Oxygen-evolving photosystem II structures during S1-S2-S3 transitions.

Photosystem II (PSII) catalyses the oxidation of water through a four-step cycle of Si states (i = 0-4) at the Mn4CaO5 cluster1-3, during which an extra oxygen (O6) is incorporated at the S3 state to form a possible dioxygen4-7. Structural changes of the metal cluster and its environment during the S-state transitions have been studied on the microsecond timescale. Here we use pump-probe serial femtosecond crystallography to reveal the structural dynamics of PSII from nanoseconds to milliseconds after illumination with one flash (1F) or two flashes (2F). YZ, a tyrosine residue that connects the reaction centre P680 and the Mn4CaO5 cluster, showed structural changes on a nanosecond timescale, as did its surrounding amino acid residues and water molecules, reflecting the fast transfer of electrons and protons after flash illumination. Notably, one water molecule emerged in the vicinity of Glu189 of the D1 subunit of PSII (D1-E189), and was bound to the Ca2+ ion on a sub-microsecond timescale after 2F illumination. This water molecule disappeared later with the concomitant increase of O6, suggesting that it is the origin of O6. We also observed concerted movements of water molecules in the O1, O4 and Cl-1 channels and their surrounding amino acid residues to complete the sequence of electron transfer, proton release and substrate water delivery. These results provide crucial insights into the structural dynamics of PSII during S-state transitions as well as O-O bond formation.

[Usefulness of web-based application for health surveys before and after peripheral blood stem cell harvest from healthy donors].

Health surveys to assess adverse events after peripheral blood stem cell harvest (PBSCH) have conventionally been conducted by phone, but phone calls are suboptimal for conducting frequent surveys. We developed a web-based application (donor app) that enables donors to inform healthcare professionals (HCPs) of their health status as an electronic patient-reported outcome (ePRO). In this prospective observational study, we compared the usefulness of this donor app to phone calls for conducting health surveys. App users reported ePRO daily, and patients called by HCPs reported their health status at least once a week when called. The observation period was from the first administration of granulocyte colony-stimulating factor to the first follow-up visit after PBSCH, excluding the hospitalization period. Each group consisted of eight donors with a median age of 32 years (range: 19-58). Nine (56.3%) were female. There were eight related donors in the phone call group and four in the donor app group. During the observation period, HCPs obtained health status reports more frequently from app users than from phone call recipients (mean proportion of days with reports made during the observation period, 27.0% vs 53.5%; p<0.05). Average time spent by the HCPs for one follow-up and total follow-ups were both significantly shorter when the donor app was used. There were no differences in donor burden or satisfaction with donation. Our study suggests that use of a donor app could provide more detailed health survey data without increasing the burden on donors and HCPs.

[Identification of Δ8-Tetrahydrocannabinol (THC) and Δ9-THC Analogs, with Different Lengths of Alkyl Chain at C-3 Position, in Oil Products Distributed on the Internet].

Since around 2021, products claiming to contain a Δ9-tetrahydrocannabinol (THC) analog with different lengths of alkyl chain at C-3 position have been sold on the internet in Japan. Δ9-THC has a pentyl group derived from the precursor olivetol at the C-3 position. These products include liquid cartridges for electronic cigarettes, herbal products, and gummy products. This study analyzed and determined the ingredients in five oil products distributed on the internet from 2022 to 2023 that claim to contain THC analogs. Samples of each product were used for GC-MS and LC-MS measurements. After isolating and purifying the unknown components from the products, structural analysis was performed by measuring 1H, 13C-NMR and various two-dimensional NMR [HH correlation spectroscopy (H-H COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple-bond correlation (HMBC), and nuclear Overhauser effect spectroscopy (NOESY)]. The analysis identified Δ8-tetrahydrocannabivarin (THCV), Δ9-THCV, Δ8-tetrahydrocannabutol (THCB), Δ9-THCB, Δ8-tetrahydrocannabihexol (THCH), Δ9-THCH, Δ8-3-octyl-THC (THCjd) and Δ9-THCjd. These compounds were Δ8-THC or Δ9-THC analogs with different lengths of alkyl chain at C-3 position. Meanwhile, Δ4(8)-iso-THCV and Δ11-THCB were identified as minor components of the product, and were considered to be the reaction byproducts of the synthesis of the Δ8-THC or Δ9-THC analogs. In the future, there are concerns about the distribution of products containing new THC analogs. Therefore, continuous provision monitoring of newly detected in the products is important.

Estimation of threshold thickness of residual normal tissue in lung dysfunction detectable by dynamic chest radiography: A virtual imaging trial.

BACKGROUND: Dynamic chest radiography (DCR) is a recently developed functional x-ray imaging technique that detects pulmonary ventilation impairment as a decrease in changes in lung density during respiration. However, the diagnostic performance of DCR is uncertain owing to an insufficient number of clinical cases. One solution is virtual imaging trials (VITs), which is an emerging alternative method for efficiently evaluating medical imaging technology via computer simulation techniques. PURPOSE: This study aimed to estimate the typical threshold thickness of residual normal tissue below which the presence of emphysema may be detected by DCR via VITs using virtual patients with different physiques and a user-defined ground truth. METHODS: Twenty extended cardiac-torso (XCAT) phantoms that exhibited changes in lung density during respiration were generated to simulate virtual patients. To simulate a locally collapsed lung, an air sphere was inserted into each lung regions in the phantom. The XCAT phantom was virtually projected using an x-ray simulator. The respiratory changes in pixel value (ΔPV) were measured on the projected air spheres (simulated lesions) to calculate the percentage of decrease (ΔPV%) relative to ΔPVexp-ins in the absence of an air sphere. The relationship between the amount of residual normal tissue and ΔPV% was fitted to a cubic approximation curve (hereafter, performance curve), and the threshold at which the ΔPV% began to decrease (normal-tissuethre) was determined. The goodness of fit for each performance curve was evaluated according to the coefficient of determination (R2) and the 95% confidence interval derived from the standard errors between the measured and theoretical values corresponding to each performance curve. The ΔPV% was also visualized as a color scaling to validate the results of the VITs in both virtual and clinical patients. RESULTS: For each lung region in all body sizes, the ΔPV% decreased as the amount of residual normal tissue decreased and could be defined as a function of the amount of residual normal tissue in front of and behind the simulated lesions with high R2 values. Meanwhile, the difference between the measured and theoretical values corresponding to each performance curve was only partially included in the 95% confidence interval. The normal-tissuethre values were 146.0, 179.5, and 170.9 mm for the upper, middle, and lower lungs, respectively, which were demonstrated in virtual patients and one real patient, where the value of the residual normal tissue was less than that of normal-tissuethre; any reduction in the residual normal tissue was reflected as a reduced ΔPV and depicted as a reduced color intensity. CONCLUSIONS: The performance of DCR-based pulmonary impairment assessment depends on the amount of residual normal tissue in front of and behind the lesion rather than on the lesion size. The performance curve can be defined as a function of the amount of residual normal tissue in each lung region with a specific threshold of normal tissue remaining where lesions become detectable, shown as a decrease in ΔPV. The results of VITs are expected to accelerate future clinical trials for DCR-based pulmonary function assessment.

Association of placental weight at birth with maternal whole blood concentration of heavy metals (cadmium, lead, mercury, selenium, and manganese): The Japan Environment and Children's Study (JECS).

BACKGROUND: Lifelong health is dependent on prenatal growth and development, influenced by the placental intrauterine environment. Charged with dual functions--exchange of oxygen and nutrients as well as a barrier against toxins--the placenta itself is susceptible to environmental exposure to heavy metals. OBJECTIVE: To examine the use of placenta weight as a biomarker for heavy metal exposure using a large Japanese cohort of pregnant women. METHODS: The placenta weight, as a biomarker of exposure to heavy metals (cadmium, lead, and mercury), was investigated using data from the Japan Environment and Children's Study (2011-2014). Selenium and manganese were included as factors directly affecting fetal growth or heavy metal toxicity. Maternal blood samples collected in the second or third trimester were used to measure heavy metal concentrations. The association between maternal blood metal concentrations and placenta weight was explored by applying Z scores and multivariable logistic regression analysis and classifying participants into quartiles (Q1, Q2, Q3, and Q4) according to metal concentrations. RESULTS: This study included a total of 73,005 singleton pregnant women who delivered via live births and met the inclusion criteria. The median heavy metal concentrations in the maternal whole blood were 0.662 ng/g cadmium, 5.85 ng/g lead, 3.61 ng/g mercury, 168 ng/g selenium, and 15.3 ng/g manganese. Regression analysis revealed a significant correlation between placenta weight Z scores and maternal blood metal concentrations: cadmium, 0.0660 (standard error = 0.0074, p < 0.001); selenium, -0.3137 (standard error = 0.0276, p < 0.001); and manganese, 0.1483 (standard error = 0.0110, p < 0.001). CONCLUSION: This study provides a robust examination of the association between heavy metal exposure and placenta weight. Cadmium and manganese showed a positive correlation with significant differences, whereas selenium showed a negative correlation. Essential elements notably affect placenta weight differently. No significant association was noted between lead or mercury and placenta weight.

Proceedings Virtual Imaging Trials in Medicine 2024.

This submission comprises the proceedings of the 1st Virtual Imaging Trials in Medicine conference, organized by Duke University on April 22-24, 2024. The listed authors serve as the program directors for this conference. The VITM conference is a pioneering summit uniting experts from academia, industry and government in the fields of medical imaging and therapy to explore the transformative potential of in silico virtual trials and digital twins in revolutionizing healthcare. The proceedings are categorized by the respective days of the conference: Monday presentations, Tuesday presentations, Wednesday presentations, followed by the abstracts for the posters presented on Monday and Tuesday.

Real-time observation of a metal complex-driven reaction intermediate using a porous protein crystal and serial femtosecond crystallography.

Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO)3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions.