Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating ...mechanism of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-elicited conformational change that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure show a highly dynamic nature: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. This work illuminates a progressive propagating transition towards channel opening, highlighting structural plasticity within the mechanism of action of allosteric effectors.
Wireless photoelectrochemical (PEC) devices promise easy device fabrication as well as reduced losses. Here, the design and fabrication of a stand‐alone ion exchange material‐embedded, Si ...membrane‐based, photoelectrochemical cell architecture with micron‐sized pores is shown, to overcome the i) pH gradient formation due to long‐distance ion transport, ii) product crossover, and iii) parasitic light absorption by application of a patterned catalyst. The membrane‐embedded PEC cell with micropores utilizes a triple Si junction cell as the light absorber, and Pt and IrOx as electrocatalysts for the hydrogen evolution reactions and oxygen evolution reactions, respectively. The solar‐to‐hydrogen efficiency of 7% at steady‐state operation, as compared to an unpatterned ηPV of 10.8%, is mainly attributed to absorption losses by the incorporation of the micropores and catalyst microdots. The introduction of the Nafion ion exchange material ensures an intrinsically safe PEC cell, by reducing the total gas crossover to <0.1%, while without a cation exchange membrane, a crossover of >6% is observed. Only in a pure electrolyte of 1 m H2SO4, a pH gradient‐free system is observed thus completely avoiding the build‐up of a counteracting potential.
A triple junction Si photovoltaic cell is converted into a stand‐alone microporous photoelectrochemical cell with a solar‐to‐hydrogen efficiency of 7% with a stability >40 days. Micropores introduced into a photoelectrochemical cell mitigate ionic resistances caused by long proton diffusion distances between anode and cathode. A Nafion membrane in the micropores ensures O2‐H2 gas separation between compartments.
Background
Human papillomavirus (HPV)‐driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16INK4a in formalin fixed paraffin embedded (FFPE) HNSCC ...from Argentina, Brazil, Colombia, and Peru.
Methods
HPV was genotyped by PCR‐hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16INK4a immunohistochemistry.
Results
HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV‐16 was the most detected. Other HPVs were found in LC. Higher rates of p16INK4a positivity were observed among HPV positive OPC/OCC cases compared to LC cases.
Conclusions
Our results support a role for HPV‐16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.
The fate of selected UV filters (UVFs) was investigated in two soil aquifer treatment (SAT) systems, one supplemented with a reactive barrier containing clay and vegetable compost and the other as a ...traditional SAT reference system. We monitored benzophenone-3 (BP-3) and its transformation products (TPs), including benzophenone-1 (BP-1), 4,4′-dihydroxybenzophenone (4DHB), 4-hydroxybenzophenone (4HB), and 2,2′-dihydroxy-4-methoxybenzophenone (DHMB), along with benzophenone-4 (BP-4) and avobenzone (AVO) in all involved compartments (water, aquifer sediments, and biofilm). The reactive barrier, which enhances biochemical activity and biofilm development, improved the removal of all detected UVFs in water samples. Among monitored UVFs, only 4HB, BP-4, and AVO were detected in sediment and biofilm samples. But the overall retained amounts were several orders of magnitude larger than those dissolved. These amounts were quantitatively reproduced with a specifically developed simple analytical model that consists of a mobile compartment and an immobile compartment. Retention and degradation are restricted to the immobile water compartment, where biofilm absorption was simulated with well-known compound-specific K ow values. The fact that the model reproduced observations, including metabolites detected in the biofilm but not in the (mobile) water samples, supports its validity. The results imply that accumulation ensures significant biodegradation even if the degradation rates are very low and suggest that our experimental findings for UVFs and TPs can be extended to other hydrophobic compounds. Biofilms act as accumulators and biodegraders of hydrophobic compounds.
According to FAO (2024), soil degradation is defined as a change in the soil health status resulting in a diminished capacity of the ecosystem to provide goods and services. In this context, if ...mitigation solutions are not taken in time, continued soil degradation will cause irreparable losses. ...introducing practicable mitigation solutions, such as new amendments, better land use management, and appropriate remediation technologies, is crucial to stopping soil degradation as a key challenge to maintaining soil health. Otherwise, cultivated soils will face severe degradation, threatening food production and security. ...it is necessary to improve soil quality in agricultural systems with the use of appropriate soil control and management, with emphasis on the responses of agricultural systems to soil variations.
Cilostazol is used for the treatment of intermittent claudication. The impact of cilostazol on the outcomes of peripheral vascular interventions (PVIs) remains controversial. This study assesses the ...use and impact of cilostazol on patients undergoing PVI for peripheral arterial disease (PAD).
The Vascular Quality Initiative (VQI) database files for PVI were reviewed. Patients with PAD who underwent PVI for chronic limb threatening-ischemia or claudication were included and divided based on the use of cilostazol preoperatively. After propensity matching for patient demographics and comorbidities, the short-term and long-term outcomes of the 2 groups (preoperative cilostazol use versus no preoperative cilostazol use) were compared. The Kaplan-Meier method was used to determine outcomes.
A total of 245,309 patients underwent PVI procedures and 6.6% (N = 16,366) were on cilostazol prior to intervention. Patients that received cilostazol were more likely to be male (62% vs 60%; P < 0.001), White (77% vs. 75%; P < 0.001), and smokers (83% vs. 77%; P < 0.001). They were less likely to have diabetes mellitus (50% vs. 56%; P < 0.001) and congestive heart failure (14% vs. 23%; P < 0.001). Patient on cilostazol were more likely to be treated for claudication (63% vs. 40%, P < 0.001), undergo prior lower extremity revascularization (55% vs. 51%, P < 0.001) and less likely to have undergone prior minor and major amputation (10% vs. 19%; P < 0.001) compared with patients who did not receive cilostazol. After 3:1 propensity matching, there were 50,265 patients included in the analysis with no differences in baseline characteristics. Patients on cilostazol were less likely to develop renal complications and more likely to be discharged home. Patients on cilostazol had significantly lower rates of long-term mortality (11.5% vs. 13.4%, P < 0.001 and major amputation (4.0% vs. 4.7%, P = 0.022). However, there were no significant differences in rates of reintervention, major adverse limb events, or patency after PVI. Amputation-free survival rates were significantly higher for patients on cilostazol, after 4 years of follow up (89% vs. 87%, P = 0.03).
Cilostazol is underutilized in the VQI database and seems to be associated with improved amputation-free survival. Cilostazol therapy should be considered in all patients with PAD who can tolerate it prior to PVI.
This study aimed to investigate energy, nutrient and food group intakes at breakfast in Spain and to examine for the first time, their relationship to the overall Diet Quality (DQ). The data used ...were from the Spanish ANIBES (anthropometric data, macronutrients and micronutrients intake, practice of physical activity, socioeconomic data and lifestyles in Spain), a cross-sectional study using a nationally representative sample of the Spanish population (9⁻75 years old). DQ was assessed using the Nutrient Rich Foods Index, adapted to total diets (NRF9.3d). Most (>85%) of the Spanish population were regular breakfast consumers, although one in five adolescents were breakfast skippers. Breakfast provides just 16⁻19% of the daily intake of energy. Relative to its daily energy contribution, the Spanish breakfast contributed a higher proportion of daily total carbohydrates, added sugars, sodium, thiamin, riboflavin, folates, iron, potassium, magnesium, phosphorus and especially in calcium. By contrast, the breakfast is low in water intake, protein, dietary fibre, total fat, polyunsaturated fatty acids, beta-carotene and vitamins E and D. In children and teenagers, the most commonly consumed breakfast food was chocolate (mainly as chocolate-flavoured milk and powder), followed by bakery and pastry, whole milk and semi-skimmed milk. In the older groups, a bigger variety of foods were reported. Consumers in the highest NRF9.3d tertile for diet quality tended to have a higher intake of positive nutrients at breakfast than other tertiles, most notably among adults.
Summary
This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) ...patients. Forty‐seven RRMM patients with a median of three prior lines (2–8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1·25 mg/m2 of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1–21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% ≥MR, resulting in a median progression‐free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1‐acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0·04), which also translated into a longer mPFS (9 vs. 2 months; P = 0·014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy.
Trial registration: clinicaltrials.gov identifier: NCT02384083.
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