock model and subcutaneous pentylenetetrazol model but had no effect in the pilocarpine-induced status epilepticus model. Arbidol shows promising potential as an anticonvulsant agent, providing a unique mode of action that sets it apart from existing SCBs.

Soil development and ancient Maya land use in the tropical karst landscape: Case of Busiljá, Chiapas, México

AbstractThe soil mantle of the tropical karstic landscapes of Southern Mexico was shaped by specific processes of pedogenesis and long‐term human impacts of ancient Maya agriculture. To understand the interaction between natural and human‐induced soil‐forming processes in the calcareous mountains of Chiapas state, we studied soil toposequences around the Classic Maya site of Budsilhá and related them to the archaeological evidence of settlement and land‐use distribution. Soil chemical analysis, micromorphological observations, and clay mineral identification were carried out in key soil profiles at the main geoforms. Limestone hills are occupied by shallow Rendolls which are usually perceived as incipient soils. However, high content of silicate clay composed of kaolinite and vermiculite and ferruginous clayey soil material observed at macro‐ and microscale backed the hypothesis that these soils were formed from the residues of thick Terra Rossa after their erosion. Swampy lowlands are occupied by thick clayey gleyic soils with clay mineral assemblages similar to those in the upland Rendolls. We suppose that the mineral matrix of the lowland soils is largely derived from the pedosediments of eroded upland Terra Rossa, which lost original ferruginous pigmentation and aggregation due to redoximorphic processes. Some wetland soils contain neoformed gypsum that is atypical for humid tropics; sulfide‐sulfate transformation under fluctuating redox conditions could promote gypsum synthesis. Ancient Maya land use was closely related to soil‐geomorphic conditions: settlements with homegardens occupied calcareous hills, whereas the primary agricultural domain was developed on lowland soils after their drainage by artificial canals.

Hyperintensity in Bilateral Posterior Limbs of Internal Capsule Due to Hypernatremia

Abstract Purpose: Osmotic demyelination syndrome is usually caused by rapid correction of hyponatremia but sometimes develops from acute severe hypernatremia. Studies suggested that serum sodium increasing at the rate of <6~8 mmol/L in 24 hours has a low risk of osmotic demyelination syndrome, but sometimes exceptions present. Aside from the classical sites of involvement, such as pons and basal ganglia, internal capsules are rarely affected. We report a case with acute paraparesis caused by acute hypernatremia-induced extrapontine myelinolysis involving the posterior limbs of bilateral internal capsules. Case: A 54-year-old man was admitted for aseptic encephalitis and moved to the intensive care unit due to poor consciousness and respiratory failure. Although cerebrospinal fluid pleocytosis was improved later, acute hypernatremia due to partial diabetes insipidus developed. He presented acute paraplegia two days later with a negative result on the whole spine MRI. Although the increasing rate of serum sodium did not exceed the recommended safety range, the extrapontine myelinolysis involving posterior limbs of the bilateral internal capsule, as long as the corpus callosum, still developed. The patient regained partial walking ability after one year. Conclusion: This case report extends the spectrum of classical osmotic demyelination in clinical manifestations, image findings, and the causal range of electrolyte derangements.

Synthesis and estrogenic activity of BODIPY-labeled estradiol conjugates

Novel BODIPY–estradiol conjugates have been synthesized by selecting position C-3-O for labeling. The conjugation strategy was based on Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) or etherification. Estradiol derivatives used as azide partners bearing an ω-azidoalkyl function through C4–C8-long linkers have been prepared. CuAAC reactions of estradiol azides with BODIPY alkyne furnished fluorescent 3-O-labeled conjugates bearing the triazole ring as a coupling moiety. Williamson etherifications of 3-O-(ω-bromoalkyl)-17β-estradiol derivatives with BODIPY-OH resulted in labeled conjugates connected with an ether moiety. Interactions of the conjugates with estrogen receptor (ER) were investigated using molecular docking calculations in comparison with estradiol. The conjugates occupied both the classical and alternative binding sites on human ERα, with slightly lower binding affinity to references estradiol and diethystilbestrol. All compounds have displayed reasonable estrogenic activity. They increased the proliferation of ER-positive breast cancer cell line MCF7 contrary to ER-negative SKBR-3 cell line. The most potent compound 13a induced the transcriptional activity of ER in dose-dependent manner in dual luciferase recombinant reporter model and increased progesterone receptor's expression, proving the retained estrogenic activity. The fluorescence of candidate compound 13a co-localised with the ERα. The newly synthesized labeled compounds might serve as good starting point for further development of fluorescent probes for modern biological applications. In addition to studying steroid uptake and transport in cells, e.g. in the processes of biodegradation of estrogen-hormones micropollutants, they could also be utilized in examination of estrogen-binding proteins.

FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist.

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.

Three exonic variants in the COL4A5 gene alter RNA splicing in a minigene assay.

X-linked Alport syndrome (XLAS) is an inherited renal disease caused by rare variants of COL4A5 on chromosome Xq22. Many studies have indicated that single nucleotide variants (SNVs) in exons can disrupt normal splicing process of the pre-mRNA by altering various splicing regulatory signals. The male patients with XLAS have a strong genotype-phenotype correlation. Confirming the effect of variants on splicing can help to predict kidney prognosis. This study aimed to investigate whether single nucleotide substitutions, located within three bases at the 5' end of the exons or internal position of the exons in COL4A5 gene, cause aberrant splicing process. We analyzed 401 SNVs previously presumed missense and nonsense variants in COL4A5 gene by bioinformatics programs and identified candidate variants that may affect the splicing of pre-mRNA via minigene assays. Our study indicated three of eight candidate variants induced complete or partial exon skipping. Variants c.2678G>C and c.2918G>A probably disturb classic splice sites leading to corresponding exon skipping. Variant c.3700C>T may disrupt splicing enhancer motifs accompanying with generation of splicing silencer sequences resulting in the skipping of exon 41. Our study revealed that two missense variants positioned the first nucleotides of the 5' end of COL4A5 exons and one internal exonic nonsense variant caused aberrant splicing. Importantly, this study emphasized the necessity of assessing the effects of SNVs at the mRNA level.

Integron cassettes integrate into bacterial genomes via widespread non-classical attG sites.

Integrons are genetic elements involved in bacterial adaptation which capture, shuffle and express genes encoding adaptive functions embedded in cassettes. These events are governed by the integron integrase through site-specific recombination between attC and attI integron sites. Using computational and molecular genetic approaches, here we demonstrate that the integrase also catalyses cassette integration into bacterial genomes outside of its known att sites. Once integrated, these cassettes can be expressed if located near bacterial promoters and can be excised at the integration point or outside, inducing chromosomal modifications in the latter case. Analysis of more than 5 × 105 independent integration events revealed a very large genomic integration landscape. We identified consensus recombination sequences, named attG sites, which differ greatly in sequence and structure from classical att sites. These results unveil an alternative route for dissemination of adaptive functions in bacteria and expand the role of integrons in bacterial evolution.

Neuroanatomical refinement of Kocher's point for enhanced precision in ventriculostomy: A technical note and a literature review.

This study was designed to assess the effectiveness and safety of using a modified Kocher's point for ventriculostomy using endoscopic third ventriculostomy (ETV) and external ventricular drainage (EVD) in 200 patients at PAR Private Hospital in Erbil, Iraqi Kurdistan. In this retrospective analysis, a total of 200 patients who were diagnosed with obstructive hydrocephalus and underwent ETV and EVD utilizing a modified entry site were included. The revised Kocher point was located 11.5 cm posterior and superior to the nasion, 3 cm laterally, and 0-1 cm before the coronal suture. The use of this modified Kocher's point has brought much improvement in surgical precision and safety. This would minimize incidences of bleeding and misplacement of the catheters. The anatomical structure was well organized, and nothing was challenging in the process of traversing through the foramen of Monro into the third ventricle. It was easily introduced through the modified Kocher point with increasing efficacy and near zero possibility of sustaining injury to the limiting cerebral region. Using the modified point of Kocher provides added reliability and accuracy to ventriculostomy, thereby reducing complications and increasing the overall outcome of surgeries. It overcomes all the drawbacks of classical entry sites and, further, helps in increasing the productivity of ETV and EVD. More research must be done to support the benefits of this modification in other clinical settings.

Monte Carlo global variance reduction method combining source bias and weight window

The global tally problem has a wide range of applications in major research fields such as Monte Carlo simulations of pin-by-pin reactor models and time-dependent particle transport problems in multi-physics coupling calculations. Due to the uneven power distribution of the simulated system, the statistical errors of all tallies are unevenly distributed, resulting in some low global efficiency. For this kind of problem with global characteristics, it is necessary to develop global variance reduction techniques to obtain the accurate distribution of target tallies in the entire space. A large number of global variance reduction algorithms have been studied based on the consideration of flattening global tally error distribution, so as to improve global efficiency. This work focuses on the combination of two efficient global variance reduction algorithms, namely, the uniform tally density algorithm and the weight window algorithm, which belong to source bias and transport process bias, respectively. In tally, a method is proposed to adjust the weight window parameters by using the bias factor of the uniform tally density algorithm. Then, the weight window method will be used to reduce the weight fluctuation caused by the uniform tally density method. In this way, an organic combination of these two algorithms can be realized. A series of comparative tests are carried out based on the Hoogenboom-Martin pressurized water reactor benchmark, and it is verified that the hybrid global variance reduction algorithm proposed in this work is better than the single weight window algorithm or the uniform tally density algorithm. In terms of reducing the maximum error, the global efficiency of the hybrid algorithm is 2.6 times and 3 times that of the weight window algorithm and the uniform tally density algorithm, respectively. In addition, through the comparative analysis of computational asymmetry degree and computational efficiency, it is verified that the uniform tally density algorithm has better performance than the classical uniform fission site algorithm, and the performance advantages of the uniform tally density algorithm are quantitatively evaluated based on some new indicators. The results show that the hybrid global variance reduction algorithm proposed in this work can solve the global tally problem efficiently, thereby further promoting research in related fields.

Using Cs-137 measurements and RUSLE model to explore the effect of land use changes on soil erosion and deposition rates in a mid-sized catchment in southern Italy

In some areas of southern Italy, the change in land use over the last 4–5 decades has increased pressure on land and water resources and caused different forms of soil degradation. In order to mitigate the magnitude of soil erosion, different strategies that include construction of flood control structures and reforestation programs have been done in several areas. However, quantifying the effectiveness of these strategies is difficult in absence of direct measurements of soil erosion. To cover this information gap, the use of distributed numerical models coupled with measurements of the radionuclide cesium-137 (137Cs) offers a good alternative to the classic experimental sites (plot, catchments) that, on the contrary, require long term datasets to produce reliable estimates of soil loss. In this paper, measurements of 137Cs in a floodplain area are firstly described for a representative Calabrian catchment as an example to reconstruct the trend of soil deposition rates during the last six decades. These measurements have been integrated with estimates of soil loss obtained with the Revised Universal Soil Loss Equation (RUSLE) model for which land use maps of different periods are available. The final comparison between estimates of soil erosion provided by the RUSLE at catchment scale and sedimentation rates derived from 137Cs measurements on depositional areas allowed interesting information on the trend of soil erosion and deposition rates in these areas to be obtained.

THU558 Combination Therapy Of Acetyl-CoA Synthetase Inhibitor And Fulvestrant Reverse Epigenetic Alterations Of Metastatic Breast Cancer Cells And Reduce Cancer Cell Proliferation

Abstract Disclosure: A.N. Mogol: None. Z. Madak Erdogan: None. Endocrine therapies exploit the hormone dependencies of the cancer cells in various ways, including by targeting estrogen receptor alpha (ERα) that is expressed by approximately 70% of human breast cancers. After treatment, recurrence and metastasis are still observed in 30-40% of ER+ patients and the 5-year relative overall survival rate for these patients is just 24%. Acetyl-CoA production significantly regulates histone acetylation and gene regulation, which support tumor progression. In our previous study, we showed the synergistic effect of the ERα agonist Fulvestrant (Fulv) and Acetyl-CoA Synthase Inhibitor (ACSI) in reducing cell viability in ER+ metastatic breast cancer (MBC) cells in vitro. To study the synergistic contribution of ACSS2 to endocrine resistance, we used ChIP analysis, which showed that ACSS2 was recruited to ERα binding sites with Fulv treatment in cell line xenograft tumors and PDX samples. We used the CUT&RUN method to investigate specific protein (H3k27ac, ERα and ACSS2) and DNA interactions in ER+ MBC cells globally. Enriched chromatin samples were then used for qPCR and sequencing. Combination therapy of the ACSI and Fulv significantly altered the epigenetic landscape of the breast cancer cells in a manner to decrease cell viability. High histone acetylation at lysine 27 residue was observed in Veh treatment group and combination therapy of ACSI+Fulv further decreased the enrichment of this histone modification in classical ER binding sites. Interestingly, ACSS2 binding was increased with Fulv treatment. Targeting epigenetic alterations caused by cancer cell adaptations is a novel approach that could potentially lead to new therapies to reduce metastasis mortality. Presentation: Thursday, June 15, 2023