24036 research outputs found
Sort by
Loss of structural specificity in 3D genome organization upon viral infection is predicted by polymer physics
No full textIn the last years, it has been proved that some viruses are able to re-structure chromatin organization and alter the epigenomic landscape of the host genome. In addition, they are able to affect the physical mechanisms shaping chromatin 3D structure, with a consequent impact on gene activity. Here, we investigate with polymer physics genome re-organization of the host genome upon SARS-CoV-2 viral infection and how it can impact structural variability within the population of single-cell chromatin configurations. Using published Hi-C data and molecular dynamics simulations, we build ensembles of 3D configurations representing single-cell chromatin conformations in control and SARS-CoV-2 infected conditions. We focus on genomic length scales of TADs and consider, as a case study, models of real loci containing DDX58 and IL6 genes, belonging, respectively, to the antiviral interferon response and pro-inflammatory genes. Clustering analysis applied to the ensemble of polymer configurations reveals a generally increased variability and a more heterogeneous population of 3D structures in infected conditions. This points toward a scenario in which viral infection leads to a loss of chromatin structural specificity with, likely, a consequent impact on the correct regulation of host cell genes
Prognostic value of CD163(+) macrophages in solid tumor malignancies: a scoping review
Get PDFTumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163(+) TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163(+) TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163(+) cells was associated with poor patient outcome, and this association was more frequently observed when CD163(+) cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163(+) TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163(+) TAMs as targets of future immunotherapies
Everolimus with or without mycophenolate mofetil for graft-versus-host disease prophylaxis after hematopoietic stem cell transplantation in children with acute kidney injury: a single-center retrospective Analysis
Get PDFHematopoietic stem cell transplantation (HSCT) serves as a therapeutic intervention for various pediatric diseases. Acute and chronic graft-versus-host disease (GVHD) are decisive determinants of successful allogeneic HSCT. The immunosuppressive agent cyclosporin A (CsA) is most often used to prevent GVHD in pediatric patients, but it is known to be nephrotoxic. Acute kidney injury (AKI) affects 17% to 47% of pediatric HSCT recipients, compromising clinical outcomes. This retrospective single-institution analysis scrutinized the practice of substituting nephrotoxic CsA with an everolimus/mycophenolate mofetil (MMF) combination as GVHD prophylaxis in 57 patients with AKI (n = 53) or central nervous system side effects due to calcineurin inhibitor (CNI) treatment (n = 4) following first allogeneic HSCT. This retrospective cohort study analyzed the clinical courses of 57 children who were switched from CNI-based GVHD prophylaxis (CsA or tacrolimus in single cases) to the everolimus/MMF combination (n = 48) or everolimus alone (n = 9) after undergoing their first allogeneic HSCT at the Charité University Medicine Berlin. Serving as a control group were 74 patients undergoing their first allogeneic HSCT during the same period who did not receive everolimus at any time post-transplantation. Patients undergoing mismatched family donor transplantation without subsequent CNI treatment for GVHD prophylaxis were excluded. Study endpoints encompassed the retention parameter course subsequent to the GVHD prophylaxis switch, overall survival (OS), and incidences of underlying disease relapse and acute and chronic GVHD in both treatment groups. Renal function improved significantly after switching from CsA to the everolimus/MMF combination. Crucially, the transition to everolimus did not adversely affect OS following HSCT (hazard ratio [HR], 1.6; 95% confidence interval [CI], 0.74 to 3.5; P = .23), especially for patients with nonmalignant diseases (HR, 1.4; 95% CI, 0.34 to 5.9; P = .64). The incidences of grade III-IV acute GVHD (HR, 1.82; 95% CI, 0.45 to 7.4; P = .40) and severe chronic GVHD (HR, 2.76; 95% CI, 0.69 to 11.0; P = .15) were comparable in patients treated with the everolimus/MMF combination and those receiving standard CsA treatment in the control group. OS in patients with malignant underlying diseases was lower in the everolimus group (HR, 2.7; 95% CI, 1.1 to 6.9; P = .03), however, event-free survival was similar in patients with an underlying malignant disease treated with either the everolimus/MMF combination or CsA (HR, 0.87; 95% CI, 0.39 to 1.9; P = .73). Renal function improved significantly in patients who switched their immunosuppression regimen from CsA to everolimus with or without MMF cotreatment after diagnosis of AKI. Patient outcomes in the everolimus group were comparable to those in the control group. This study provides compelling real-world clinical evidence to support replacing CsA with the everolimus/MMF combination in the management of AKI following HSCT in children
Preventive effects of botulinum neurotoxin long-term therapy: comparison of the ‘experienced’ benefits and ‘suspected’ worsening across disease entities
Get PDFBackground: Repetitive intramuscular injections of botulinum neurotoxin (BoNT) have become the treatment of choice for a variety of disease entities. But with the onset of BoNT therapy, the natural course of a disease is obscured. Nevertheless, the present study tries to analyze patients' "suspected" course of disease severity under the assumption that no BoNT therapy had been performed and compares that with the "experienced" improvement during BoNT treatment. Methods: For this cross-sectional study, all 112 BoNT long-term treated patients in a botulinum toxin out-patient department were recruited who did not interrupt their BoNT/A therapy for more than two injection cycles during the last ten years. Patients had to assess the remaining severity of their disease as a percentage of the severity at onset of BoNT therapy and to draw three different graphs: (i) the CoDB-graph showing the course of severity of patient's disease from onset of symptoms to onset of BoNT/A therapy, (ii) the CoDA-graph illustrating the course of severity from onset of BoNT/A therapy until recruitment, and (iii) the CoDS-graph visualizing the suspected development of disease severity from onset of BoNT/A therapy until recruitment under the assumption that no BoNT/A therapy had been performed. Three different types of graphs were distinguished: the R-type indicated a rapid manifestation or improvement, the C-type a continuous worsening or improvement, and the D-type a delayed manifestation or response to BoNT therapy. Four patient subgroups (cervical dystonia, other cranial dystonia, hemifacial spasm, and the migraine subgroup) comprised 91 patients who produced a complete set of graphs which were further analyzed. The "experienced" improvement and "suspected" worsening of disease severity since the onset of BoNT/A therapy were compared and correlated with demographical and treatment related data. Results: Improvement was significant (p < 0.05) and varied between 45 and 70% in all four patient subgroups, the "suspected" worsening was also significantly (p < 0.05) larger than 0, except in the migraine patients and varied between 10 and 70%. The "total benefit" (sum of improvement and prevented "suspected" worsening) was the highest in the other cranial dystonia group and the lowest in the migraine subgroup. The distributions of R-,C-,D-type graphs across CoDB-, CoDS-, and CoDB-graphs and across the four patient subgroups were significantly different. Conclusions: (i) Most BoNT long-term treated patients have the opinion that their disease would have further progressed and worsened if no BoNT/A therapy had been performed, (ii) The type of response to BoNT/A is different across different subgroups of BoNT/A long-term treated patients
Diurnal timing of physical activity in relation to obesity and diabetes in the German National Cohort (NAKO)
Get PDFBACKGROUND: Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes. METHODS: We cross-sectionally analyzed hip-worn accelerometry data from 61,116 participants aged 20–75 in the German National Cohort between 2015 and 2019. We divided physical activity into sex- and age-standardized quartiles of total morning (06:00–11:59), afternoon (12:00–17:59), evening (18:00–23:59), and nighttime (00:00–06:00) physical activity. Using multivariable logistic regression, we estimated associations of physical activity timing with obesity (BMI ≥ 30.0 kg/m2) and diabetes (self-reported or HbA1c ≥ 6.5%). We accounted for sex, age, study region, education, employment, risky alcohol use, smoking, night shift work, and sleep duration. RESULTS: High afternoon (top vs. bottom quartile, OR: 0.36, 95% CI: 0.33–0.38) and evening physical activity (OR: 0.45, 95% CI: 0.42–0.48) showed lower obesity odds than high morning activity (OR: 0.71, 95% CI: 0.66–0.76), whereas nighttime activity increased obesity odds (OR: 1.58, 95% CI: 1.48–1.68). Associations were similar for diabetes, with the lowest odds for afternoon (OR: 0.47, 95% CI: 0.42–0.53), followed by evening (OR: 0.56, 95% CI: 0.50–0.62) and morning activity (OR: 0.80, 95% CI: 0.71–0.89), and higher odds for nighttime activity (OR: 1.43, 95% CI: 1.29–1.58). Findings were not modified by employment status, night shift work, and sleep duration. CONCLUSIONS: Our cross-sectional findings require longitudinal corroboration but suggest afternoon and evening activity provide greater metabolic health benefits than morning activity, while nighttime activity is discouraged
Generation of a human induced pluripotent stem cell line (BIHi292-A) from PBMCs of a female patient diagnosed with Nasu-Hakola disease (NHD)/polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) carrying a novel heterozygous mutation in the TREM2 gene
Get PDFNHD/PLOSL is an orphan disease characterized by progressive presenile dementia associated with recurrent fractures due to polycystic bone lesions. In this study, we generated the human induced pluripotent stem cell (hiPSC) line BIHi292-A from a 30-year-old women diagnosed with NHD/PLOSL, carrying two compound heterozygous frameshift mutations [c.313del (p.Ala105fs) and c.199del (p.His67fs)] in the TREM2 (triggering receptor expressed on myeloid cells 2) gene. BIHi292-A hiPSCs are karyotypically normal, express typical markers for the undifferentiated state and have pluripotent differentiation potential. BIHi292-A cells will provide a valuable tool for investigating pathogenic mechanisms of NHD/PLOSL and TREM2-related research questions
Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion
Get PDFHerpes simplex virus 1 (HSV-1) infects about 50-80% of the entire human population and persists in the neurons of affected individuals. A fraction of affected individuals suffer from recurrent cold sores caused by reactivating virus, in rare but severe cases the virus can cause encephalitis. During lytic infection, the virus relies on host factors such as RNA polymerase II and accessory proteins involved in transcription to express its genes and ensure successful replication. In general, RNA molecules in cells are bound by RNA-binding proteins (RBPs) during their entire lifecycle. Importantly, RBPs are increasingly described to also regulate transcription, an aspect long time outside the scope of investigations, especially during viral infections. Here, we examined the impact of five nuclear proteins (FUBP1, SLBP, SFPQ, SPT5 and SAF-B) with known RNA-binding activities on HSV-1 transcription. Additionally, we evaluated their importance for human adenovirus C5 (HAdV) growth to assess whether these host factors are specific to HSV-1 infections or might have broader relevance for the general transcription of dsDNA viruses. We show that the transcriptional elongation factor SPT5 coded by SUPT5H accumulates on HSV-1 genomes early during the infection and is required for the transcription of the immediate-early gene UL54. Its depletion affects also HAdV replication, indicating a general role in transcription of viruses that depend on the host transcriptional machinery. In contrast, depletion of the transcriptional repressor and paraspeckle protein SFPQ reduces UL54 RNA levels in HSV-1 infection, but does not cause significant changes in HAdV growth. Since SFPQ does not co-localize with HSV-1 genomes, this suggests a function not directly associated to viral DNA
OCT-based retina assessment reflects visual impairment in multiple sclerosis
Get PDFPURPOSE: To explore the relationship between visual performance and retinal morphology as assessed by optical coherence tomography (OCT), and the ability of OCT to reflect visual impairment in people with multiple sclerosis (PwMS) compared with healthy controls (HC). METHODS: We gathered data from two neurology referral centers on PwMS and HC. Neurological and ophthalmological assessments, including OCT, high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA), area under the log contrast sensitivity function (AULCSF), and vision-related quality of life (National Eye Institute Visual Function Questionnaire), were conducted between 2018 and 2020, with follow-up at 1 year. RESULTS: A total of 137 PwMS (271 eyes) and 118 HC (236 eyes) were available for analysis. The peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell layer and inner plexiform layer volume (mGCIPL) volume were both reduced in PwMS (92 µm in PwMS vs 98 µm in HC [P < 0.001], 0.55 mm3 vs 0.62 mm3 [P < 0.001], respectively). A cutoff effect for visual impairment was observed in PwMS when pRNFL fell below 68.8 µm (HCVA), 71.4 µm (LCVA), and 72.6 µm (AULCSF). Using mixed effects models, the mGCIPL volume emerged as the variable most strongly associated with the AULCSF (P < 0.001). The AULCSF showed the strongest correlation with both pRNFL and mGCIPL (P < 0.001), with optic neuritis being a significant contributing factor (P < 0.001). CONCLUSIONS: AULCSF outperformed standard HCVA and LCVA, closely reflecting retinal atrophy. mGCIPL loss showed stronger associations with vision tests and detected neurodegeneration without the cutoff effect seen in pRNFL, making it the best marker for neuronal atrophy
Gut microbiome alterations precede graft rejection in kidney transplantation patients
Get PDFKidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might be associated with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of whom 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring chronic kidney disease (CKD)-to-health transition as indicated by an increase in Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and short-chain fatty acid–producing taxa. Functional analysis highlighted a decreased potential for short-chain fatty acid production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Postrejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions