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The inherent ambiguity in reconstructed images from coherent diffraction imaging (CDI) poses an intrinsic challenge, as images derived from the same dataset under varying initial conditions often display inconsistencies. This study introduces a method that employs the Noise2Noise approach combined with neural networks to effectively mitigate these ambiguities. We applied this methodology to hundreds of ambiguous reconstructed images retrieved from a single diffraction pattern using a conventional retrieval algorithm. Our results demonstrate that ambiguous features in these reconstructions are effectively treated as inter‐reconstruction noise and are significantly reduced. The post‐Noise2Noise treated images closely approximate the average and singular value decomposition analysis of various reconstructions, providing consistent and reliable reconstructions. [ABSTRACT FROM AUTHOR]

A library of water-soluble dynamic single-chain polymeric nanoparticles (SCPN) was prepared using a controlled radical polymerisation technique followed by the introduction of functional groups, including probes at targeted positions. The combined tools of electron paramagnetic resonance (EPR) and Overhauser dynamic nuclear polarization (ODNP) reveal that these SCPNs have structural and surface hydration properties resembling that of enzymes.

Protein aggregation plays a critical role in the pathogenesis of neurodegenerative diseases, and the mechanism of its progression is poorly understood. Here, we examine the structural and dynamic characteristics of transiently evolving protein aggregates under ambient conditions by directly probing protein surface water diffusivity, local protein segment dynamics, and interprotein packing as a function of aggregation time, along the third repeat domain and C terminus of Δtau187 spanning residues 255-441 of the longest isoform of human tau. These measurements were achieved with a set of highly sensitive magnetic resonance tools that rely on site-specific electron spin labeling of Δtau187. Within minutes of initiated aggregation, the majority of Δtau187 that is initially homogeneously hydrated undergoes structural transformations to form partially structured aggregation intermediates. This is reflected in the dispersion of surface water dynamics that is distinct around the third repeat domain, found to be embedded in an intertau interface, from that of the solvent-exposed C terminus. Over the course of hours and in a rate-limiting process, a majority of these aggregation intermediates proceed to convert into stable β-sheet structured species and maintain their stacking order without exchanging their subunits. The population of β-sheet structured species is >5% within 5 min of aggregation and gradually grows to 50-70% within the early stages of fibril formation, while they mostly anneal block-wisely to form elongated fibrils. Our findings suggest that the formation of dynamic aggregation intermediates constitutes a major event occurring in the earliest stages of tau aggregation that precedes, and likely facilitates, fibril formation and growth.

Dimethyl sulfoxide (DMSO) is a common solvent and biological additive possessing well-known utility in cellular cryoprotection and lipid membrane permeabilization, but the governing mechanisms at membrane interfaces remain poorly understood. Many studies have focused on DMSO-lipid interactions and the subsequent effects on membrane-phase behavior, but explanations often rely on qualitative notions of DMSO-induced dehydration of lipid head groups. In this work, surface forces measurements between gel-phase dipalmitoylphosphatidylcholine membranes in DMSO-water mixtures quantify the hydration- and solvation-length scales with angstrom resolution as a function of DMSO concentration from 0 mol% to 20 mol%. DMSO causes a drastic decrease in the range of the steric hydration repulsion, leading to an increase in adhesion at a much-reduced intermembrane distance. Pulsed field gradient NMR of the phosphatidylcholine (PC) head group analogs, dimethyl phosphate and tetramethylammonium ions, shows that the ion hydrodynamic radius decreases with increasing DMSO concentration up to 10 mol% DMSO. The complementary measurements indicate that, at concentrations below 10 mol%, the primary effect of DMSO is to decrease the solvated volume of the PC head group and that, from 10 mol% to 20 mol%, DMSO acts to gradually collapse head groups down onto the surface and suppress their thermal motion. This work shows a connection between surface forces, head group conformation and dynamics, and surface water diffusion, with important implications for soft matter and colloidal systems.

Dimethyl sulfoxide (DMSO) has been broadly used in biology as a cosolvent, a cryoprotectant, and an enhancer of membrane permeability, leading to the general assumption that DMSO-induced structural changes in cell membranes and their hydration water play important functional roles. Although the effects of DMSO on the membrane structure and the headgroup dehydration have been extensively studied, the mechanism by which DMSO invokes its effect on lipid membranes and the direct role of water in this process are unresolved. By directly probing the translational water diffusivity near unconfined lipid vesicle surfaces, the lipid headgroup mobility, and the repeat distances in multilamellar vesicles, we found that DMSO exclusively weakens the surface water network near the lipid membrane at a bulk DMSO mole fraction (XDMSO) of 0.1, DMSO enters the lipid interface and restricts the lipid headgroup motion. We postulate that DMSO acts as an efficient cryoprotectant even at low concentrations by exclusively disrupting the water network near the lipid membrane surface, weakening the cohesion between water and adhesion of water to the lipid headgroups, and so mitigating the stress induced by the volume change of water during freeze-thaw.

Elucidating the physical effect of cholesterol (Chol) on biological membranes is necessary towards rationalizing their structural and functional role in cell membranes. One of the debated questions is the role of hydration water in Chol-embedding lipid membranes, for which only little direct experimental data are available. Here, we study the hydration dynamics in a series of Chol-rich and depleted bilayer systems using an approach termed (1)H Overhauser dynamic nuclear polarization (ODNP) NMR relaxometry that enables the sensitive and selective determination of water diffusion within 5-10 Å of a nitroxide-based spin label, positioned off the surface of the polar headgroups or within the nonpolar core of lipid membranes. The Chol-rich membrane systems were prepared from mixtures of Chol, dipalmitoyl phosphatidylcholine and/or dioctadecyl phosphatidylcholine lipid that are known to form liquid-ordered, raft-like, domains. Our data reveal that the translational diffusion of local water on the surface and within the hydrocarbon volume of the bilayer is significantly altered, but in opposite directions: accelerated on the membrane surface and dramatically slowed in the bilayer interior with increasing Chol content. Electron paramagnetic resonance (EPR) lineshape analysis shows looser packing of lipid headgroups and concurrently tighter packing in the bilayer core with increasing Chol content, with the effects peaking at lipid compositions reported to form lipid rafts. The complementary capability of ODNP and EPR to site-specifically probe the hydration dynamics and lipid ordering in lipid membrane systems extends the current understanding of how Chol may regulate biological processes. One possible role of Chol is the facilitation of interactions between biological constituents and the lipid membrane through the weakening or disruption of strong hydrogen-bond networks of the surface hydration layers that otherwise exert stronger repulsive forces, as reflected in faster surface water diffusivity. Another is the concurrent tightening of lipid packing that reduces passive, possibly unwanted, diffusion of ions and water across the bilayer.

Knowing the topology and location of protein segments at water-membrane interfaces is critical for rationalizing their functions, but their characterization is challenging under physiological conditions. Here, we debut a unique spectroscopic approach by using the hydration dynamics gradient found across the phospholipid bilayer as an intrinsic ruler for determining the topology, immersion depth, and orientation of protein segments in lipid membranes, particularly at water-membrane interfaces. This is achieved through the site-specific quantification of translational diffusion of hydration water using an emerging tool, (1)H Overhauser dynamic nuclear polarization (ODNP)-enhanced NMR relaxometry. ODNP confirms that the membrane-bound region of α-synuclein (αS), an amyloid protein known to insert an amphipathic α-helix into negatively charged phospholipid membranes, forms an extended α-helix parallel to the membrane surface. We extend the current knowledge by showing that residues 90-96 of bound αS, which is a transition segment that links the α-helix and the C terminus, adopt a larger loop than an idealized α-helix. The unstructured C terminus gradually threads through the surface hydration layers of lipid membranes, with the beginning portion residing within 5-15 Å above the phosphate level, and only the very end of C terminus surveying bulk water. Remarkably, the intrinsic hydration dynamics gradient along the bilayer normal extends to 20-30 Å above the phosphate level, as demonstrated with a peripheral membrane protein, annexin B12. ODNP offers the opportunity to reveal previously unresolvable structure and location of protein segments well above the lipid phosphate, whose structure and dynamics critically contribute to the understanding of functional versatility of membrane proteins.

Chlorhexidine dodecyl sulfate (CHX-DS) was synthesized and characterized via single-crystal X-ray diffraction (SC-XRD), 1H nuclear magnetic resonance (NMR) spectroscopy, 1H nuclear Overhauser effect spectroscopy (NOESY), and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR). The solid-state structure, comprising a 1 : 2 stoichiometric ratio of chlorhexidine cations [C22H30Cl2N10]2+ to dodecyl sulfate anions [C12H25SO4]−, is the first report of chlorhexidine isolated with a surfactant. CHX-DS exhibits broad-spectrum antibacterial activity and demonstrates superior efficacy for reducing bacteria-generated volatile sulfur compounds (VSCs) as compared to chlorhexidine gluconate (CHG). The minimum inhibitory concentrations (MICs) of CHX-DS were 7.5, 2.5, 2.5, and 10 μM for S. enterica, E. coli, S. aureus, and S. mutans, respectively. Furthermore, MIC assays for E. coli and S. mutans demonstrate that CHX-DS and CHX exhibit a statistically significant efficacy enhancement in 2.5 μM treatment as compared to CHG. CHX-DS was incorporated into SBA-15, a mesoporous silica nanoparticle (MSN) framework, and its release was qualitatively measured via UV-vis in aqueous media, which suggests its potential as an advanced functional material for drug delivery applications. [ABSTRACT FROM AUTHOR]

Electrospray-assisted laser desorption/ionization (ELDI) combined with mass spectrometry allows chemical and biochemical compounds to be characterized directly from hydrophilic and hydrophobic organic solutions mixed with carbon powders under ambient conditions. Organic and inorganic compounds dissolved in polar or nonpolar solvent such as methanol, tetrahydrofuran, ethyl acetate, toluene, dichloromethane, or hexane can be detected using this ambient ionization technique without prior pretreatment. We have used this technique to monitor the progress in several ongoing reactions: the epoxidation of chalcone in ethanol, the chelation of ethylenediaminetetraacetic acid with copper and nickel ions in aqueous solution, the chelation of 1,l0-phenanthroline with iron(II) in methanol, and the tryptic digestion of cytochrome c in aqueous solution. Liquid-ELDI analyses simply require irradiation of the surface of the sample solution with a pulsed ultraviolet laser; the laser energy is adsorbed by the carbon powder presuspended in the sample solution; the absorbed laser energy is then transferred to the surrounding solvent and to the analyte molecules in the solution, leading to their desorption; the desorbed gaseous analyte molecules are then postionized within an electrospray (ESI) plume to generate ESI-like analyte ions.

What is known and objective: Adverse drug events (ADEs) are a major public health concern worldwide and may prolong hospital stays, causing a burden on the healthcare system and increasing the associated costs. Therefore, optimizing medication use and reducing ADEs are priorities for public health. Medication safety can be monitored and improved by identifying ADEs. The utilization of diagnoses coded according to the International Statistical Classification of Diseases and Related Health Problems (ICD) system for the identification of ADEs has been firmly established. In Taiwan, however, the validity of recording ADEs on the basis of inpatient ICD‐10‐CM T codes has not been evaluated. Therefore, this study investigated the potential usefulness of ICD‐10‐CM T codes in routine hospital data for the identification of ADEs and for increasing the rate of reporting. Methods: We use hospital claims data of hospitalized patients from one medical centre in northern Taiwan between 1 July 2016 and 30 June 2018. We defined an ADE to have taken place if an ICD‐10‐CM T code was present among the primary or secondary diagnosis codes. The inpatients who were discharged with T codes in a primary or secondary diagnosis were identified by the computerized T code information platform, and the retrospective review of the medical charts was performed by pharmacists to confirm the ADEs. Results and discussion: 1384 inpatients who were discharged with the relevant T codes in a primary or secondary diagnosis were identified during the study period. Code T36 (poisoning by, adverse effect of or underdosing of systemic antibiotics) was the most common code, accounting for 56.6%, followed by T42 (17.7%; poisoning by, adverse effect of or underdosing of antiepileptic, sedative‐hypnotic or antiparkinsonism drug). Overall, 789 clinically significant ADEs were identified after medical chart review. The dermatologic system was the most commonly involved. The overall positive predictive value for a flagged code representing an ADE was 57%. Furthermore, the use of T codes to confirm the number of ADE cases increased the ADE reporting rate by 9.17%. What is new and conclusion: The PPV of ICD‐10‐CM T codes analysed in our study was insufficient for identifying ADEs during hospitalization. The sensitivity and specificity of this were inadequate. However, the T code system can be used as an auxiliary resource for pharmacists to identify potential ADEs and report the information as prompts on the physician order entry system. When a physician prescribes a drug that may cause an ADE in a patient, an alert is issued to ensure medication safety. In conclusion, the T codes did not perform well in our study and caution should be exercised in their use to identify ADEs on their own. [ABSTRACT FROM AUTHOR]

What is known and objective: Gut microbiota plays an important role in shaping immune responses. Several studies have reported that antibiotics may alter gut microbiota diversity and compromise the therapeutic response to immune checkpoint inhibitors (ICIs). Nevertheless, the impact of a specific class of antibiotics on ICIs therapy is still not known. The aim of this study was to analyse the influence of antibiotics on the clinical outcomes of non‐small cell lung cancer (NSCLC) patients treated with ICIs and to compare the effects of fluoroquinolones vs. other broad‐spectrum antibiotics. Methods: This retrospective cohort study (n = 340) analysed data from Chang Gung Research Database, which comprises work from seven medical institutions in Taiwan. Patients with NSCLC who received ICIs between January 2016 and March 2019 were evaluated. The data of patients who received antibiotics (ie fluoroquinolone) within 30 days prior to ICIs therapy were analysed. Overall survival (OS) was the goal of our study and was calculated from the time the ICIs therapy start. Survival analysis was estimated using the Kaplan‐Meier and Cox statistics. Results: A total of 340 patients were identified for analysis. Of the 340 patients, only over one third (38%) of patients received antibiotics 30 days prior to ICI therapy. These patients exhibited a shorter OS compared with those not receiving antibiotics (median OS, 266 days vs. 455 days; hazard ratio (HR), 2.9; 95% confidence interval (CI), 1.1–8.1, p = 0.003). In this study, 127 out of 128 patients who were exposed to antibiotics had received at least one broad‐spectrum antibiotic. We observed patients who had received fluoroquinolone had a shorter OS compared with those receiving other broad‐spectrum antibiotics (median OS, 121 days vs. 370 days; HR, 1.582; 95% CI 1.007–2.841; p = 0.047). What is new and conclusion: Antibiotic treatment, especially fluoroquinolone, prior to ICIs therapy was associated with poorer clinical efficacy in NSCLC patients. Antibiotics should not be withheld when there is a clear need for them despite the possibility of interfering with the microbiome, which may, in turn, adversely affect the ICI's effectiveness. However, one should consider avoiding the use of fluoroquinolones antibiotics. [ABSTRACT FROM AUTHOR]

Background: Pseudoprogression is difficult to diagnose in patients undergoing immunotherapy. Subjective response assessment is still common in clinical practice.Purpose: To evaluate the differences between response evaluation criteria in solid tumors version 1.1 (RECIST 1.1), immune-related response criteria (irRC), and modified RECIST 1.1 for immunotherapy (iRECIST) through semi-automatic software, and to compare iRECIST-based response evaluation with subjective assessment.Material and Methods: The best overall response of each patient based on RECIST 1.1, irRC, and iRECIST was determined on CT scans through semi-automatic software and the differences between the criteria were evaluated. Criteria-based response evaluation through semi-automatic software was compared with subjective assessment on radiology report by correlating the best overall response to overall survival.Results: A total of 21 patients were included (five patients with melanoma, 12 patients with non-small-cell lung cancer, and four patients with hepatocellular carcinoma). Two patients with progressive disease by RECIST 1.1 but non-progressive disease by irRC and iRECIST eventually experienced tumor response and had favorable outcomes, indicating pseudoprogression. The survival difference between patients with non-progressive disease and progressive disease was better stratified through iRECIST-based response evaluation (P = 0.078) than that through subjective assessment (P = 0.501).Conclusion: Pseudoprogression in immunotherapy may be captured through semi-automatic software utilizing irRC or iRECIST criteria. iRECIST-based response evaluation may provide a better survival stratification compared with subjective assessment. [ABSTRACT FROM AUTHOR]