Inorganic Composition Modulation of Solid Electrolyte Interphase for Fast Charging Lithium Metal Batteries.

The solid electrolyte interphase (SEI) with lithium fluoride (LiF) is critical to the performance of lithium metal batteries (LMBs) due to its high stability and mechanical properties. However, the low Li ion conductivity of LiF impedes the rapid diffusion of Li ions in the SEI, which leads to localized Li ion oversaturation dendritic deposition and hinders the practical applications of LMBs at high-current regions (>3 C). To address this issue, a fluorophosphated SEI rich with fast ion-diffusing inorganic grain boundaries (LiF/Li3P) is introduced. By utilizing a sol electrolyte that contains highly dispersed porous LiF nanoparticles modified with phosphorus-containing functional groups, a fluorophosphated SEI is constructed and the presence of electrochemically active Li within these fast ion-diffusing grain boundaries (GBs-Li) that are non-nucleated is demonstrated, ensuring the stability of the Li || NCM811 cell for over 1000 cycles at fast-charging rates of 5 C (11 mA cm-2). Additionally, a practical, long cycling, and intrinsically safe LMB pouch cell with high energy density (400 Wh kg-1) is fabricated. The work reveals how SEI components and structure design can enable fast-charging LMBs.

The employment of art therapy to develop empathy and foster wellbeing for junior doctors in a palliative medicine rotation - a qualitative exploratory study on acceptability.

BACKGROUND: The interdisciplinary realm of medical humanities explores narratives and experiences that can enhance medical education for physicians through perspective-taking and reflective practice. However, there is a gap in comprehension regarding its appropriateness at the postgraduate level, especially when utilising art therapists as faculty. This study aims to assess the acceptability of an innovative art therapy-focused educational initiative among junior doctors during a palliative care rotation, with the goal of cultivating empathy and promoting well-being. METHODS: A qualitative research project was conducted at the Division of Supportive and Palliative Care (DSPC) in the National Cancer Centre Singapore (NCCS). The study involved the recruitment of junior doctors who had successfully completed a three-month palliative care rotation program, spanning from January 2020 to April 2021. In a single small-group session lasting 1.5 h, with 3 to 4 participants each time, the individuals participated in activities such as collage making, group reflection, and sharing of artistic creations. These sessions were facilitated by an accredited art therapist and a clinical psychologist, focusing on themes related to empathy and wellbeing. To assess the acceptability of the program, two individual interviews were conducted three months apart with each participant. An independent research assistant utilised a semi-structured question guide that considered affective attitude, burden, perceived effectiveness, coherence, and self-efficacy. Thematic analysis of the transcribed data was then employed to scrutinise the participants' experiences. RESULTS: A total of 20 individual interviews were completed with 11 participants. The three themes identified were lack of pre-existing knowledge of the humanities, promotors, and barriers to program acceptability. CONCLUSIONS: The participants have mixed perceptions of the program's acceptability. While all completed the program in its entirety, the acceptability of the program is impeded by wider systemic factors such as service and manpower needs. It is vital to address these structural limitations as failing to do so risks skewing current ambivalence towards outright rejection of future endeavours to integrate humanities programs into medical education.

Correction: A novel Multi-Level Refined (MLR) knowledge graph design and chatbot system for healthcare applications.

[This corrects the article DOI: 10.1371/journal.pone.0296939.].

Development of a Novel, Potent, and Selective Sialyltransferase Inhibitor for Suppressing Cancer Metastasis.

Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC50 = 7.8 µM) and ST3GAL3 (IC50 = 9.45 µM) relative to ST3GAL1 (IC50 > 400 µM) and ST8SIA4 (IC50 > 100 µM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC50 = 2.6 µM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC50 = 55 µM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.

Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

OBJECTIVES: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. RESULTS: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). CONCLUSION: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

Biological evaluation of sulfonate and sulfate analogues of lithocholic acid: A bioisosterism-guided approach towards the discovery of potential sialyltransferase inhibitors for antimetastatic study.

The naturally occurring bile acid lithocholic acid (LCA) has been a crucial core structure for many non-sugar-containing sialyltranferase (ST) inhibitors documented in literature. With the aim of elucidating the impact of the terminal carboxyl acid substituent of LCA on its ST inhibition, in this present study, we report the (bio)isosteric replacement-based design and synthesis of sulfonate and sulfate analogues of LCA. Among these compounds, the sulfate analogue SPP-002 was found to selectively inhibit N-glycan sialylation by at least an order of magnitude, indicating a substantial improvement in both potency and selectivity when compared to the unmodified parent bile acid. Molecular docking analysis supported the stronger binding of the synthetic analogue in the enzyme active site. Treatment with SPP-002 also hampered the migration, adhesion, and invasion of MDA-MB-231 cells in vitro by suppressing the expression of signaling proteins involved in the cancer metastasis-associated integrin/FAK/paxillin pathway. In totality, these findings offer not only a novel structural scaffold but also valuable insights for the future development of more potent and selective ST inhibitors with potential therapeutic effects against tumor cancer metastasis.

Subarachnoid Haemorrhage Incidence Pattern Analysis with Circular Statistics.

Knowledge about biological rhythms of diseases may not only help in understanding the pathophysiology of diseases but can also help health service policy makers and emergency department directors to allocate resources efficiently. Aneurysmal subarachnoid haemorrhage (SAH) has high rates of morbidity and mortality. The incidence of SAH has been attributed to patient-related factors such as characteristics of aneurysms, smoking, and hypertension. There are studies showing that the incidence of aneurysmal SAH appears to behave in periodic fashions over long time periods. However, there are inconsistencies in the literature regarding the impact of chronobiological factors such as circadian, seasonal, and lunar cycle factors on the occurrence of SAH. In this study, we focused on the analysis of a temporal pattern of SAH (infradian rhythms) with a novel approach using circular statistical methods. We aimed to see whether there is a circular pattern for the occurrence of SAH at all and if so, whether it can be related to known temporal patterns based on available literature. Our study did not support the notion that aneurysmal subarachnoid haemorrhages occur on any specific day in a cycle with specific lengths up to 365 days including specific weekdays, full moon, equinoxes, and solstices. Hence, we found no relationship between SAH incidence and timing. Study in larger populations using similar circular statistical methods is suggested.

Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.

Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.

RNA-based detection of genetically modified plants via current-voltage characteristic measurement.

The widespread adoption of genetically modified (GM) crops has escalated concerns about their safety and ethical implications, underscoring the need for efficient GM crop detection methods. Conventional detection methods, such as polymerase chain reaction, can be costly, lab-bound, and time-consuming. To overcome these challenges, we have developed RapiSense, a cost-effective, portable, and sensitive biosensor platform. This sensor generates a measurable voltage shift (0.1-1 V) in the system's current-voltage characteristics, triggered by an increase in membrane's negative charge upon hybridization of DNA/RNA targets with a specific DNA probe. Probes designed to identify the herbicide resistance gene hygromycin phosphotransferase show a detection range from ∼1 nM to ∼10 µM and can discriminate between complementary, non-specific, and mismatched nucleotide targets. The incorporation of a small membrane sensor to detect fragmented RNA samples substantially improve the platform's sensitivity. In this study, RapiSense has been effectively used to detect specific DNA and fragmented RNA in transgenic variants of Arabidopsis, sweet potato, and rice, showcasing its potential for rapid, on-site GM crop screening.

A novel Multi-Level Refined (MLR) knowledge graph design and chatbot system for healthcare applications.

Imagine having a knowledge graph that can extract medical health knowledge related to patient diagnosis solutions and treatments from thousands of research papers, distilled using machine learning techniques in healthcare applications. Medical doctors can quickly determine treatments and medications for urgent patients, while researchers can discover innovative treatments for existing and unknown diseases. This would be incredible! Our approach serves as an all-in-one solution, enabling users to employ a unified design methodology for creating their own knowledge graphs. Our rigorous validation process involves multiple stages of refinement, ensuring that the resulting answers are of the utmost professionalism and solidity, surpassing the capabilities of other solutions. However, building a high-quality knowledge graph from scratch, with complete triplets consisting of subject entities, relations, and object entities, is a complex and important task that requires a systematic approach. To address this, we have developed a comprehensive design flow for knowledge graph development and a high-quality entities database. We also developed knowledge distillation schemes that allow you to input a keyword (entity) and display all related entities and relations. Our proprietary methodology, multiple levels refinement (MLR), is a novel approach to constructing knowledge graphs and refining entities level-by-level. This ensures the generation of high-quality triplets and a readable knowledge graph through keyword searching. We have generated multiple knowledge graphs and developed a scheme to find the corresponding inputs and outputs of entity linking. Entities with multiple inputs and outputs are referred to as joints, and we have created a joint-version knowledge graph based on this. Additionally, we developed an interactive knowledge graph, providing a user-friendly environment for medical professionals to explore entities related to existing or unknown treatments/diseases. Finally, we have advanced knowledge distillation techniques.

Genome-wide identification of the GRF family in sweet orange (Citrus sinensis) and functional analysis of the CsGRF04 in response to multiple abiotic stresses.

BACKGROUND: Citrus is one of the most valuable fruits worldwide and an economic pillar industry in southern China. Nevertheless, it frequently suffers from undesirable environmental stresses during the growth cycle, which severely restricts the growth, development and yield of citrus. In plants, the growth-regulating factor (GRF) family of transcription factors (TF) is extensively distributed and plays an vital part in plant growth and development, hormone response, as well as stress adaptation. However, the systematic identification and functional analysis of GRF TFs in citrus have not been reported. RESULTS: Here, a genome-wide identification of GRF TFs was performed in Citrus sinensis, 9 members of CsGRFs were systematically identified and discovered to be scattered throughout 5 chromosomes. Subsequently, physical and chemical properties, phylogenetic relationships, structural characteristics, gene duplication events, collinearity and cis-elements of promoter were elaborately analyzed. In particular, the expression patterns of the CsGRF genes in response to multiple phytohormone and abiotic stress treatments were investigated. Predicated on this result, CsGRF04, which exhibited the most differential expression pattern under multiple phytohormone and abiotic stress treatments was screened out. Virus-induced gene silencing (VIGS) technology was utilized to obtain gene silenced plants for CsGRF04 successfully. After the three stress treatments of high salinity, low temperature and drought, the CsGRF04-VIGS lines showed significantly reduced resistance to high salinity and low temperature stresses, but extremely increased resistance to drought stress. CONCLUSIONS: Taken together, our findings systematically analyzed the genomic characterization of GRF family in Citrus sinensis, and excavated a CsGRF04 with potential functions under multiple abiotic stresses. Our study lay a foundation for further study on the function of CsGRFs in abiotic stress and hormone signaling response.

Prenatal hormone stress triggers embryonic cardiac hypertrophy outcome by ubiquitin-dependent degradation of mitochondrial mitofusin 2.

Prenatal stress has been extensively documented as a contributing factor to adverse cardiac development and function in fetuses and infants. The release of glucocorticoids (GCs), identified as a significant stressor, may be a potential factor inducing cardiac hypertrophy. However, the underlying mechanism remains largely unknown. Herein, we discovered that corticosterone (CORT) overload induced cardiac hypertrophy in embryonic chicks and fetal mice in vivo, as well as enlarged cardiomyocytes in vitro. The impaired mitochondria dynamics were observed in CORT-exposed cardiomyocytes, accompanied by dysfunction in oxidative phosphorylation and ATP production. This phenomenon was found to be linked to decreased mitochondrial fusion protein mitofusin 2 (MFN2). Subsequently, we found that CORT facilitated the ubiquitin-proteasome-system-dependent degradation of MFN2 with an enhanced binding of appoptosin to MFN2, serving as the underlying cause. Collectively, our findings provide a comprehensive understanding of the mechanisms by which exposure to stress hormones induces cardiac hypertrophy in fetuses.

Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRASG12C-mutant non-small cell lung cancer.

The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1H-pyrazolo[3,4-b]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC50 value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRASG12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC50 value of 0.58 µM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRASG12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRASG12C mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.

Association Between Risk of Clostridium difficile Infection and Duration of Proton Pump Inhibitor or H2-Receptor Antagonist Use in Hospitalized Patients.

INTRODUCTION: Limited studies have evaluated the association between Clostridium difficile infection (CDI) and the duration of proton pump inhibitor (PPI) or histamine H2-receptor blocker (H2RA) use and provided a cutoff duration for PPI or H2RA use to mitigate a substantially increased risk of CDI. We aimed to evaluate these associations in hospitalized patients using a nationwide insurance claims database. METHODS: We conducted a nested case-control study to identify cases with a first ever record of CDI in a study cohort undergoing PPI or H2RA therapy from the National Health Insurance Database from 2012 to 2018. Each case was matched with one control by age, sex, and calendar year. We used conditional logistic regression to estimate the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC ROC). Youden's J statistic was used to identify the optimal cutoff duration in days for PPI or H2RA use. RESULTS: In the main analysis, the AUC ROC was 0.64 (95% CI 0.63-0.66) and optimal cutoff duration was 15 days for PPI users. The AUC ROC was 0.63 (95% CI 0.62-0.64) and optimal cutoff duration was 16 days for H2RA users. In the sensitivity analyses, the results were similar to those of the main analysis, and the optimal cutoff duration was in the range of 14-15 days. CONCLUSIONS: The optimal cutoff duration for PPI and H2RA use was about 2 weeks. It is necessary to be cautious regarding the risk of CDI in patients taking PPIs or H2RAs for longer than 2 weeks.

Adjustable Cuffless Smartphone Attachment (ACSA+) for Estimation of Blood Pressure Trends: A Pilot Study.

Among the elderly, hypertension remains one of the prevalent health conditions, which requires monitoring and intervention strategies. Nevertheless, regular reporting of blood pressure (BP) from these individuals still poses multiple challenges. However, most people own cell phone and are engaged in phone conversations daily. Here, we propose an adjustable cuffless smartphone attachment (ACSA+) equipped with a PPG sensor for the estimation of BP during phone conversations. ACSA+ can be easily attached to the back of any modern cell phone. ACSA+ will help to continuously collect BP data and store it as a trend line.

Generation of two induced pluripotent stem cell lines from two sporadic amyotrophic lateral sclerosis patients.

Peripheral blood mononuclear cells were obtained from two patients diagnosed with amyotrophic lateral sclerosis (ALS), a 47-year-old female and a 45-year-old male. Induced pluripotent stem cells (iPSCs) were generated using a non-integrating SeV-based method, delivering the transcription factors OCT4, SOX2, c-MYC, and KLF4. These transgene-free iPSC lines exhibited typical pluripotent cell morphology, expressed pluripotency-associated markers, and had tri-lineage differentiation potential. Both iPSC lines were free of mycoplasma contamination and displayed normal karyotypes. The availability of these two cell lines provides a promising opportunity to use sporadic ALS models for investigating the intricate pathological mechanisms of ALS.

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database.

BACKGROUND: Bevacizumab is used for the treatment of advanced malignant tumors; it acts by inhibiting angiogenesis. This study aimed to examine adverse events (AEs) of bevacizumab, especially hemorrhage, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. RESEARCH DESIGN AND METHODS: The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were used to analyze the AEs of bevacizumab using FAERS registration data from January 2004 to September 2022. Clinical information regarding hemorrhagic signals was further analyzed. RESULTS: The number of bevacizumab-associated AE reports was 96,477. Our study found that 892 significant preferred terms (PTs) were spread throughout 25 organ systems. The system organ classes (SOCs) focus on general disorders, administration site conditions, blood and lymphatic system disorders, injury, poisoning, and procedural complications. A total of 2,847 bevacizumab-related hemorrhage cases were reported, and 37 hemorrhagic signals were identified. Hemorrhagic signals were focused on SOC levels in vascular, gastrointestinal, and nervous system disorders. Colorectal, lung, and breast cancers are the three most common malignancies associated with BV-induced hemorrhage. CONCLUSION: The AE report from the present study confirms the majority of label information for bevacizumab, while also identifying new AEs. In addition, this was a large descriptive study of bevacizumab-induced hemorrhage.

Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study.

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 µM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 µM and 0.39 ± 0.05 µM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 µM, 2.04 ± 0.28 µM, and 11.79 ± 0.83 µM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.

Erratum: CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain: Erratum.

[This corrects the article DOI: 10.7150/thno.44364.].