Liver autotransplantation and atrial reconstruction on a patient with multiorgan alveolar echinococcosis: a case report.

BACKGROUND: Alveolar echinococcosis (AE) primarily affects the liver and potentially spreads to other organs. Managing recurrent AE poses significant challenges, especially when it involves critical structures and multiple major organs. CASE PRESENTATION: We present a case of a 59-year-old female with recurrent AE affecting the liver, heart, and lungs following two previous hepatectomies, the hepatic lesions persisted, adhering to major veins, and imaging revealed additional diaphragmatic, cardiac, and pulmonary involvement. The ex vivo liver resection and autotransplantation (ELRA), first in human combined with right atrium (RA) reconstruction were performed utilizing cardiopulmonary bypass, and repairs of the pericardium and diaphragm. This approach aimed to offer a potentially curative solution for lesions previously considered inoperable without requiring a donor organ or immunosuppressants. The patient encountered multiple serious complications, including atrial fibrillation, deteriorated liver function, severe pulmonary infection, respiratory failure, and acute kidney injury (AKI). These complications necessitated intensive intraoperative and postoperative care, emphasizing the need for a comprehensive management strategy in such complicated high-risk surgeries. CONCLUSIONS: The multidisciplinary collaboration in this case proved effective and yielded significant therapeutic outcomes for a rare case of advanced hepatic, cardiac, and pulmonary AE. The combined approach of ELRA and RA reconstruction under extracorporeal circulation demonstrated distinct advantages of ELRA in treating complex HAE. Meanwhile, assessing diaphragm function during the perioperative period, especially in patients at high risk of developing pulmonary complications and undergoing diaphragmectomy is vital to promote optimal postoperative recovery. For multi-resistant infection, it is imperative to take all possible measures to mitigate the risk of AKI if vancomycin administration is deemed necessary.

Triglyceride-glucose index and the prognosis of patients with heart failure: A meta-analysis.

The triglyceride-glucose index (TyGI) is a novel indicator of insulin resistance, which has been associated with an increased risk of cardiovascular diseases. The aim of this meta-analysis was to determine the association between TyGI and the prognosis of patients with heart failure (HF). Cohort studies relevant to the aim of the meta-analysis were retrieved by searching electronic databases, including PubMed, Web of Science, and Embase. A random-effects model was used to combine the data, incorporating the influence of between-study heterogeneity. Twelve studies involving 20,639 patients with HF were included. Pooled results showed that compared to patients with the lowest category of TyGI at baseline, those with the highest TyGI index were associated with a higher risk of all-cause mortality during follow-up (relative risk [RR] 1.71, 95% confidence interval [CI] 1.46 - 2.00; P < 0.001; I² = 55%). Sensitivity analyses limited to studies after adjustment for confounding factors showed similar results (RR 1.89, 95% CI 1.67 - 2.21; P < 0.001; I² = 13%). Subsequent meta-analyses also showed that a high TyGI at baseline was related to the incidence of cardiovascular death (RR 1.87, 95% CI 1.42 - 2.47; P < 0.001; I² = 57%), HF rehospitalization (RR 1.33, 95% CI 1.04 - 1.69; P < 0.02; I² = 46%), and major adverse cardiovascular events (RR 1.69, 95% CI 1.39 - 2.06; P < 0.001; I² = 17%) during follow-up. In conclusion, a high TyGI may be associated with a poor clinical prognosis for patients with HF.

ULV: A robust statistical method for clustered data, with applications to multi-subject, single-cell omics data.

Molecular and genomic technological advancements have greatly enhanced our understanding of biological processes by allowing us to quantify key biological variables such as gene expression, protein levels, and microbiome compositions. These breakthroughs have enabled us to achieve increasingly higher levels of resolution in our measurements, exemplified by our ability to comprehensively profile biological information at the single-cell level. However, the analysis of such data faces several critical challenges: limited number of individuals, non-normality, potential dropouts, outliers, and repeated measurements from the same individual. In this article, we propose a novel method, which we call U-statistic based latent variable (ULV). Our proposed method takes advantage of the robustness of rank-based statistics and exploits the statistical efficiency of parametric methods for small sample sizes. It is a computationally feasible framework that addresses all the issues mentioned above simultaneously. We show that our method controls false positives at desired significance levels. An additional advantage of ULV is its flexibility in modeling various types of single-cell data, including both RNA and protein abundance. The usefulness of our method is demonstrated in two studies: a single-cell proteomics study of acute myelogenous leukemia (AML) and a single-cell RNA study of COVID-19 symptoms. In the AML study, ULV successfully identified differentially expressed proteins that would have been missed by the pseudobulk version of the Wilcoxon rank-sum test. In the COVID-19 study, ULV identified genes associated with covariates such as age and gender, and genes that would be missed without adjusting for covariates. The differentially expressed genes identified by our method are less biased toward genes with high expression levels. Furthermore, ULV identified additional gene pathways likely contributing to the mechanisms of COVID-19 severity.

Ultrasonographic Features and Pregnancy Outcomes of Complications in Monochorionic Twin Pregnancy During Various Pregnancy Periods.

Objective: It was to explore the ultrasonic characteristics of complications of twin pregnancies with monochorionic diamniotic (MCDA) during various pregnancy periods and the differences in pregnancy outcomes. Methods: One hundred pregnant women with MCDA were included in the study. They were rolled into a complication group (44 cases) and a non-complication group (56 cases) according to whether they had complications. The pulsatility index (PI), resistance index (RI), and systolic/diastolic (S/D) values of ultrasound in pregnant women and the final neonatal situation at each time period were compared and analyzed. Results: In pregnant women with twin-twin transfusion syndrome (TTTS), there was no significant difference in RI and S/D values between the larger and smaller twin during pregnancy (P > .05). Compared to the group without complications, the incidence of neonatal death was significantly increased in the complication group, and the newborn's weight, length, head circumference, and Apgar score were significantly lower (P < .05). In pregnant women with selective intrauterine growth restriction (sIUGR), the RI and PI values of the larger twin were significantly higher than those of the smaller twin during pregnancy, and S/D values were significantly lower (P < .05). The newborns in the group without complications had significantly higher body weight, length, and head circumference (P < .05). In pregnant women with gestational diabetes mellitus (GDM), there was no significant difference in RI and S/D values between the larger and smaller twin during pregnancy (P > .05), and there were no significant differences in other indicators compared to the group without complications. In pregnant women with premature rupture of membrane (PROM), there was no significant difference in RI and S/D values between the larger and smaller twin during pregnancy (P > .05), but the newborns in the group without complications had significantly higher weight, length, Apgar score, and lower incidence of neonatal death (P < .05). In pregnant women with preeclampsia (PE), there was no significant difference in RI and S/D values between the larger and smaller twin during pregnancy (P > .05), and there were no significant differences in other indicators compared to the group without complications (P > .05). Conclusion: Pregnant women with sIUGR had significantly higher RI and PI values in the larger twin and significantly lower S/D values compared to the smaller twin during pregnancy, while no significant differences were observed for other complications. The combination of TTTS and PROM decreased the birth weight, body length, head circumference, and Apgar score of twins and increased the mortality rate.

Intranasal Delivery of Ketamine Induces Cortical Disinhibition.

Our previous studies find that subcutaneously administered (s.c.) subanesthetic ketamine promotes sustained cortical disinhibition and plasticity in adult mouse binocular visual cortex (bV1). We hypothesized that intranasal delivery (i.n.) of subanesthetic ketamine may have similar actions. To test this, we delivered ketamine (10 mg/kg, i.n.) to adult mice and then recorded excitatory pyramidal neurons or PV+ interneurons in L2/3 of bV1 slices. In pyramidal neurons the baseline IPSC amplitudes from mice treated with ketamine are significantly weaker than those in control mice. Acute bath application of neuregulin-1 (NRG1) to cortical slices increases these IPSC amplitudes in mice treated with ketamine but not in controls. In PV+ interneurons, the baseline EPSC amplitudes from mice treated with ketamine are significantly weaker than those in control mice. Acute bath application of NRG1 to cortical slices increases these EPSC amplitudes in mice treated with ketamine but not in controls. We also found that mice treated with ketamine exhibit increased pCREB staining in L2/3 of bV1. Together, our results show that a single intranasal delivery of ketamine reduces PV+ interneuron excitation and reduces pyramidal neuron inhibition and that these effects are acutely reversed by NRG1. These results are significant as they show that intranasal delivery of ketamine induces cortical disinhibition, which has implications for the treatment of psychiatric, neurologic, and ophthalmic disorders.

The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.

JTE-607 is an anticancer and anti-inflammatory compound and its active form, compound 2, directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-messenger RNA (pre-mRNA) 3' processing. Surprisingly, compound 2-mediated inhibition of pre-mRNA cleavage is sequence specific and the drug sensitivity is predominantly determined by sequences flanking the cleavage site (CS). Using massively parallel in vitro assays, we identified key sequence features that determine drug sensitivity. We trained a machine learning model that can predict poly(A) site (PAS) relative sensitivity to compound 2 and provide the molecular basis for understanding the impact of JTE-607 on PAS selection and transcription termination genome wide. We propose that CPSF73 and associated factors bind to the CS region in a sequence-dependent manner and the interaction affinity determines compound 2 sensitivity. These results have not only elucidated the mechanism of action of JTE-607, but also unveiled an evolutionarily conserved sequence specificity of the mRNA 3' processing machinery.

Single cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer's risk gene mutation.

INTRODUCTION: The R47H missense mutation of the TREM2 gene is a strong risk factor for development of Alzheimer's Disease. We investigate cell-type-specific spatial transcriptomic changes induced by the Trem2R47H mutation to determine the impacts of this mutation on transcriptional dysregulation. METHODS: We profiled 15 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics. Single-cell spatial transcriptomics and neuropathology data were analyzed using our custom pipeline to identify plaque and Trem2R47H induced transcriptomic dysregulation. RESULTS: The Trem2R47H mutation induced consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2R47H; 5xFAD mice. CONCLUSION: Spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2R47H mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.

Dynamic Contrast-enhanced CT Lymphangiography to Quantify Thoracic Duct Lymphatic Flow.

Background CT lymphangiography has been used to image the lymphatic anatomy and assess lymphatic abnormalities. There is, however, a need to develop a method for quantification of lymphatic flow rate in the thoracic duct (TD). Purpose To develop and validate a TD lymphatic flow measurement technique using dynamic contrast-enhanced CT lymphangiography. Materials and Methods Lymphatic flow rate was measured with two techniques: a first-pass analysis technique based on a single compartment model and a thresholding technique distinguishing between opacified and nonopacified voxels within the TD. The measurements were validated in a swine animal model between November 2021 and September 2022. CT images were acquired at 100 kV and 200 mA using a fast-pitched helical scan mode covering the entire TD following contrast material injection into the bilateral inguinal lymph nodes. Two helical CT scans, acquired at the base and peak contrast enhancement of the TD, were used to measure lymphatic flow rate. A US flow probe surgically placed around the TD provided the reference standard measurement. CT lymphatic flow measurements were compared with the reference US flow probe measurements using regression and Bland-Altman analysis. Repeatability was determined using repeated flow measurements within approximately 10 minutes of each other. Results Eleven swine (10 male; mean weight, 43.6 kg ± 2.6 [SD]) were evaluated with 71 dynamic CT acquisitions. The lymphatic flow rates measured using the first-pass analysis and thresholding techniques were highly correlated with the reference US flow probe measurements (r = 0.99 and 0.91, respectively) and showed good agreement with the reference standard, with Bland-Altman analysis showing small mean differences of 0.04 and 0.05 mL/min, respectively. The first-pass analysis and thresholding techniques also showed good agreement for repeated flow measurements (r = 0.94 and 0.90, respectively), with small mean differences of 0.09 and 0.03 mL/min, respectively. Conclusion The first-pass analysis and thresholding techniques could be used to accurately and noninvasively quantify TD lymphatic flow using dynamic contrast-enhanced CT lymphangiography. © RSNA, 2023 See also the editorial by Choyke in this issue.

Pilot randomized controlled trial of biofeedback on reducing psychological and physiological stress among persons experiencing homelessness.

People experiencing homelessness report increased exposure to traumatic life events and higher rates of depression, anxiety, and post-traumatic stress disorder as compared with the general population. Heart rate variability-biofeedback (HRV-BF) has been shown to decrease symptoms of stress, anxiety, depression, and PTSD. However, HRV-BF has not been tested with the most vulnerable of populations, homeless adults. The purpose of this randomized controlled trial was to compare the effectiveness of an HRV-BF intervention versus a Health Promotion (HP) active control intervention focused on improving mental health symptoms among homeless adults. Guided by a community advisory board, homeless adults residing in Skid Row, Los Angeles (n = 40) were randomized to either the HRV-BF or an active HP control group and received eight weekly, 30-min sessions over two months, delivered by a nurse-led community health worker team. Dependent variables of HRV, mental health, anxiety, depression, and PTSD were measured at baseline, the 8-week session, and/or 2-month follow-up. All intervention sessions were completed by 90% (36/40) of participants. Both the HRV-BF and HP interventions showed significant increases in HRV from baseline to 2-month follow-up, with no significant difference between the intervention groups. The HRV-BF programme revealed a somewhat greater, although non-significant, improvement in anxiety, depression, and PTSD symptoms than the HP programme. The usefulness of both interventions, focused on emotional and physical health, warrants future studies to examine the value of a combined HRV-BF and HP intervention.

Centralized health management based on hot spring resort improves physical examination indicators and sleep quality in people at high risk of chronic diseases: a randomized controlled trial.

We study the effects of centralized health management based on hot spring resorts on the physical examination index and sleep quality of people at high risk of chronic diseases. We recruited 114 volunteers at high risk of chronic diseases. We then divided them into 57 in the intervention group and 57 in the control group. The intervention group collectively received 4 weeks (28 days) of comprehensive health management interventions at Tongjing Hotspring Resort, including regular schedules, balanced diet, appropriate exercise, targeted health education, etc. The main outcomes are physical examination indicators (height, weight, waist circumference, blood pressure, lipids, and glucose) and sleep quality. Both groups underwent a questionnaire and physical examination at baseline, 2 weeks and 4 weeks. Intragroup comparisons grouped by exposure criteria showed decreases in BMI, waist circumference, triglycerides, total cholesterol, and blood glucose in the intervention group at both 2 and 4 weeks (all P < 0.05); however, in the control group, only triglycerides decreased at 4 weeks (P < 0.05). Intergroup comparisons showed BMI and waist circumference were significantly lower in the intervention group than in the control group at 4 weeks (all P < 0.05). Intragroup comparisons of insomnia severity index (ISI) scores showed a significant decrease in the intervention group at both 2 and 4 weeks (all P < 0.001) with no significant change in the control group (P > 0.05). Intergroup comparisons showed that the insomnia severity index (ISI) scores were significantly higher in the intervention group than in the control group at baseline (P = 0.006) but became significantly lower than the control group at 2 and 4 weeks (all P < 0.001). Thus, this pattern significantly improved BMI, waist circumference, triglycerides, and sleep in the intervention group. TRIAL REGISTRATION NUMBER: Chinese Clinical Trials Registry: ChiCTR2100053201, registered 14 Nov 2021. (Retroactive Registration).

Exosomes Promote Atherosclerosis Progression by Regulating Circ_100696/miR-503-5p/PAPPA Axis-Mediated Vascular Smooth Muscle Cells Proliferation and Migration.

Circular RNAs (circRNAs) are known to play a crucial role in the progression of atherosclerosis (AS). In this study, we aim to explore the function of oxidized low-density lipoprotein (ox-LDL)-induced macrophage-derived exosomal circ_100696 in AS.THP-1 macrophages were induced by ox-LDL to mimic AS cell model. A quantitative real-time polymerase chain reaction (qRT-PCR) assay was applied to determine the expression of circ_100696, microRNA-503-5p (miR-503-5p), and pregnancy-associated plasma protein A (PAPPA). The morphology and size distribution of exosomes were examined by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Western blot assay was performed for protein levels. Cell proliferation was assessed using 5-ethynyl-2'-deoxyuridine (EdU) assay. Flow cytometry analysis was performed to analyze the cell cycle. Wound-healing assay and transwell assay were done to examine cell migration. RNA pull-down assay, dual-luciferase reporter assay, and RNA immunoprecipitation (RIP) assay were employed to analyze the relationship among circ_100696, miR-503-5p, and PAPPA.Circ_100696 level was increased in ox-LDL-induced THP-1 macrophages and ox-LDL-treated THP-1 macrophage-derived exosomes (OM-Exo). OM-Exo promoted the proliferation, cell cycle, and migration of vascular smooth muscle cells (VSMCs). Circ_100696 was upregulated in VSMCs cocultured with OM-Exo. Circ_100696 knockdown reversed the effects of OM-Exo on VSMC proliferation and migration. Circ_100696 was demonstrated to function as the sponge for miR-503-5p, and miR-503-5p directly targeted PAPPA. Circ_100696 overexpression facilitated VSMC proliferation and migration, with miR-503-5p upregulation or PAPPA silencing reversing these effects. Moreover, circ_100696 overexpression promoted PAPPA expression by targeting miR-503-5p.OM-Exo promoted VSMC growth and migration by regulating the circ_100696/miR-503-5p/PAPPA axis, thereby promoting AS progression.

N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial.

BACKGROUND: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. OBJECTIVES AND METHODS: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). RESULTS: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points. CONCLUSIONS: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.

Anatomical and molecular characterization of parvalbumin-cholecystokinin co-expressing inhibitory interneurons: implications for neuropsychiatric conditions.

Inhibitory interneurons are crucial to brain function and their dysfunction is implicated in neuropsychiatric conditions. Emerging evidence indicates that cholecystokinin (CCK)-expressing interneurons (CCK+) are highly heterogenous. We find that a large subset of parvalbumin-expressing (PV+) interneurons express CCK strongly; between 40 and 56% of PV+ interneurons in mouse hippocampal CA1 express CCK. Primate interneurons also exhibit substantial PV/CCK co-expression. Mouse PV+/CCK+ and PV+/CCK- cells show distinguishable electrophysiological and molecular characteristics. Analysis of single nuclei RNA-seq and ATAC-seq data shows that PV+/CCK+ cells are a subset of PV+ cells, not of synuclein gamma positive (SNCG+) cells, and that they strongly express oxidative phosphorylation (OXPHOS) genes. We find that mitochondrial complex I and IV-associated OXPHOS gene expression is strongly correlated with CCK expression in PV+ interneurons at both the transcriptomic and protein levels. Both PV+ interneurons and dysregulation of OXPHOS processes are implicated in neuropsychiatric conditions, including autism spectrum (ASD) disorder and schizophrenia (SCZ). Analysis of human brain samples from patients with these conditions shows alterations in OXPHOS gene expression. Together these data reveal important molecular characteristics of PV-CCK co-expressing interneurons and support their implication in neuropsychiatric conditions.

Exploratory assessment: Nurse-led community health worker delivered HCV intervention for people experiencing homelessness.

BACKGROUND: Getting and maintaining Hepatitis C Virus (HCV) cure is challenging among people experiencing homelessness (PEH) as a result of critical social determinants of health such as unstable housing, mental health disorders, and drug and alcohol use. OBJECTIVES: The purpose of this exploratory pilot study was to compare a registered nurse/community health worker (RN/CHW)-led HCV intervention tailored for PEH, "I am HCV Free," with a clinic-based standard of care (cbSOC) for treating HCV. Efficacy was measured by sustained virological response at 12 weeks after stopping antivirals (SVR12), and improvement in mental health, drug and alcohol use, and access to healthcare. METHODS: An exploratory randomized controlled trial design was used to assign PEH recruited from partner sites in the Skid Row Area of Los Angeles, California, to the RN/CHW or cbSOC programs. All received direct-acting antivirals. The RN/CHW group received directly observed therapy in community-based settings, incentives for taking HCV medications, and wrap-around services, including connection to additional healthcare services, housing support, and referral to other community services. For all PEH, drug and alcohol use and mental health symptoms were measured at month 2 or 3 and 5 or 6 follow-up, depending on HCV medication type, while SVR12 was measured at month 5 or 6 follow-up. RESULTS: Among PEH in the RN/CHW group, 75% (3 of 4) completed SVR12 and all three attained undetectable viral load. This was compared with 66.7% (n = 4 of 6) of the cbSOC group who completed SVR12; all four attained undetectable viral load. The RN/CHW group, as compared to the cbSOC, also showed greater improvements in mental health, and significant improvement in drug use, and access to healthcare services. DISCUSSION: While this study shows significant improvements in drug use and health service access among the RN/-CHW group, the sample size of the study limits the validity and generalizability of the results. Further studies using larger sample sizes are necessitated.

The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.

JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3' processing machinery.

The Role of MicroRNAs in Predicting the Neurological Outcome of Patients with Subarachnoid Hemorrhage: A Meta-analysis.

Subarachnoid hemorrhage (SAH) is a hemorrhagic cerebrovascular disease with an extremely poor prognosis. The molecular mechanism and biomarkers involved in neurological outcome after SAH still need to be explored. This study assessed the microRNA expression characteristics of SAH patients with different neurological outcomes by meta-analysis. Public databases were searched from database inception until December 2022. The study reported that microRNA expression data in SAH patients with different neurological outcomes were included in the analysis. The differential expression of miRNAs was evaluated by meta-analysis. Overrepresentation analysis was performed for the targeted genes of significant miRNAs. The XGBoost algorithm was used to assess the predictive ability for neurological outcomes with clinical characteristics and significantly expressed miRNAs. Seven studies were finally included in the meta-analysis. The results showed that the levels of miR-152-3p (SMD: - 0.230; 95% CI - 0.389, - 0.070; padj = 0.041), miR-221-3p (SMD: - 0.286; 95% CI - 0.446, - 0.127; padj = 0.007), and miR-34a-5p (SMD: - 0.227; 95% CI - 0.386, - 0.067; padj = 0.041) were significantly lower in SAH patients with good neurological outcomes than in those with poor neurological outcomes. The PI3K-AKT signaling pathway may have an important role in neurological recovery after SAH. Based on the XGBoost algorithm, the neurological outcome could be accurately predicted with clinical characteristics plus the three miRNAs. The expression levels of miR-152-3p, miR-221-3p, and miR-34a-5p were significantly lower in patients with good neurological outcomes than in those with poor outcomes. These miRNAs can serve as potential predictive biomarkers for neurological outcomes. The molecular mechanism and biomarkers involved in neurological outcome after SAH still need to be explored. Our study analyzed microRNA expression characteristics of SAH patients with different neurological outcomes by meta-analysis. After analyze studies reporting the microRNA expression data in SAH patients with different neurological outcomes, results show that the levels of miR-152-3p, miR-221-3p, and miR-34a-5p were significantly lower in SAH patients with good neurological outcomes than in those with poor neurological outcomes. The PI3K-AKT signaling pathway may have an important role in neurological recovery after SAH. Based on the XGBoost algorithm, the neurological outcome could be accurately predicted with clinical characteristics plus the three miRNAs.

Bayesian nonparametric analysis for the detection of spikes in noisy calcium imaging data.

Recent advancements in miniaturized fluorescence microscopy have made it possible to investigate neuronal responses to external stimuli in awake behaving animals through the analysis of intracellular calcium signals. An ongoing challenge is deconvolving the temporal signals to extract the spike trains from the noisy calcium signals' time series. In this article, we propose a nested Bayesian finite mixture specification that allows the estimation of spiking activity and, simultaneously, reconstructing the distributions of the calcium transient spikes' amplitudes under different experimental conditions. The proposed model leverages two nested layers of random discrete mixture priors to borrow information between experiments and discover similarities in the distributional patterns of neuronal responses to different stimuli. Furthermore, the spikes' intensity values are also clustered within and between experimental conditions to determine the existence of common (recurring) response amplitudes. Simulation studies and the analysis of a dataset from the Allen Brain Observatory show the effectiveness of the method in clustering and detecting neuronal activities.

Handsome or Rugged? : A Speed-Dating Study of Ovulatory Shifts in Women's Preferences for Masculinity in Men.

We tested the good genes ovulatory shift hypothesis through speed-dating, an ecologically valid paradigm with real life consequences. Fifteen speed-dating sessions of 262 single Asian Americans were held. We analyzed 850 speed-dates involving 132 men and 100 normally ovulating women, finding ovulatory shifts in the desirability of men with more masculine facial measurements (smaller eye-mouth-eye angle, larger lower face to full face height ratio, and smaller facial width to lower face height ratio) in the predicted direction. However, there was no support for ovulatory shifts in preferences for men's self-reported height. In addition, the expected shifts were not found for women's second date offers to men. Therefore, with natural stimuli and in a competitive dating scenario, we partially replicated previously documented ovulatory shifts in women's preferences for men.

Nocturnal mosquito Cryptochrome 1 mediates greater electrophysiological and behavioral responses to blue light relative to diurnal mosquito Cryptochrome 1.

Nocturnal Anopheles mosquitoes exhibit strong behavioral avoidance to blue-light while diurnal Aedes mosquitoes are behaviorally attracted to blue-light and a wide range of other wavelengths of light. To determine the molecular mechanism of these effects, we expressed light-sensing Anopheles gambiae (AgCRY1) and Aedes aegypti (AeCRY1) Cryptochrome 1 (CRY) genes under a crypGAL4-24 driver line in a mutant Drosophila genetic background lacking native functional CRY, then tested behavioral and electrophysiological effects of mosquito CRY expression relative to positive and negative CRY control conditions. Neither mosquito CRY stops the circadian clock as shown by robust circadian behavioral rhythmicity in constant darkness in flies expressing either AgCRY1 or AeCRY1. AgCRY1 and AeCRY1 both mediate acute increases in large ventral lateral neuronal firing rate evoked by 450 nm blue-light, corresponding to CRY's peak absorbance in its base state, indicating that both mosquito CRYs are functional, however, AgCRY1 mediates significantly stronger sustained electrophysiological light-evoked depolarization in response to blue-light relative to AeCRY1. In contrast, neither AgCRY1 nor AeCRY1 expression mediates measurable increases in large ventral lateral neuronal firing rates in response to 405 nm violet-light, the peak of the Rhodopsin-7 photoreceptor that is co-expressed in the large lateral ventral neurons. These results are consistent with the known action spectra of type 1 CRYs and lack of response in cry-null controls. AgCRY1 and AeCRY1 expressing flies show behavioral attraction to low intensity blue-light, but AgCRY1 expressing flies show behavioral avoidance to higher intensity blue-light. These results show that nocturnal and diurnal mosquito Cryptochrome 1 proteins mediate differential physiological and behavioral responses to blue-light that are consistent with species-specific mosquito behavior.

Circ_0026218 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell dysfunction by regulating miR-188-3p/TLR4/NF-κB pathway.

BACKGROUND: Circular RNAs (circRNAs) have shown important regulatory roles in cardiovascular diseases, including atherosclerosis (AS). However, the role and mechanism of circ_0026218 in AS remain unclear. METHODS: The cell model of AS in vitro was established by stimulating human umbilical vein endothelial cells (HUVECs) with oxidized low-density lipoprotein (ox-LDL). In addition, circ_0026218, microRNA-188-3p (miR-188-3p), and toll-like receptor 4 (TLR4) expression was determined via real-time quantitative polymerase chain reaction (RT-qPCR) in serum samples from AS patients and healthy volunteers. Cell proliferation was assessed using Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was measured using flow cytometry. The inflammatory response was assessed using enzyme-linked immunosorbent assay (ELISA). Oxidative stress level was assessed using corresponding kits. Nitric oxide (NO) level was examined using NO detection assay. The interaction between miR-188-3p and circ_0026218 or TLR4 was determined via dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. Exosomes were observed using transmission electron microscopy (TEM). The size distribution of exosomes was analyzed using nanoparticle tracking analysis (NTA). RESULTS: Ox-LDL treatment caused HUVEC dysfunction by inhibiting cell proliferation and promoting apoptosis, inflammation, and oxidative stress. Circ_0026218 was upregulated in AS serum samples and ox-LDL-treated HUVECs. Knockdown of circ_0026218 attenuated ox-LDL-induced dysfunction in HUVECs. MiR-188-3p acted as a target of circ_0026218, and miR-188-3p downregulation reversed the suppression role of circ_0026218 knockdown on ox-LDL-induced HUVEC disorder. TLR4 was a target of miR-188-3p, and miR-188-3p overexpression alleviated ox-LDL-induced dysfunction in HUVECs by targeting TLR4. Circ_0026218 could deregulate the TLR4/NF-κB pathway by sponging the miR-188-3p. Importantly, circ_0026218 was overexpressed in exosomes from ox-LDL-treated HUVECs and could be delivered via exosomes. CONCLUSION: Circ_0026218 knockdown attenuated ox-LDL-induced dysfunction in HUVECs via regulating miR-188-3p/TLR4/NF-κB pathway.