Prediction of Novel Trigonal Chloride Superionic Conductors as Promising Solid Electrolytes for All-Solid-State Lithium Batteries.

Recently emerging lithium ternary chlorides have attracted increasing attention for solid-state electrolytes (SSEs) due to their favorable combination between ionic conductivity and electrochemical stability. However, a noticeable discrepancy in Li-ion conductivity persists between chloride SSEs and organic liquid electrolytes, underscoring the need for designing novel chloride SSEs with enhanced Li-ion conductivity. Herein, an intriguing trigonal structure (i.e., Li3SmCl6 with space group P3112) is identified using the global structure searching method in conjunction with first-principles calculations, and its potential for SSEs is systematically evaluated. Importantly, the structure of Li3SmCl6 exhibits a high ionic conductivity of 15.46 mS cm-1 at room temperature due to the 3D lithium percolation framework distinct from previous proposals, associated with the unique in-plane cation ordering and stacking sequences. Furthermore, it is unveiled that Li3SmCl6 possesses a wide electrochemical window of 0.73-4.30 V vs Li+/Li and excellent chemical interface stability with high-voltage cathodes. Several other Li3MCl6 (M = Er, and In) materials with isomorphic structures to Li3SmCl6 are also found to be potential chloride SSEs, suggesting the broader applicability of this structure. This work reveals a new class of ternary chloride SSEs and sheds light on strategy for structure searching in the design of high-performance SSEs.

A Nomogram for Predicting Overall Survival of Patients With Primary Spinal Cord Glioblastoma.

OBJECTIVE: Primary spinal cord glioblastoma (PSCGBM) is a rare malignancy with a poor prognosis. To date, no prognostic nomogram for this rare disease was established. Hence, we aimed to develop a nomogram to predict overall survival (OS) of PSCGBM. METHODS: Clinical data of patients with PSCGBM was retrospectively collected from the neurosurgery department of Soochow University Affiliated Second Hospital and the Surveillance Epidemiology and End Results database. Information including age, sex, race, tumor extension, extent of resection, adjuvant treatment, marital status, income, year of diagnosis and months from diagnosis to treatment were recorded. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for PSCGBM. A nomogram was constructed to predict 1-year, 1.5-year, and 2-year OS of PSCGBM. RESULTS: A total of 132 patients were included. The 1-year, 1.5-year, and 2-year OS were 45.5%, 29.5%, and 18.9%, respectively. Four variables: age groups, tumor extension, extent of resection, and adjuvant therapy, were identified as independent prognostic factors. The nomogram showed robust discrimination with a C-index value for the prediction of 1-year OS, 1.5-year OS, and 2-year of 0.71 (95% confidence interval [CI], 0.61-0.70), 0.72 (95% CI, 0.62-0.70), and 0.70 (95% CI, 0.61-0.70), respectively. The calibration curves exhibited high consistencies between the predicted and observed survival probability in this cohort. CONCLUSION: We have developed and internally validated a nomogram for predicting the survival outcome of PSCGBM for the first time. The nomogram has the potential to assist clinicians in making individualized predictions of survival outcome of PSCGBM.

Chemical Bath Deposited Antimony Oxide Thin Films for Efficient Perovskite Solar Cells.

The metal oxide electron transport layers (ETLs) of n-i-p perovskite solar cells (PSCs) are dominated by TiO2 and SnO2, while the efficacy of the other metal oxide ETLs still lags far behind. Herein, an emerging, economical, and environmentally friendly metal oxide, antimony oxide (Sb2Ox, x = 2.17), prepared by chemical bath deposition is reported as an alternative ETL for PSCs. The deposited Sb2Ox film is amorphous and very thin (∼10 nm) but conformal on rough fluorine-doped tin oxide substrates, showing matched energy levels, efficient electron extraction, and then reduced nonradiative recombination in PSCs. The champion PSC based on the Sb2Ox ETL delivers an impressive power conversion efficiency of 24.7% under one sun illumination, which represents the state-of-the-art performance of all metal oxide ETL-based PSCs. Additionally, the Sb2Ox-based devices show improved operational and thermal stability compared to their SnO2-based counterparts. Armed with these findings, we believe this work offers an optional ETL for perovskites-based optoelectronic devices.

Acoustic vibration promotes in vitro expansion of human embryonic stem cells.

OBJECTIVES: This study aimed to investigate the effect of acoustic vibration on the pluripotency of human embryonic stem cells (hESCs) and evaluate cell proliferation and self-renewal ability post-treatment. METHODS: The human ES cell line H1 was used for the experiments. hESCs were treated with an acoustic vibration device. Their proliferative ability was subsequently detected using a colony formation assay, while the expression of pluripotency-related markers was detected via immunofluorescence staining. Finally, changes in gene expression levels were examined using quantitative polymerase chain reaction (qPCR) in the presence of appropriate primers. RESULTS: Compared with normal cells in the control group, the morphology of experimental cells subjected to acoustic vibration did not significantly change. Contrastingly, the colony-forming efficiency of the experimental cells significantly increased. Immunofluorescence staining results showed the cells in experimental group were positive for the pluripotency markers NANOG, octamer-binding transcription factor 4 gene (OCT4), and SRY (sex determining region Y)-box 2 (SOX2). In addition, the expression levels of pluripotency genes NANOG, OCT4, SOX2, and Yes-associated protein (YAP)-related genes were up-regulated following acoustic vibration. CONCLUSIONS: Our results revealed that acoustic vibration enhanced the proliferative ability of hESCs and increased the expression levels of NANOG, OCT4, SOX2, and YAP-related genes, indicating that acoustic vibration can optimize the self-renewal ability of hESCs and that the YAP signaling pathway may play a critical role in the functional process of acoustic vibration.

Establishment of a normal control model of children's brain 18-fluorodeoxyglucose positron emission tomography and analysis of the changing pattern in patients aged 0-14 years.

Background: It is difficult to obtain 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) data from normal children, and changes in brain metabolism in children due to growth and development are poorly understood. For the first time, we established a normal control model of brain 18FDG-PET in children and evaluated its feasibility. The association of PET with age in children aged 0-14 years was analyzed. This study aimed to establish a normal control model of brain 18FDG-PET in children for the first time and to verify its feasibility, and to analyze the trend of PET with age in children aged 0-14 years. Methods: In this retrospective cohort study, the 18FDG-PET imaging data of patients with no epileptiform discharge involvement contralateral to the epileptogenic zone were consecutively collected from January 2015 to June 2022 according to strictly defined screening criteria. For the normal control data, the hemisphere contralateral to the epileptogenic zone was mirrored and spliced to form an intact brain. The cohort of children aged 0-14 years was divided into 14 groups according age by year. Subsequently, patients who underwent lesionectomy with clear hypometabolism that roughly coincided with the extent of surgical resection were examined. The PET scan was compared with the control model, and the ratio of overlapping parts (hypometabolic areas ∩ surgical resection area) to hypometabolic parts (ROH) was calculated. Multiple regression analysis was performed on the normal control model for every 3- to 4-year age interval. Results: A total of 159 normal control models were established. Five patients were randomly selected to verify the reliability of each yearly model. The average ROH was 0.968. Metabolism increasing with age in the different brain regions was observed at ages 0-2~, 3-5~, and 6-10 years. No age-related metabolic increase or decrease was found in the 10- to 14-year-old group. The metabolism in the 7- to 8-year-old group was higher than that in the 13- to 14-year-old group. Conclusions: With strict screening criteria, the method of mirroring the contralateral hemisphere of the epileptic zone and splicing it into a complete brain as a means of creating a normal control group is feasible. The method offers convenience to the studies that lack healthy pediatric controls. Children under 10 years of age (especially 0-6 years old) experience considerable metabolic changes year on year. After the age of 10 years, the changes in metabolism gradually decrease, and metabolism also slowly decreases. Our findings provide guidance the clinical interpretation of areas with hypometabolism and emphasize the importance of establishing a normal control model of the child's brain, which should not be replaced by an adult model.

The levels of circulating cytokines and risk of neuromyelitis optica spectrum disorder: a Mendelian randomization study.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease affecting the central nervous system (CNS). NMOSD pathogenesis involves systemic inflammation. However, a causal relationship between circulating cytokine levels and NMOSD remains unclear. Methods: Mendelian randomization (MR) approaches were used to investigate the potential association between genetically determined circulating 19 inflammatory cytokines and 12 chemokines levels and the risk of developing NMOSD. Results: After Bonferroni correction, the risk of aquaporin 4-antibody (AQP4-ab)-positive NMOSD was suggested to be causally associated with the circulating levels of three cytokines, including interleukin (IL)-4 [odds ratio (OR): 11.01, 95% confidence interval (CI): 1.16-104.56, P = 0.037], IL-24 (OR: 161.37; 95% CI: 2.46-10569.21, P = 0.017), and C-C motif chemokine 19 (CCL19) (OR: 6.87, 95% CI: 1.78-26.93, P = 0.006). Conclusion: These findings suggest that a genetic predisposition to higher levels of IL-4, IL-24, and CCL19 may exert a causal effect on the risk of AQP4-ab-positive NMOSD. Further studies are warranted to clarify how these cytokines affect the development of AQP4-ab-positive NMOSD.

Animation-guided family empowerment program on perioperative care after neurosurgery: A randomized controlled trial for preventing respiratory complications.

Background: This study aimed to evaluate the effectiveness of using animation as education material for family empowerment program on perioperative care for caregivers whose children were to undergo neurosurgery. Methods: A total of 204 caregivers were randomly assigned to either the face-to-face oral nursing educated group (Oral Group) or the animation-assisted nursing educated group (Animated Group). The nursing education primarily focused on instructing caregivers about the manual vibration method. The primary outcome of interest in this study was participants' knowledge level, collected by a 10-item questionnaire. Secondary outcomes included child patients' clinical data, including hospitalization days, treatments, and signs of pneumonia. Results: Participants in the Animated Group exhibited significantly higher accuracy in perioperative care knowledge assessment, and patients in this group had a lower chance of requiring atomization therapy compared to the Oral Group. Conclusions: The animation-assisted nursing education program effectively enhances pediatric caregivers' knowledge, reduces respiratory complications after surgery, and offers valuable insights for future studies on the use of such programs to instruct caregivers.

Microscale geometrical modulation of PIEZO1 mediated mechanosensing through cytoskeletal redistribution.

The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1's activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints.

Magnetic excitations in strained infinite-layer nickelate PrNiO2 films.

Strongly correlated materials respond sensitively to external perturbations such as strain, pressure, and doping. In the recently discovered superconducting infinite-layer nickelates, the superconducting transition temperature can be enhanced via only ~ 1% compressive strain-tuning with the root of such enhancement still being elusive. Using resonant inelastic x-ray scattering (RIXS), we investigate the magnetic excitations in infinite-layer PrNiO2 thin films grown on two different substrates, namely SrTiO3 (STO) and (LaAlO3)0.3(Sr2TaAlO6)0.7 (LSAT) enforcing different strain on the nickelates films. The magnon bandwidth of PrNiO2 shows only marginal response to strain-tuning, in sharp contrast to the enhancement of the superconducting transition temperature Tc in the doped superconducting samples. These results suggest the bandwidth of spin excitations of the parent compounds is similar under strain while Tc in the doped ones is not, and thus provide important empirics for the understanding of superconductivity in infinite-layer nickelates.

Stress-induced nuclear translocation of ONAC023 improves drought and heat tolerance through multiple processes in rice.

Drought and heat are major abiotic stresses frequently coinciding to threaten rice production. Despite hundreds of stress-related genes being identified, only a few have been confirmed to confer resistance to multiple stresses in crops. Here we report ONAC023, a hub stress regulator that integrates the regulations of both drought and heat tolerance in rice. ONAC023 positively regulates drought and heat tolerance at both seedling and reproductive stages. Notably, the functioning of ONAC023 is obliterated without stress treatment and can be triggered by drought and heat stresses at two layers. The expression of ONAC023 is induced in response to stress stimuli. We show that overexpressed ONAC23 is translocated to the nucleus under stress and evidence from protoplasts suggests that the dephosphorylation of the remorin protein OSREM1.5 can promote this translocation. Under drought or heat stress, the nuclear ONAC023 can target and promote the expression of diverse genes, such as OsPIP2;7, PGL3, OsFKBP20-1b, and OsSF3B1, which are involved in various processes including water transport, reactive oxygen species homeostasis, and alternative splicing. These results manifest that ONAC023 is fine-tuned to positively regulate drought and heat tolerance through the integration of multiple stress-responsive processes. Our findings provide not only an underlying connection between drought and heat responses, but also a promising candidate for engineering multi-stress-resilient rice.

Interface-regulated S-type core-shell PCN-224@TiO2 heterojunction for visible-light-driven generation of singlet oxygen for selective photooxidation of 2-chloroethyl ethyl sulfide.

Selective oxidation of sulfur mustard gas (HD) to non-toxic sulfoxide by the visible-light-catalyzed generation of singlet oxygen (1O2) is a promising degradation strategy. Although PCN-224 can absorb visible light, it suffers from rapid electron-hole recombination and low redox capacity, which limits the performance of HD degradation. Titanium dioxide (TiO2) is an excellent photocatalyst but it lacks visible-light-activity in degrading HD. In this study, PCN-224@TiO2 heterojunction with S-type core-shell structure was synthesized by in-situ growth method to prolong the visible light absorption capacity of TiO2 and inhibit the rapid recombination of PCN-224. The interface formation and internal electric field were optimized by adjusting the Zr/Ti ratio to enhance the charge transfer, redox capacity, electron-hole separation, and visible light absorption. In this study, the formation of heterojunction composites based on Zr-O-Ti linkages is demonstrated by a series of characterization methods. It is demonstrated by experiments and theoretical calculations that PCN-224@TiO2 can generate nearly 100 % 1O2 under visible light conditions without a sacrificial agent, resulting in efficient and selective oxidation of 2-chloroethyl ethyl sulfide (CEES), a simulant of HD, to non-toxic sulfoxide form.

A highly sensitive Golgi-targeted fluorescent probe for the simultaneous detection of malondialdehyde and formaldehyde in living systems and foods.

Malondialdehyde (MDA) and formaldehyde (FA) are highly active carbonyl substances widely present in both biological and abiotic systems. The detection of MDA and FA is of great significance for disease diagnosis and food safety monitoring. However, due to the similarity in structural properties between MDA and FA, very few probes for synergistically detecting MDA and FA were reported. In addition, functional abnormalities in the Golgi apparatus are closely related to MDA and FA, but currently there are no fluorescent probes that can detect MDA and FA in the Golgi apparatus. Therefore, we constructed a simple Golgi-targetable fluorescent probe GHA based on hydrazine moiety as the recognition site to produce a pyrazole structure after reaction with MDA and to generate a CN double bond after reaction with FA, allowing MDA and FA to be distinguished due to different emission wavelengths during the recognition process. The probe GHA has good specificity and sensitivity. Under the excitation of 350 nm, the blue fluorescence was significantly enhanced at 424 nm when the probe reacted with MDA, and the detection limit was 71 nM. At the same time, under the same excitation of 350 nm, the reaction with FA showed a significant enhancement of green fluorescence at 520 nm, with a detection limit of 12 nM for FA. And the simultaneous and high-resolution imaging of MDA and FA in the Golgi apparatus of cells was achieved. In addition, the applications of the probe GHA in food demonstrated it can provide a powerful method for food safety monitoring. In summary, this study offers a promising tool for the synergistic identification and determination of MDA and FA in the biosystem and food, facilitating the revelation of their detailed functions in Golgi apparatus and the monitoring of food safety.

Excellent Electroluminescent Property of Eu3+-Induced Polystyrene-co-poly(acrylic acid) Aggregates (EIPAs) in Polymeric Light-Emitting Diodes.

Eu3+-induced polystyrene-co-poly(acrylic acid) aggregates (EIPAs) were synthesized using a self-assembly approach, and their structures and photophysical characteristics were examined to achieve effective monochromatic red emission in polymer light-emitting diodes (PLEDs). By adjusting the monomer ratio in RAFT polymerization, the size of Eu3+-induced block copolymer nanoaggregates can be regulated, thereby modulating the luminescence intensity. High-performance bilayer polymer light-emitting devices were fabricated using poly(9,9-dioctylfluorene) (PFO) and 2-(tert-butylphenyl)-5-biphenylyl-1,3,4-oxadiazole (PBD) as the host matrix, with EIPAs as the guest dopant. The devices exhibited narrow red emission at 615 nm with a full width at half-maximum (fwhm) of 15 nm across doping concentrations of 1, 3, 5, and 10 wt %. At a doping concentration of 3 wt %, the device achieved a maximum brightness of 1864.48 cd/m2 at 193.82 mA/cm2 and an external quantum efficiency of 3.20% at a current density of 3.5 mA/cm2. These results indicate that incorporating polystyrene-co-poly(acrylic acid) with Eu3+ complexes enhances the excitation and emission intensity, as well as the structural stability of the emitting layer in PLEDs, thereby improving the device performance.

PRRX1-OLR1 axis supports CAFs-mediated lung cancer progression and immune suppression.

OBJECTIVE: To investigate the mechanism by which cancer-associated fibroblasts (CAFs) affect the growth and immune evasion of lung cancer cells. METHODS: Initially, datasets comparing CAFs with normal fibroblasts were downloaded from the GEO dataset GSE48397. Genes with the most significant differential expression were selected and validated using clinical data. Subsequently, CAFs were isolated, and the selected genes were knocked down in CAFs. Co-culture experiments were conducted with H1299 or A549 cells to analyze changes in lung cancer cell growth, migration, and immune evasion in vitro and in vivo. To further elucidate the upstream regulatory mechanism, relevant ChIP-seq data were downloaded from the GEO database, and the regulatory relationships were validated through ChIP-qPCR and luciferase reporter assays. RESULTS: OLR1 was significantly overexpressed in CAFs and strongly correlated with adverse prognosis in lung cancer patients. Knockdown of OLR1 markedly inhibited CAFs' support for the growth and immune evasion of lung cancer cells in vitro and in vivo. ChIP-seq results demonstrated that PRRX1 can promote OLR1 expression by recruiting H3K27ac and H3K4me3, thereby activating CAFs. Knockdown of PRRX1 significantly inhibited CAFs' function, while further overexpression of OLR1 restored CAFs' support for lung cancer cell growth, migration, and immune evasion. CONCLUSION: PRRX1 promotes OLR1 expression by recruiting H3K27ac and H3K4me3, activating CAFs, and thereby promoting the growth, migration, and immune evasion of lung cancer cells.

NADPH mimics the antidepressant effects of exercise in a chronic unpredictable stress rat model.

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.

Causal association of circulating immune cells and lymphoma: A Mendelian randomization study.

Background: Malignant lymphoma (ML) is a group of malignant tumors originating from the lymphatic hematopoietic system. Previous studies have found a correlation between circulating immune cells and ML. Nonetheless, the precise influence of circulating immune cells on ML remains uncertain. Methods: Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and ML risk. A total of four types of immune signatures, median fluorescence intensities, relative cell, absolute cell, and morphological parameters were included. Primary analysis was performed using inverse variance weighting (IVW) to assess the causal relationship between circulating immune cells and the risk of ML. Sensitivity analysis was conducted using Cochran's Q test, the Mendelian randomization Egger regression intercept test, and leave-one-out analysis. Results: ML had a statistically significant effect on immunophenotypes. Twenty-three immunophenotypes were identified to be significantly associated with Hodgkin lymphoma risk through the IVW approach, and the odds ratio values of CD64 on CD14- CD16+ monocyte [2.31, 95% confidence interval (CI) = 1.41-3.79, P1 = 0.001], IgD+ CD24+ B-cell %lymphocyte (2.06, 95% CI = 1.13-3.79, P1 = 0.018), B-cell %lymphocyte (1.94, 95% CI = 1.08-3.50, P1 = 0.027), CD24+ CD27+ B-cell %lymphocyte (1.68, 95% CI = 1.03-2.74, P1 = 0.039), and CD14+ CD16- monocyte %monocyte (1.60, 95% CI = 1.15-2.24, P1 = 0.006) ranked in the top five. Eleven immunophenotypes were identified to be significantly associated with non-Hodgkin lymphoma risk, CD86 on granulocyte (2.35, 95% CI = 1.18-4.69, P1 = 0.015), CD28-CD8+ T-cell absolute count (1.76, 95% CI = 1.03-2.99, P1 = 0.036), CCR2 on myeloid dendritic cell (CD24+ CD27+ B cell, 95% CI = 1.02-1.66, P1 = 0.034), CD3 on effector memory CD8+ T cell (1.29, 95% CI = 1.02-1.64, P1 = 0.012), and natural killer T %lymphocyte (1.28, 95% CI = 1.01-1.62, P1 = 0.046) were ranked in the top five. Conclusion: This study presents compelling evidence indicating the correlation between circulating immune cells and lymphoma, thus providing guidance for future clinical research.

A privacy-preserving platform oriented medical healthcare and its application in identifying patients with candidemia.

Federated learning (FL) has emerged as a significant method for developing machine learning models across multiple devices without centralized data collection. Candidemia, a critical but rare disease in ICUs, poses challenges in early detection and treatment. The goal of this study is to develop a privacy-preserving federated learning framework for predicting candidemia in ICU patients. This approach aims to enhance the accuracy of antifungal drug prescriptions and patient outcomes. This study involved the creation of four predictive FL models for candidemia using data from ICU patients across three hospitals in China. The models were designed to prioritize patient privacy while aggregating learnings across different sites. A unique ensemble feature selection strategy was implemented, combining the strengths of XGBoost's feature importance and statistical test p values. This strategy aimed to optimize the selection of relevant features for accurate predictions. The federated learning models demonstrated significant improvements over locally trained models, with a 9% increase in the area under the curve (AUC) and a 24% rise in true positive ratio (TPR). Notably, the FL models excelled in the combined TPR + TNR metric, which is critical for feature selection in candidemia prediction. The ensemble feature selection method proved more efficient than previous approaches, achieving comparable performance. The study successfully developed a set of federated learning models that significantly enhance the prediction of candidemia in ICU patients. By leveraging a novel feature selection method and maintaining patient privacy, the models provide a robust framework for improved clinical decision-making in the treatment of candidemia.

Synthesis and evaluation of neuroactive steroids with novel pharmacophore at C-21 let identify a compound with advantageous PK profile and higher EC50 and Emax as PAM on GABAA receptor.

Zuranolone (SAGE-217) is a neuroactive steroid (γ-aminobutyric acid)A (GABAA) receptor positive allosteric modulator (PAM) as the first oral drug approved by the FDA in 2023, which is used to treat patients with postpartum depression (PPD). SAGE-217 has a "black box" warning with impairing ability to drive or engage in other potentially hazardous activities. In addition, SAGE-217 can cause CNS depressant effects such as somnolence and confusion, suicidal thoughts and behavior and embryo-fetal toxicity. Based on the structure-activity relationship (SAR) of SAGE-217, a total of 28 neuroactive steroids with novel pharmacophore at C-21 modulated SAGE-217 derivatives were designed and synthesized. The biological activities were evaluated by both synaptic α1ß2γ2 GABAA receptor and extrasynaptic α4ß3δ GABAA receptor cell assays. The optimal compound S28 exhibited much more potent potency and similar efficacy at extrasynaptic GABAA receptor than SAGE-217. Different from above, compound S28 exhibited similar potency and lower efficacy at synaptic GABAA receptor than SAGE-217, which were consistent with the analysis of molecular docking and dynamics simulation results. The appropriate lower efficacy at synaptic GABAA receptor of compound S28 might contribute to reduce the side effects of excessive sedation. Furthermore, compound S28 was demonstrated to have excellent in vivo pharmacokinetic (PK) parameters, robust in vivo pharmacodynamic (PD) effects and good safety profiles. Therefore, compound S28 represents a potentially promising treatment of PPD candidate that warrants further investigation.

Comparison between capillary electrophoresis and fluorescence anisotropy competitive immunoassay for glucagon.

Glucagon plays a crucial role in regulating glucose homeostasis; unfortunately, the mechanisms controlling its release are still unclear. Capillary electrophoresis (CE)- and fluorescence anisotropy (FA)-immunoassays (IA) have been used for online measurements of hormone secretion on microfluidic platforms, although their use in glucagon assays is less common. We set out to compare a glucagon-competitive IA using these two techniques. Theoretical calibration curves were generated for both CE- and FA-IA and results indicated that CE-IA provided higher sensitivity than FA-IA. These results were confirmed in an experiment where both assays showed limits of detection (LOD) of 30 nM, but the CE-IA had ∼300-fold larger sensitivity from 0 to 200 nM glucagon. However, in online experiments where reagents were mixed within the device, the sensitivity of the CE-IA was reduced ∼3-fold resulting in a higher LOD of 70 nM, whereas the FA-IA remained essentially unchanged. This lowered sensitivity in the online CE-IA was likely due to poor sampling by electroosmotic flow from the high salt solution necessary in online experiments, whereas pressure-based sampling used in FA-IA was not affected. We conclude that FA-IA, despite lowered sensitivity, is more suitable for online mixing scenarios due to the ability to use pressure-driven flow and other practical advantages such as the use of larger channels.

Spin-lattice relaxation with non-linear couplings: Comparison between Fermi's golden rule and extended dissipaton equation of motion.

Fermi's golden rule (FGR) offers an empirical framework for understanding the dynamics of spin-lattice relaxation in magnetic molecules, encompassing mechanisms like direct (one-phonon) and Raman (two-phonon) processes. These principles effectively model experimental longitudinal relaxation rates, denoted as T1-1. However, under scenarios of increased coupling strength and nonlinear spin-lattice interactions, FGR's applicability may diminish. This paper numerically evaluates the exact spin-lattice relaxation rate kernels, employing the extended dissipaton equation of motion formalism. Our calculations reveal that when quadratic spin-lattice coupling is considered, the rate kernels exhibit a free induction decay-like feature, and the damping rates depend on the interaction strength. We observe that the temperature dependence predicted by FGR significantly deviates from the exact results since FGR ignores the higher order effects and the non-Markovian nature of spin-lattice relaxation. Our methods can be easily extended to study other systems with nonlinear spin-lattice interactions and provide valuable insights into the temperature dependence of T1 in molecular qubits when the coupling is strong.