Lineage-aware evolutionary analysis of hepatitis C virus within-host dynamics

Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e. treatment failure) and had sequenced virus from multiple timepoints. For each individual, we tracked concordance in nucleotide variant frequencies through time. Using a sliding window approach, we applied sequenced-based and tree-based clustering algorithms across the entire HCV genome. Finally, we reconstructed viral haplotypes and estimated lineage specific within-host divergence rates from the haplotype phylogenies. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates or different selection pressures. We propose lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations

Diagnostic and prognostic role of circRNAs in pancreatic cancer: a meta-analysis

BackgroundCircular RNAs (circRNAs) are types of endogenous noncoding RNAs produced by selective splicing that are expressed highly specifically in various organisms and tissues and have numerous clinical implications in the regulation of cancer development and progression. Since circRNA is resistant to digestion by ribonucleases and has a long half-life, there is increasing evidence that circRNA can be used as an ideal candidate biomarker for the early diagnosis and prognosis of tumors. In this study, we aimed to reveal the diagnostic and prognostic value of circRNA in human pancreatic cancer (PC).MethodsA systematic search for publications from inception to 22 July 2022 was conducted on Embase, PubMed, Web of Science (WOS), and the Cochrane Library databases. Available studies that correlated circRNA expression in tissue or serum with the clinicopathological, diagnostic, and prognostic values of PC patients were enrolled. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to evaluate clinical pathological characteristics. Area under the curve (AUC), sensitivity, and specificity were adopted to assess diagnostic value. Hazard ratios (HRs) were utilized to assess disease-free survival (DFS) and overall survival (OS).ResultsThis meta-analysis enrolled 32 eligible studies, including six on diagnosis and 21 on prognosis, which accounted for 2,396 cases from 245 references. For clinical parameters, high expression of carcinogenic circRNA was significantly associated with degree of differentiation (OR = 1.85, 95% CI = 1.47–2.34), TNM stage (OR = 0.46, 95% CI = 0.35–0.62), lymph node metastasis (OR = 0.39, 95% CI = 0.32–0.48), and distant metastasis (OR = 0.26, 95% CI = 0.13–0.51). As for clinical diagnostic utility, circRNA could discriminate patients with pancreatic cancer from controls, with an AUC of 0.86 (95% CI: 0.82–0.88), a relatively high sensitivity of 84%, and a specificity of 80% in tissue. In terms of prognostic significance, carcinogenic circRNA was correlated with poor OS (HR = 2.00, 95% CI: 1.76–2.26) and DFS (HR = 1.96, 95% CI: 1.47–2.62).ConclusionIn summary, this study demonstrated that circRNA may act as a significant diagnostic and prognostic biomarker for pancreatic cancer

Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure

Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations

Mulberry biomass-derived nanomedicines mitigate colitis through improved inflamed mucosa accumulation and intestinal microenvironment modulation

The therapeutic outcomes of conventional oral medications against ulcerative colitis (UC) are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment. Herein, a fluorinated pluronic (FP127) was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles (MLNs) loading with resveratrol nanocrystals (RNs). The obtained FP127@RN-MLNs possessed exosome-like morphologies, desirable particle sizes (around 171.4 nm), and negatively charged surfaces (â 14.8 mV). The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect. These MLNs could efficiently be internalized by colon epithelial cells and macrophages, reconstruct disrupted epithelial barriers, alleviate oxidative stress, provoke macrophage polarization to M2 phenotype, and down-regulate inflammatory responses. Importantly, in vivo studies based on chronic and acute UC mouse models demonstrated that oral administration of chitosan/alginate hydrogel-embedding FP127@RN-MLNs achieved substantially improved therapeutic efficacies compared with nonfluorinated MLNs and a first-line UC drug (dexamethasone), as evidenced by decreased colonic and systemic inflammation, integrated colonic tight junctions, and intestinal microbiota balance. This study brings new insights into the facile construction of a natural, versatile nanoplatform for oral treatment of UC without adverse effects.We are grateful to Dr. J. Sun from University of Oxford for his corrections and improvement of this manuscript. Funding: This study was supported by the National Natural Science Foundation of China (82072060 and 22008201), the Fundamental Research Funds for the Central Universities (SWU-XDPY22006), the Venture & Innovation Support Program for Chongqing Overseas Returnees (2205012980212766), the Natural Science Foundation Project of Chongqing (cstc2020jcyj-msxmX0292), and the Natural Science Foundation Project of Chongqing for Distinguished Young Scholar. Author contributions: W.Y., M.W., X.S., and B.X. designed experiments, supervised the project, and wrote the manuscript draft. W.Y., Y.M., H.X., Z.Z., J.W., C.X., W.S., and E.Z. performed the experiments. R.L.R., S.C.K., M.W., X.S., and B.X. edited and revised the manuscript. All authors have approved the final version of the manuscript. Competing interests: The authors declare that there is no con flict of interest regarding the publication of this article

Structural and functional changes of the cerebellum in temporal lobe epilepsy

AimsThis study aimed to comprehensively explore the cerebellar structural and functional changes in temporal lobe epilepsy (TLE) and its association with clinical information.MethodsThe SUIT toolbox was utilized to perform cerebellar volume and diffusion analysis. In addition, we extracted the average diffusion values of cerebellar peduncle tracts to investigate microstructure alterations. Seed-based whole-brain analysis was used to investigate cerebellar–cerebral functional connectivity (FC). Subgroup analyses were performed to identify the cerebellar participation in TLE with/without hippocampal sclerosis (HS)/focal-to-bilateral tonic–clonic seizure (FBTCS) and TLE with different lateralization.ResultsTLE showed widespread gray matter atrophy in bilateral crusII, VIIb, VIIIb, left crusI, and left VIIIa. Both voxel and tract analysis observed diffusion abnormalities in cerebellar afferent peduncles. Reduced FC between the right crus II and the left parahippocampal cortex was found in TLE. Additionally, TLE showed increased FCs between left lobules VI–VIII and cortical nodes of the dorsal attention and visual networks. Across all patients, decreased FC was associated with poorer cognitive function, while increased FCs appeared to reflect compensatory effects. The cerebellar structural changes were mainly observed in HS and FBTCS subgroups and were regardless of seizure lateralization, while cerebellar–cerebral FC alterations were similar in all subgroups.ConclusionTLE exhibited microstructural changes in the cerebellum, mainly related to HS and FBTCS. In addition, altered cerebellar–cerebral functional connectivity is associated with common cognitive alterations in TLE

Low-dose emapalumab treatment in refractory macrophage activation syndrome secondary to adult onset still’s disease/systemic lupus erythematosus: insights from nine cases

ObjectiveMacrophage activation syndrome (MAS) is frequently secondary to rheumatic diseases, with features including a cytokine storm and hemophagocytosis. Emapalumab is a monoclonal antibody that targets interferon-γ and has the ability to precisely regulate cytokines. This study aimed to investigate the efficacy and safety of low-dose emapalumab for patients with refractory MAS in the Chinese population.MethodsFrom January 2022 to July 2024, 9 patients with MAS secondary to adult-onset Still’s disease (AOSD) or systemic lupus erythematosus (SLE) received low-dose emapalumab following no response to prior conventional therapies. The laboratory parameters, therapeutic response, and safety were assessed following low-dose emapalumab-based treatment.ResultsOf the nine MAS patients, 5 patients were secondary to AOSD and 4 patients were secondary to SLE. The overall response rate was 66.7% (6/9), 77.8% (7/9), 88.9% (8/9) and 88.9% (8/9) at week 1, 2, 4 and week 8, respectively. At the end of the follow-up period, up to 88.9% (8/9) of patients achieved complete remission. All patients demonstrated improvement or normalization of clinical manifestations and laboratory parameters. Notably, the median prednisone-equivalent dose for the patients was reduced by 85.5% during the treatment. Cytomegalovirus infection occurred in 33.9% (3/9) of patients, with no occurrence of serious adverse events reported.ConclusionOur findings suggest that low-dose emapalumab may be a promising salvage option for refractory MAS in the Chinese population, but confirmation in larger prospective studies is required

Case Report: Clinical management of a severe DBA patient with a novel RPS19 mutation

Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by defective erythropoiesis, typically caused by mutations in ribosomal protein (RP) genes, most commonly RPS19. It usually presents in early infancy with severe anemia, growth retardation, and an increased risk of congenital malformations and malignancies. However, cases of DBA leading to severe anemia and shock are exceedingly rare. This case report describes a life-threatening presentation of DBA in a 56-day-old female infant who presented with severe anemia and shock. The infant was admitted with a 2-day history of poor feeding and persistent crying, accompanied by hypothermia (34.4°C), unresponsiveness, and profound pallor. Initial laboratory findings revealed critical anemia (hemoglobin 18 g/L) and severe metabolic acidosis (pH 6.61, base excess −36.06 mmol/L). Hemodynamic instability, including undetectable blood pressure and prolonged capillary refill time, indicated shock. Immediate interventions, including volume expansion with normal saline, correction of acidosis with sodium bicarbonate, and packed red blood cells (PRBCs) transfusion, stabilized the infant. Genetic testing identified a de novo heterozygous mutation in the RPS19 gene (c.3G > T), confirming the diagnosis of DBA. Over the course of a 1-year follow-up, the infant required regular blood transfusions at approximately 4-week intervals to sustain hemoglobin levels within the range of 69–86 g/L. Growth retardation and poor appetite were observed, consistent with the known complications of DBA. This case highlights the importance of early recognition and aggressive management of severe anemia in infants, particularly in the context of DBA, to prevent life-threatening complications such as shock and metabolic acidosis. The role of genetic testing in confirming the diagnosis and guiding long-term management is emphasized. This report also reviews the literature on DBA, focusing on the pathophysiology of anemia, the association between RPS19 mutations and clinical phenotypes, and the challenges of managing transfusion-dependent patients. The findings underscore the need for a multidisciplinary approach to DBA, including regular monitoring for complications such as iron overload, growth retardation, and malignancy risk. Early genetic counseling and tailored therapeutic strategies are crucial for improving outcomes in this rare and complex disorder

Synthesis and White-Light Emission of ZnO/HfO2: Eu Nanocables

ZnO/HfO2:Eu nanocables were prepared by radio frequency sputtering with electrospun ZnO nanofibers as cores. The well-crystallized ZnO/HfO2:Eu nanocables showed a uniform intact core–shell structure, which consisted of a hexagonal ZnO core and a monoclinic HfO2 shell. The photoluminescence properties of the samples were characterized. A white-light band emission consisted of blue, green, and red emissions was observed in the nanocables. The blue and green emissions can be attributed to the zinc vacancy and oxygen vacancy defects in ZnO/HfO2:Eu nanocables, and the yellow–red emissions are derived from the inner 4f-shell transitions of corresponding Eu3+ ions in HfO2:Eu shells. Enhanced white-light emission was observed in the nanocables. The enhancement of the emission is ascribed to the structural changes after coaxial synthesis