Hepatic amyloidosis in a patient with chronic liver failure: A case report.

BACKGROUND: Amyloidosis is a rare disorder that can be classified into various types, and the most common type is the systemic light chain type. The prognosis of this disease is extremely poor. In general, amyloidosis mainly affects the kidneys and heart and manifests as abnormal proliferation of clonal plasma cells. Cases in which the liver is the primary organ affected by amyloidosis, as in this report, are less common in clinical practice. CASE SUMMARY: A 62-year-old man was admitted with persistent liver dysfunction of unknown cause and poor treatment outcomes. His condition persisted, and he developed chronic liver failure, with severe cholestasis in the later stage that was gradually accompanied by renal injury. Ultimately, he was diagnosed with hepatic amyloidosis through liver biopsy and pathological examination. CONCLUSION: Hepatic amyloidosis rarely occurs in the clinic, and liver biopsy and pathological examination can assist in the accurate and effective diagnosis of this condition.

Piggybacking functionalized DNA nanostructures into live-cell nuclei.

DNA origami nanostructures (DOs) are promising tools for applications including drug delivery, biosensing, detecting biomolecules, and probing chromatin substructures. Targeting these nanodevices to mammalian cell nuclei could provide impactful approaches for probing, visualizing, and controlling biomolecular processes within live cells. We present an approach to deliver DOs into live-cell nuclei. We show that these DOs do not undergo detectable structural degradation in cell culture media or cell extracts for 24 hours. To deliver DOs into the nuclei of human U2OS cells, we conjugated 30-nanometer DO nanorods with an antibody raised against a nuclear factor, specifically the largest subunit of RNA polymerase II (Pol II). We find that DOs remain structurally intact in cells for 24 hours, including inside the nucleus. We demonstrate that electroporated anti-Pol II antibody-conjugated DOs are piggybacked into nuclei and exhibit subdiffusive motion inside the nucleus. Our results establish interfacing DOs with a nuclear factor as an effective method to deliver nanodevices into live-cell nuclei.

The survival and cost-effectiveness analysis of adjunctive Chinese medicine therapy for patients with non-small cell lung cancer: a nationwide cohort study in Taiwan.

Introduction: Cancer, particularly lung cancer, is a significant global healthcare challenge. Non-Small Cell Lung Cancer (NSCLC) constitutes 85% of cases. Patients often seek alternative therapies like Chinese medicine alongside Western treatments. This study investigates the survival outcomes and cost-effectiveness of adjunctive Chinese medicine therapy for NSCLC patients in Taiwan. Methods: We utilized the National Health Insurance Research Database in a retrospective cohort study from 2000 to 2018, focusing on NSCLC patients diagnosed between 2007 and 2013. After propensity score matching 1:5 ratio, then compared patients with and without adjunctive Chinese medicine therapy. Survival outcomes, cost-effectiveness, and sensitivity analyses were conducted. Results: The study involved 43,122 NSCLC patients with 5.76% receiving adjunctive Chinese medicine. There is no significant associated between the risk of death and adjuvant Chinese medicine therapy until 181-365 days of adjuvant treatment could reduce the risk of death (HR = 0.88, 95% CI: 0.80-0.98). Cost-effectiveness analysis showed an incremental cost-effectiveness ratio of 880,908 NT$/year. Conclusion: Adjunctive Chinese medicine therapy, particularly when administered for 181-365 days, significantly reduced the mortality risk among stage IV NSCLC patients. The cost-effectiveness aligns with willingness-to-pay thresholds, indicating economic benefit.

Deletion of endothelial IGFBP5 protects against ischaemic hindlimb injury by promoting angiogenesis.

BACKGROUND: Angiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin-like growth factor (IGF) family is crucial for angiogenesis. Insulin-like growth factor-binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it. METHODS AND RESULTS: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI. CONCLUSION: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.

Palladium-catalyzed selective C-C bond cleavage of keto-vinylidenecyclopropanes: construction of structurally rich dihydrofurans and tetrahydrofurans.

Palladium-catalyzed selective cleavage of the distal C-C bond and proximal C-C bond of keto-vinylidenecyclopropanes by altering the sterically bulky phosphine ligands has been realized. The proximal C-C bond cleavage can be achieved by using dtbpf as a phosphine ligand, affording bicyclic products containing dihydrofuran skeletons in good yields along with broad substrate scope. In proximal C-C bond cleavage reactions, the eight-membered cyclic palladium intermediate plays a key role in the reaction. The [3 + 2] cycloaddition of keto-vinylidenecyclopropanes through the distal C-C bond cleavage can be effectively accomplished with t BuXPhos as a phosphine ligand and ZnCl2 as an additive, delivering bicyclic products containing tetrahydrofuran skeletons in good yields. The further transformation of these bicyclic products has been demonstrated, and the reaction mechanisms of two different C-C bond cleavage reactions have been investigated by control experiments and DFT calculations.

Novel clinical risk stratification and treatment strategies in relapsed/refractory peripheral T-cell lymphoma.

Peripheral T cell lymphoma (PTCL) represents a group of heterogeneous hematological malignancies, which are notoriously challenging to treat and outcomes are typically poor. Over the past two decades, clinical prognostic indices for patient risk stratification have evolved, while several targeted agents are now available to complement combination chemotherapy in the frontline setting or as a salvage strategy. With further understanding of the molecular pathobiology of PTCL, several innovative approaches incorporating immunomodulatory agents, epigenetic therapies, oncogenic kinase inhibitors and immunotherapeutics have come to the forefront. In this review, we provide a comprehensive overview of the progress in developing clinical prognostic indices for PTCL and describe the broad therapeutic landscape, emphasizing novel targetable pathways that have entered early phase clinical studies.

The impact of long-term care interventions on healthcare utilisation among older persons: a scoping review of reviews.

BACKGROUND: As the ageing population grows, the demand for long-term care (LTC) services will rise, concurrently amplifying healthcare utilisation. This review aims to examine and consolidate information on LTC interventions that influence healthcare utilisation among older persons. METHODS: A scoping review was performed through a systematic search in PubMed, EBSCO CINAHL, EBM Reviews - Cochrane Database of Systematic Reviews, Embase, APA PsycInfo, EBM Reviews - Health Technology Assessment, and EBM Reviews - NHS Economic Evaluation Database. Systematic reviews with meta-analyses published between 1 January 2010 and 2 June 2022 among older persons aged 60 and above were included. The characteristics of LTC interventions were mapped to the World Health Organization (WHO) Healthy Ageing Framework. The effect sizes of healthcare utilisations for LTC interventions were recalculated using a random-effects model. The methodological quality was assessed with the AMSTAR-2 checklist, while the quality of evidence for each association was evaluated using GRADE. RESULTS: Thirty-seven meta-analyses were included. The most prominent domain of the healthy ageing framework was managing chronic conditions. One hundred twelve associations between various LTC interventions and healthcare utilisations were identified, with 22 associations impacting healthcare utilisation. Four interventions were supported by suggestive or convincing evidence. Preventive home visits were found to reduce hospital admission (OR: 0.73, 95% CI: 0.59, 0.91, p = 0.005), caregiver integration during discharge planning (OR: 0.68, 95% CI: 0.57, 0.81, p < 0.001), and continuity of care (OR: 0.76, 95% CI: 0.61, 0.95, p = 0.018) reduced hospital readmission, and perioperative geriatric interventions reduced the length of hospital stay (MD: -1.50, 95% CI: -2.24, -0.76, p < 0.001). None of the associations impacted emergency department visits, medication use, and primary care utilisations with convincing evidence. Most reviews received low methodological quality. CONCLUSION: The findings suggest that LTC interventions could benefit from transitioning to a community-based setting involving a multidisciplinary team, including carers. The spectrum of services should incorporate a comprehensive assessment to ensure continuous care.

Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets. miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.

Activating transcription factor 3 is an antitumor gene synergizing with growth differentiation factor 15 to modulate cell growth in human bladder cancer.

BACKGROUND: The functions of activating transcription factor 3 (ATF3) within the human bladder remain unexplored. This study delves into the expressions, functions, and regulatory mechanisms of ATF3 in human bladder cancer. MATERIAL AND METHODS: Gene expressions were determined by immunoblot, RT-qPCR, and reporter assays. Assays of Ki67, colony formation, Matrigel invasion, and the xenograft animal study were used to assess the cell proliferation, invasion, and tumorigenesis in vitro and in vivo. Silico analysis from TCGA database examined the correlations between GDF15 and ATF3 expressions, clinicopathologic features, and progression-free survival rates. RESULTS: Silico analysis confirmed that ATF3 is an antitumor gene, and the expression positively correlates with GDF15 in bladder cancer tissues. Multivariate analysis revealed that low ATF3/GDF15 but not a single low expression of ATF3 is an independent prognostic factor for progression-free survival of bladder cancer patients. Ectopic overexpression of ATF3 downregulated cell proliferation and invasion in bladder cancer cells in vitro, while ATF3-knockdown reversed these results. Knockdown of ATF3 upregulated EMT markers to enhance cell invasion in vitro and downregulated GDF15, NDRG1, and KAI-1 to elevate tumor growth in vivo. The activation of metformin on ATF3 and GDF15 in bladder cancer cells was blocked by SB431542, a TGFß receptor inhibitor. ATF3 positively regulated GDF15 expression in bladder cancer cells through a feedback loop. CONCLUSIONS: Our results identify that ATF3 is a metformin-upregulated antitumor gene. Results of Silico analysis align with cell-based studies suggesting that low ATF3/GDF15 could be a negative prognostic marker for bladder cancer.

Palladium catalyzed stereoselective intramolecular [3 + 2] cycloaddition reactions of (E) & (Z)-ene-vinylidenecyclopropanes.

A palladium-catalyzed ring-opening cyclization of (E) & (Z)-ene-vinylidenecyclopropanes has been developed via an intramolecular [3 + 2] cycloaddition process in the presence of a sterically bulky biaryl phosphine ligand, stereoselectively affording fused cis- & trans-bicyclo[4.3.0] skeletal products in good yields with a broad substrate scope and good functional tolerance. A plausible reaction mechanism was proposed on the basis of previous work and the DFT calculations.

A FRET-based multifunctional fluorescence probe for the simultaneous detection of sulfite and viscosity in living cells.

Viscosity and sulfur dioxide derivatives were significant indicators for the assessment of health threat and even cancers, therefore, on-site and real time detection of viscosity and sulfur dioxide derivatives has obtained considerable attentions. An FRET-based fluorescence probe JZX was designed and synthesized based on a novel energy donor of N,N-diethyl-4-(1H-phenanthro[9,10-d]imidazol-2-yl)benzamide fluorophore. JZX exhibited a large Stokes shift (230 nm), high energy transfer efficiency, wide emission channel gap (135 nm) and excellent stability and biocompatibility. JZX detected sulfur dioxide with low detection limit (55 nM), fast responding (16 min), high selectivity and sensitivity. Additionally, JZX tend to target endoplasmic reticulum of which normal metabolism will be disturbed by the abnormal levels of viscosity and sulfur dioxide derivatives. Prominently, JZX could concurrently detect viscosity and sulfur dioxide derivatives depending on different fluorescence signals in living cells for the screening of cancer cells. Hence, probe JZX will be a promising candidate for the detection of viscosity and sulfur dioxide derivatives, and even for the diagnosis of liver cancers.

The tether function of the anoctamins.

The core functions of the anoctamins are Cl- channel activity and phosphatidylserine (and perhaps other lipids) scrambling. These functions have been extensively studied in various tissues and cells. However, another function of the anoctamins that is less recognized and minimally explored is as tethers at membrane contact sites. This short review aims to examine evidence supporting the localization of the anoctamins at membrane contact sites, their tether properties, and their functions as tethers.

Factors influencing presentation delay among cancer patients: a cross-sectional study in Malaysia.

BACKGROUND: Cancer represents a significant global public health challenge, with escalating incidence rates straining healthcare systems. Malaysia, like many nations, has witnessed a rise in cancer cases, particularly among the younger population. This study aligns with Malaysia's National Strategic Plan for Cancer Control Programme 2021-2025, emphasizing primary prevention and early detection to address cancer's impact. Therefore, we aim to describe the timeliness of cancer care for symptom presentation, socio-demographic, patient, as well as organizational-related factors among patients in Malaysia diagnosed with breast, colorectal, nasopharyngeal, and cervical cancer. METHODS: This cross-sectional study enrolled adult cancer patients diagnosed with breast, cervical, colorectal, or nasopharyngeal cancer from 2015 to 2020 in seven public hospitals/oncology centres across Malaysia. Data were collected through patient-administered surveys and medical records. Presentation delay, defined as the duration between symptom onset and the patient's first visit to a healthcare professional exceeding 30 days, was the primary outcome. Statistical analysis included descriptive statistics and chi-square tests. RESULTS: The study included 476 cancer patients, with breast cancer (41.6%), colorectal cancer (26.9%), nasopharyngeal cancer (22.1%), and cervical cancer (9.5%). Over half (54.2%) experienced presentation delays with a median interval of 60 days. Higher proportions of presentation delay were observed among nasopharyngeal cancer patients, employed patients with lower socioeconomic statuses, and those without family history of cancer. Most patients self-discovered their first cancer symptoms (80%), while only one-third took immediate action for medical check-ups. Emotional and organizational factors, such as long waiting times during doctor's visits (47%), were potential barriers to seeking cancer care. CONCLUSION: This study highlights the significant problem of presentation delay among cancer patients in Malaysia. The delay is influenced by various factors encompassing sociodemographic characteristics, health-seeking behaviours, and healthcare system-related issues. A comprehensive approach addressing both individual barriers and institutional obstacles is imperative to mitigate this presentation delay and improve cancer outcomes.

A New Method of Constructing Methyleneindene and Quinoline Frameworks from Methylenecyclopropanes.

In this paper, we have established an operationally convenient protocol for the rapid construction of polysubstituted methyleneindene and quinoline derivatives under mild conditions. This new synthetic method is achieved through the conversion of acetyl-substituted methylenecyclopropanes with TsOH·H2O and ortho-amino-substituted methylenecyclopropanes with aromatic aldehyde and TsOH·H2O, respectively. A variety of transformations of the obtained products was demonstrated. The plausible reaction mechanisms were also proposed.

GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14.

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1ß expression levels and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor-/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor-/- Nlrp3-/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1ß transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.

The Causal Relationship between Angina Pectoris and Gout Based on Two Sample Mendelian Randomization.

Purpose: Two-sample Mendelian randomization (MR) was conducted to assess the causal relationship between angina pectoris and gout. Material and Methods. Based on genome-wide association studies, single nucleotide polymorphisms (SNPs) that were closely associated with gout were selected from the UK Biobank-Neale Lab (ukb-a-107) as genetic instrumental variables. Considering that gout is characterized by elevated blood uric acid levels, SNPs related to blood uric acid levels were screened from BioBank Japan (bbj-a-57) as auxiliary gene instrumental variables. SNPs closely associated with angina pectoris onset were screened from the FINN dataset (finn-b-I9_ANGINA) as outcome variables. Two-sample MR was conducted, with inverse variance weighting (IVW) of the random effects model as the primary result, along with the weighted median method (WME) and the MR-Egger regression method. To further confirm the causal relationship between angina and gout incidence, a meta-analysis was conducted on the IVW results of the ukb-a-107 and bbj-a-57. Results: The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger results of ukb-a-107 were (OR = 33.72; 95% CI: 2.07∼550.38), (OR = 57.94; 95% CI: 2.75∼1219.82), and (OR = 96.38; 95% CI: 0.6∼15556.93), respectively. The P values of IVW and WME were 0.014 and 0.014 (both <0.05), respectively, indicating that the development of angina pectoris was significantly associated with the incidence of gout. The odds ratios and 95% confidence intervals of the IVW, WME, and MR-Egger about bbj-a-57 were (OR = 1.20; 95% CI: 1.07∼1.34), (OR = 1.19; 95% CI: 1.02∼1.38), and (OR = 1.30; 95% CI; 1.06∼1.60), respectively. The P values of IVW, WME and MR-Egger were 0.001, 0.027 and 0.017 (all <0.05), respectively, indicating a significant correlation between angina and blood uric acid levels. Scatter plots of ukb-a-107 and bbj-a-57 showed that the causal association estimates of the IVW, MR-Egger, and weighted median methods were similar and that the MR results were accurate. Funnel plots and the MR-Egger intercept of ukb-a-107 and bbj-a-57 showed the absence of horizontal pleiotropy. The leave-out sensitivity analysis results of ukb-a-107 and bbj-a-57 are stable. The meta-analysis of IVW results for ukb-a-107 and bbj-a-57 showed (OR = 1.20; 95% CI: 1.07-1.34, P=0.02), confirming that gout characterized by high blood uric acid levels significantly increases the risk of angina attacks. Conclusions: This MR study found a clear causal relationship between angina pectoris and gout, which increases the risk of angina pectoris.

Elucidation of antioxidant activities of intracellular and extracellular polysaccharides from Cordyceps militaris in vitro and their protective effects on ulcerative colitis in vivo.

In this study, we extracted the polysaccharides from C. militaris fruiting bodies (CFIPs), mycelial intracellular polysaccharides (CMIPs), and fermentation broth extracellular polysaccharides (CFEPs) to investigate their physicochemical properties, antioxidant capacities, and effects on oxazolone-induced zebrafish ulcerative colitis (UC). Our results revealed differences in monosaccharide composition and surface structure among CFIPs, CMIPs, and CFEPs. The molar ratios of glucose to mannose in CFIPs, glucose to xylose in CMIPs, and xylose to glucose in CFEPs were 7.57: 1.6, 7.26: 1.81, and 5.44: 2.98 respectively. Moreover, CFEPs exhibited significantly (p < 0.05) higher chemical antioxidant capacity compared to CMIPs and CFIPs. Surprisingly, CFEP treatment didn't show a significant effect in protecting against H2O2-induced oxidative damage in RAW 264.7 cells. After 3 d of treatment, the levels of ROS, MDA, and MPO in the CFIPs group exhibited a significant (p < 0.05) reduction by 37.82 %, 68.15 %, and 22.77 % respectively. Additionally, the ACP and AKP increased by 60.33 % and 96.99 %. Additionally, C. militaris polysaccharides (CMPs) were found to effectively improve UC by activating the MyD88/NF-κB signaling pathway in vivo. These findings confirm the distinct physicochemical properties of these three types of CMP and their potential for development into antioxidant-rich anti-inflammatory health foods.

Mechanistic Studies on Rhodium-Catalyzed Chemoselective Cycloaddition of Ene-Vinylidenecyclopropanes: Water-Assisted Proton Transfer.

Rhodium-catalyzed cycloaddition reactions are a powerful tool for the construction of polycyclic compounds. Combined experimental and DFT studies were used to investigate the temperature-controlled chemoselectivity of cationic rhodium-catalyzed intramolecular cycloaddition reactions of ene-vinylidenecyclopropanes. After a series of mechanistic studies, it was found that trace amounts of water in the reaction system play an important role in generating the product with endo double bond located on a five-membered ring and revealed that trace amounts of water in the reaction system, including the rhodium catalyst, substrate and solvent, were sufficient to promote the formation of the product with endo double bond located on a five-membered ring, and additional water could not further accelerate the reaction. DFT calculation results show that the addition of water indeed significantly lowers the energy barrier of the proton transfer step, making the formation of the product with endo double bond located on a five-membered ring more likely to occur and confirming the rationality of water-assisted proton transfer occurring in the selective access to the product with endo double bond located on a five-membered ring.

A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility.

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population.

Pickering stabilization mechanism revealed through direct imaging of particles with tuneable contact angle in a phase-separated binary solvent.

Pickering emulsions have attracted increasing attention from multiple fields, including food, cosmetics, healthcare, pharmaceutical, and agriculture. Their stability relies on the presence of colloidal particles instead of surfactant at the droplet interface, providing steric stabilization. Here, we demonstrate the microscopic attachment and detachment of particles with tunable contact angle at the interface underlying the Pickering emulsion stability. We vary the interfacial tension continuously by varying the temperature offset of a phase-separated binary liquid from its critical point, and employ confocal microscopy to directly observe the particles at the interface to determine their coverage and contact angle as a function of the varying interfacial tension. When the interfacial tension decreases upon approaching the binary liquid's critical point, the contact angle and detachment energy (ΔE) drop, and the particles move out of the interface. Microscopic imaging suggests necking and capillary interactions lead to clustering of the particles, before they eventually desorb from the interface. Macroscopic measurements show that concomitantly, coalescence takes place, and the emulsion loses its stability. These results reveal the interplay of interfacial energies, contact angle and surface coverage that underlies the Pickering emulsion stability, opening up ways to manipulate and design the stability through the microscopic behavior of the adsorbed particles.