Aging and comprehensive molecular profiling in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion-negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA/B, platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Spinal Neuronal miR-124 Inhibits Microglial Activation and Contributes to Preventive Effect of Electroacupuncture on Chemotherapy-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a persistent and irreversible side effect of antineoplastic agents. Patients with CIPN usually show chronic pain and sensory deficits with glove-and-stocking distribution. However, whether spinal neuronal microRNA (miR)-124 is involved in cisplatin-induced peripheral neuropathy remains to be studied. In this study, miR-124 was significantly reduced in the spinal dorsal horn in CIPN mice. Overexpression of neuronal miR-124 induced by injecting adeno-associated virus with neuron-specific promoter into the spinal cord of mice prevented the development of mechanical allodynia, sensory deficits, and the loss of intraepidermal nerve fibers induced by cisplatin. Meanwhile, cisplatin-induced M1 microglia activation and the release of proinflammatory cytokines were significantly inhibited by overexpression of neuronal miR-124. Furthermore, electroacupuncture (EA) treatment upregulated miR-124 expression in the spinal dorsal horn of CIPN mice. Interestingly, downregulation of spinal neuronal miR-124 significantly inhibited the regulatory effect of EA on CIPN and microglia activity as well as spinal neuroinflammation induced by cisplatin. These results demonstrate that spinal neuronal miR-124 is involved in the prevention and treatment of EA on cisplatin-induced peripheral neuropathy in mice. Our findings suggest that spinal neuronal miR-124 might be a potential target for EA effect, and we provide, to our knowledge, a new experimental basis for EA prevention of CIPN.

DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis.

Trichoderma reesei is an economically important enzyme producer with several unique meiotic features. spo11, the initiator of meiotic double-strand breaks (DSBs) in most sexual eukaryotes, is dispensable for T. reesei meiosis. T. reesei lacks the meiosis-specific recombinase Dmc1. Rad51 and Sae2, the activator of the Mre11 endonuclease complex, promote DSB repair and chromosome synapsis in wild-type and spo11Δ meiosis. DNA methyltransferases (DNMTs) perform multiple tasks in meiosis. Three DNMT genes (rid1, dim2 and dimX) differentially regulate genome-wide cytosine methylation and C:G-to-T:A hypermutations in different chromosomal regions. We have identified two types of DSBs: type I DSBs require spo11 or rid1 for initiation, whereas type II DSBs do not rely on spo11 and rid1 for initiation. rid1 (but not dim2) is essential for Rad51-mediated DSB repair and normal meiosis. rid1 and rad51 exhibit a locus heterogeneity (LH) relationship, in which LH-associated proteins often regulate interconnectivity in protein interaction networks. This LH relationship can be suppressed by deleting dim2 in a haploid rid1Δ (but not rad51Δ) parental strain, indicating that dim2 and rid1 share a redundant function that acts earlier than rad51 during early meiosis. In conclusion, our studies provide the first evidence of the involvement of DNMTs during meiotic initiation and recombination.

A soft microrobot with highly deformable 3D actuators for climbing and transitioning complex surfaces.

The climbing microrobots have attracted growing attention due to their promising applications in exploration and monitoring of complex, unstructured environments. Soft climbing microrobots based on muscle-like actuators could offer excellent flexibility, adaptability, and mechanical robustness. Despite the remarkable progress in this area, the development of soft microrobots capable of climbing on flat/curved surfaces and transitioning between two different surfaces remains elusive, especially in open spaces. In this study, we address these challenges by developing voltage-driven soft small-scale actuators with customized 3D configurations and active stiffness adjusting. Combination of programmed strain distributions in liquid crystal elastomers (LCEs) and buckling-driven 3D assembly, guided by mechanics modeling, allows for voltage-driven, complex 3D-to-3D shape morphing (bending angle > 200°) at millimeter scales (from 1 to 10 mm), which is unachievable previously. These soft actuators enable development of morphable electroadhesive footpads that can conform to different curved surfaces and stiffness-variable smart joints that allow different locomotion gaits in a single microrobot. By integrating such morphable footpads and smart joints with a deformable body, we report a multigait, soft microrobot (length from 6 to 90 mm, and mass from 0.2 to 3 g) capable of climbing on surfaces with diverse shapes (e.g., flat plane, cylinder, wavy surface, wedge-shaped groove, and sphere) and transitioning between two distinct surfaces. We demonstrate that the microrobot could navigate from one surface to another, recording two corresponding ceilings when carrying an integrated microcamera. The developed soft microrobot can also flip over a barrier, survive extreme compression, and climb bamboo and leaf.

Transcriptome-based molecular subtypes and differentiation hierarchies improve the classification framework of acute myeloid leukemia.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1-G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6-G8, showing high expression of HOXA/B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX-primitive (G7), HOX-mixed (G8), and HOX-committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

High-Throughput Identification of Single Nanoparticles via Electrochemically Assisted High-Resolution Plasmonic Scattering Interferometric Microscopy.

The identification of nanoparticles within heterogeneous mixtures poses significant challenges due to the similarity in physical properties among different nanomaterials. Here, we present electrochemically assisted high-resolution plasmonic scattering interferometric microscopy (HR-PSIM). This technique allows for the high-throughput identification of nanoparticles by accurately measuring the refractive index of individual nanoparticles without interference from background signals. Through elimination of parabolic scattering interference and employing electrochemical modulation, HR-PSIM demonstrates high spatial resolution and stability against background noise, enabling the differentiation of nanoparticles with closely matched refractive indices, such as Au and Ag nanoparticles. The efficacy of this method is demonstrated through its application in real-time, label-free imaging of nanoparticle electrochemical activity, providing a platform for the precise and high-throughput characterization of nanomaterials. The robustness of our approach against electrochemical interference and its high spatial resolution mark a significant advancement in the field of nanomaterial analysis, promising wide-ranging applications in nanoparticle research and beyond.

Detection in Orchards of Predominant Azole-Resistant Candida tropicalis Genotype Causing Human Candidemia, Taiwan.

Fluconazole-resistant clade 4 Candida tropicalis causing candidemia in humans has been detected in tropical/subtropical areas, including those in China, Singapore, and Australia. We analyzed 704 individual yeasts isolated from fruits, soil, water, and farmers at 80 orchards in Taiwan. The most common pathogenic yeast species among 251 isolates recovered from farmers were Candida albicans (14.7%) and C. parapsilosis (11.6%). In contrast, C. tropicalis (13.0%), C. palmioleophila (6.6%), and Pichia kudriavzevii (6.0%) were prevalent among 453 environmental isolates. Approximately 18.6% (11/59) of C. tropicalis from the environment were resistant to fluconazole, and 81.8% (9/11) of those belonged to the clade 4 genotype. C. tropicalis susceptibility to fluconazole correlated with susceptibilities to the agricultural azole fungicides, difenoconazole, tebuconazole, and triadimenol. Tandem gene duplications of mutated ERG11 contributed to azole resistance. Agriculture environments are a reservoir for azole-resistant C. tropicalis; discontinuing agricultural use of azoles might reduce emergence of azole-resistant Candida spp. strains in humans.

Renalase peptides reduce pancreatitis severity in mice.

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.

Physiological, biochemical, and transcriptomic alterations in Castor (Ricinus communis L.) under polyethylene glycol-induced oxidative stress.

BACKGROUND: Castor is an important industrial raw material. Drought-induced oxidative stress leads to slow growth and decreased yields in castor. However, the mechanisms of drought-induced oxidative stress in castor remain unclear. Therefore, in this study, physiological, biochemical, and RNA-seq analyses were conducted on the roots of castor plants under PEG-6000 stress for 3 d and 7 d followed by 4 d of hydration. RESULTS: The photosynthetic rate of castor leaves was inhibited under PEG-6000 stress for 3 and 7 d. Biochemical analysis of castor roots stressed for 3 d and 7 d, and rehydrated for 4 d revealed that the activities of APX and CAT were highest after only 3 d of stress, whereas the activities of POD, GR, and SOD peaked after 7 d of stress. RNA-seq analysis revealed 2926, 1507, and 111 differentially expressed genes (DEGs) in the roots of castor plants under PEG-6000 stress for 3 d and 7 d and after 4 d of rehydration, respectively. GO analysis of the DEGs indicated significant enrichment in antioxidant activity. Furthermore, KEGG enrichment analysis of the DEGs revealed significantly enriched metabolic pathways, including glutathione metabolism, fatty acid metabolism, and plant hormone signal transduction. WGCNA identified the core genes PP2C39 and GA2ox4 in the navajowhite1 module, which was upregulated under PEG-6000 stress. On the basis of these results, we propose a model for the response to drought-induced oxidative stress in castor. CONCLUSIONS: This study provides valuable antioxidant gene resources, deepening our understanding of antioxidant regulation and paving the way for further molecular breeding of castor plants.

A new In Situ Oxidized 2D Layered MnBi2Te4 Cathode for High-Performance Aqueous Zinc-Ion Battery.

Recently, aqueous zinc ion batteries (AZIBs) with the superior theoretical capacity, high safety, low prices, and environmental protection, have emerged as a contender for advanced energy storage. However, challenges related to cathode materials, such as dissolution, instability, and structural collapse, have hindered the progress of AZIBs. Here, a novel AZIB is constructed using an oxidized 2D layered MnBi2Te4 cathode for the first time. The oxidized MnBi2Te4 cathode with large interlayer spacing and low energy barrier for zinc ion diffusion at 240 °C, exhibited impressive characteristics, including a high reversibility capacity of 393.1 mAh g-1 (0.4 A g-1), outstanding rate performance, and long cycle stability. Moreover, the corresponding aqueous button cell also exhibits excellent electrochemical performance. To demonstrate the application in practice in the realm of flexible wearable electronics, a quasi-solid-state micro ZIB (MZIB) is constructed and shows excellent flexibility and high-temperature stability (the capacity does not significantly degrade when the temperature reaches 100 °C and the bending angle exceeds 150°). This research offers effective tactics for creating high-performance cathode materials for AZIBs.

Differences in weight status among Australian children and adolescents from priority populations: a longitudinal study.

BACKGROUND AND SIGNIFICANCE: Australia has a high level of cultural and linguistic diversity, including Aboriginal and Torres Strait Islander peoples. Children from specific cultural and ethnic groups may be at greater risk of overweight and obesity and may bear the additional risk of socioeconomic disadvantage. Our aim was to identify differences in body-mass index z-score (zBMI) by: (1) Cultural and ethnic groups and; (2) Socioeconomic position (SEP), during childhood and adolescence. SUBJECTS/METHODS: We used data from the Longitudinal Study of Australian children (n = 9417) aged 2-19 years with 50870 longitudinal measurements of zBMI. Children were classified into 9 cultural and ethnic groups, based on parent and child's country of birth and language spoken at home. These were: (1) English-speaking countries; (2) Middle East & North Africa; (3) East & South-East Asia; (4) South & Central Asia; (5) Europe; (6) Sub-Saharan Africa; (7) Americas; (8) Oceania. A further group (9) was defined as Aboriginal and Torres Strait Islander from self-reported demographic information. Longitudinal cohort analyses in which exposures were cultural and ethnic group and family socioeconomic position, and the outcome was zBMI estimated using multilevel mixed linear regression models. We stratified our analyses over three periods of child development: early childhood (2-5 years); middle childhood (6-11 years); and adolescence (12-19 years). RESULTS: Across all three periods of child development, children from the Middle East and North Africa, the Americas and Oceania were associated with higher zBMI and children from the two Asian groups were associated with lower zBMI, when compared to the referent group (English). zBMI was socioeconomically patterned, with increasingly higher zBMI associated with more socioeconomic disadvantage. CONCLUSIONS: Our findings identified key population groups at higher risk of overweight and obesity in childhood and adolescence. Prevention efforts should prioritize these groups to avoid exacerbating inequalities in healthy weight in childhood.

Integrated unsupervised-supervised modeling and prediction of protein-peptide affinities at structural level.

Cell signal networks are orchestrated directly or indirectly by various peptide-mediated protein-protein interactions, which are normally weak and transient and thus ideal for biological regulation and medicinal intervention. Here, we develop a general-purpose method for modeling and predicting the binding affinities of protein-peptide interactions (PpIs) at the structural level. The method is a hybrid strategy that employs an unsupervised approach to derive a layered PpI atom-residue interaction (ulPpI[a-r]) potential between different protein atom types and peptide residue types from thousands of solved PpI complex structures and then statistically correlates the potential descriptors with experimental affinities (KD values) over hundreds of known PpI samples in a supervised manner to create an integrated unsupervised-supervised PpI affinity (usPpIA) predictor. Although both the ulPpI[a-r] potential and usPpIA predictor can be used to calculate PpI affinities from their complex structures, the latter seems to perform much better than the former, suggesting that the unsupervised potential can be improved substantially with a further correction by supervised statistical learning. We examine the robustness and fault-tolerance of usPpIA predictor when applied to treat the coarse-grained PpI complex structures modeled computationally by sophisticated peptide docking and dynamics simulation. It is revealed that, despite developed solely based on solved structures, the integrated unsupervised-supervised method is also applicable for locally docked structures to reach a quantitative prediction but can only give a qualitative prediction on globally docked structures. The dynamics refinement seems not to change (or improve) the predictive results essentially, although it is computationally expensive and time-consuming relative to peptide docking. We also perform extrapolation of usPpIA predictor to the indirect affinity quantities of HLA-A*0201 binding epitope peptides and NHERF PDZ binding scaffold peptides, consequently resulting in a good and moderate correlation of the predicted KD with experimental IC50 and BLU on the two peptide sets, with Pearson's correlation coefficients Rp = 0.635 and 0.406, respectively.

Photooxidation of Toluene Derivatives under HAT and ROS Synergy.

The valorization of toluene offers a dual solution by addressing its environmental impact while also facilitating the synthesis of a diverse array of valuable fine chemicals and pharmaceutical intermediates, thus ensuring both ecological sustainability and economic viability. We report herein a synergistic approach that harmonizes hydrogen atom transfer (HAT) process with the generation of reactive oxygen species (ROS) under mild condition and low catalyst loading, which enables the efficient synthesis of a broad spectrum of esteemed benzoic acid derivatives and aryl ketones through the photocatalytic oxidation of toluene derivatives. Mechanistic elucidation reveals that the HAT reagent anthraquinone has both the capabilities to abstract hydrogen atoms and the ability to generate singlet oxygen 1O2 during energy transfer with triplet oxygen 3O2, and the combination of these two potencies significantly improves the catalytic efficiency of the reaction. This study not only introduces the amalgamation of HAT with ROS generation but also delineates a systematic approach for the selection of HAT reagents with energy transfer proficiency for ROS generation in catalytic oxidation reactions.

Using Self-Reported Sexual Positioning as an Indicator for Rectal Chlamydia and Gonorrhea Screening Among Men Who Have Sex With Men in China: A Missed Opportunity.

BACKGROUND: Rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections among men who have sex with men (MSM) are escalating public health concerns. This study aimed to explore (1) the reliability of self-reported sexual positioning as an indicator for rectal CT and NG screening, and (2) factors associated with rectal CT and NG infections in Shenzhen, China. METHODS: A cross-sectional study was conducted in 2 settings in Shenzhen, China, from April 1, 2021, to March 31, 2022. Data on sociodemographic characteristics, sexual behaviors, and basic CT knowledge were collected. Urine and self-collected rectal swabs were collected for CT and NG testing. RESULTS: In total, 195 MSM participated in the study, and 5.1% tested positive for urogenital CT, 29.2% for rectal CT, 1.0% for urogenital NG, and 8.2% for rectal NG. Among those who reported exclusively insertive anal sex, 69.2% of CT infections and 85.7% of NG infections would have remained undetected with urine testing alone. Risk factors for rectal CT infection included engaging in both insertive and receptive anal sex, with a significant association found for coinfection with rectal NG. CONCLUSIONS: Self-reported sexual positioning was found to be an unreliable indicator for CT and NG screening, as a substantial proportion of infections would have remained undetected. The findings suggest that CT and NG screening in China should be offered to all MSM regardless of self-reported sexual positioning, and that the dual CT/NG testing is recommended.

Laboratory exploration of the use of ripasudil in descemetorhexis with a human ex vivo model.

The aim of the study was to investigate the effect of ripasudil on corneal endothelial cell survival and migration after two types of descemetorhexis on a human ex vivo model. Eleven human corneoscleral buttons were incubated in either 50 ml organ culture medium containing 10 µM ripasudil or 50 µl dimethyl sulfoxide (DMSO), the vehicle in ripasudil for 2 days prior to wound creation then for 14 days after. The wound was created with either full trephination scoring or by shallow trephination plus manual peeling. At day 14, immunohistochemistry with vimentin and Na+/K+/ATPase markers was conducted. Tissues were assessed at day 3, 7 and 14 for morphology, cell migration, cell viability and cell density. Full trephination scoring created more damage on tissues compared to shallow trephination with full Descemet membrane peeling. In the full trephination scoring group, no differences in cell viability were noted when ripasudil and DMSO were compared. With the peeling method, Ripasudil could protect the endothelial cell death and maintain the morphology compared to the control. At day 14, no differences in the peripheral cell viability and density were found between ripasudil and DMSO, although the ripasudil group presented significantly increased central cell count and cell viability. Increased cell migration was noted with ripasudil and the initial cell morphology of those migrated cells was similar to that of fibroblasts. In conclusion, ex vivo modelling suggested that peeling resulted in less cell damage than scoring and ripasudil maintained better morphology and promoted migration. These effects might be via transformation of endothelial cells into a more motile spindle-like phenotype.

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Deletion of myeloid-specific Orai1 calcium channel does not affect pancreatic tissue damage in experimental acute pancreatitis.

BACKGROUND: Store-operated Ca2+ entry (SOCE) mediated by ORAI1 channel plays a crucial role in acute pancreatitis (AP). Macrophage is an important regulator in amplifying pancreatic tissue damage, but little is known about the role of ORAI1 in macrophages. In this study, we examined the effects of macrophage-specific ORAI1 on pancreatic tissue damage in AP. METHOD: Myeloid-specific Orai1 deficient mice was generated by crossing a LysM-Cre mouse line with Orai1f/f mice. Bone marrow-derived macrophages (BMDMs) were isolated, cultured, and stimulated to induce M1 or M2 macrophage polarization. Intracellular Ca2+ signals were measured by time-lapse confocal microscope imaging, with a Ca2+ indicator (Fluo 4). Experimental AP was induced by hourly intraperitoneal injections of caerulein or retrograde biliopancreatic infusion of sodium taurocholate. Pancreatic tissue damage was assessed by histopathological scoring and immunostaining. Sepsis was induced by intraperitoneal injection of lipopolysaccharide; organ damage and serum pro-inflammatory cytokines were measured. RESULT: Myeloid-specific Orai1 deletion exhibited minimal effect on SOCE in M0 macrophages and promoted M2 macrophage polarization ex vivo. Myeloid-specific Orai1 deletion did not affect pancreatic tissue damage, nor neutrophil or macrophage infiltration in two models of AP. Similarly, myeloid-specific Orai1 deletion did not influence overall survival rate in a model of sepsis, nor lung, kidney, and liver damage; while serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1ß were higher in Orai1ΔLysM mice, but were largely reduced in mice with Orai1 inhibitor. CONCLUSION: Our data suggest that ORAI1 may not be a predominant SOCE channel in macrophages and play a limited role in mediating pancreatic tissue damage in AP.

A causal relationship between distinct immune features and acute or chronic pancreatitis: results from a mendelian randomization analysis.

OBJECTIVES: This study aimed to thoroughly examining the causal link between immune traits and four types of pancreatitis, using mendelian randomization. METHODS: Data on 731 immune traits were collected from the genome-wide association study (GWAS) database as exposure. Information regarding acute pancreatitis (AP), alcohol-induced acute pancreatitis (AAP), chronic pancreatitis (CP), and alcohol-induced chronic pancreatitis (ACP) were acquired from the FinnGen Consortium as outcomes. Mendelian randomization (MR) using inverse variance weighting (IVW) evaluated the links between immune traits and pancreatitis. We evaluated the robustness of the IVW results through sensitivity analyses and validated them using meta-analysis with AP and CP data from the UK Biobank in the GWAS catalog. RESULTS: A total of 36 immune traits showed significant associations with susceptibility of four types of pancreatitis, including AP (7 traits), AAP (8 traits), CP (14 traits), and ACP (7 traits). Twenty characteristics were found to be potential risk factors for pancreatitis, identified in B Cells (5 traits), conventional dendritic cells (cDCs, 2 traits), maturation stage of T cells (2 traits), monocytes (2 traits), myeloid cells (2 traits), T cells, B cells, natural killer cells (TBNK, 2 traits), and regulatory T cells (Treg cells, 5 traits). Multiple sensitivity analyses confirmed the validity of the findings. Meta-analysis confirmed a solid causal relationship between CX3CR1 on CD14- CD16-of monocyte panel and the susceptibility of CP. CONCLUSIONS: Our MR study identified immune traits causally linked to acute and chronic pancreatitis, offering new insights for early clinical intervention and immune cell-targeted therapies.