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Complexome profiling (CP) is a powerful tool for systematic investigation of protein interactors that has been primarily applied to study the composition and dynamics of mitochondrial protein complexes. Here, we further optimised this method to extend its application to survey mitochondrial DNA- and RNA-interacting protein complexes. We established that high-resolution clear native gel electrophoresis (hrCNE) is a better alternative to preserve DNA- and RNA-protein interactions that are otherwise disrupted when samples are separated by the widely used blue native gel electrophoresis (BNE). In combination with enzymatic digestion of DNA, our CP approach improved the identification of a wide range of protein interactors of the mitochondrial gene expression system without compromising the detection of other multi-protein complexes. The utility of this approach was particularly demonstrated by analysing the complexome changes in human mitochondria with impaired gene expression after transient, chemically-induced mtDNA depletion. Effects of RNase on mitochondrial protein complexes were also evaluated and discussed. Overall, our adaptations significantly improved the identification of mitochondrial DNA- and RNA-protein interactions by CP, thereby unlocking the comprehensive analysis of a near-complete mitochondrial complexome in a single experiment.
Bilateral simultaneous cochlear implantation is a safe method of hearing rehabilitation in adults
(2023)
Purpose: Bilateral cochlear implantation is an effective treatment for patients with bilateral profound hearing loss. In contrast to children, adults mostly choose a sequential surgery. This study addresses whether simultaneous bilateral CI is associated with higher rates of complications compared to sequential implantation.
Methods: 169 bilateral CI surgeries were analyzed retrospectively. 34 of the patients were implanted simultaneously (group 1), whereas 135 patients were implanted sequentially (group 2). The duration of surgery, the incidence of minor and major complications and the duration of hospitalization of both groups were compared.
Results: In group 1, the total operating room time was significantly shorter. The incidences of minor and major surgical complications showed no statistically significant differences. A fatal non-surgical complication in group 1 was particularly extensively reappraised without evidence of a causal relationship to the chosen mode of care. The duration of hospitalization was 0.7 days longer than in unilateral implantation but 2.8 days shorter than the combined two hospital stays in group 2.
Conclusion: In the synopsis of all considered complications and complication-relevant factors, equivalence of simultaneous and sequential cochlear implantation in adults in terms of safety was found. However, potential side effects related to longer surgical time in simultaneous surgery must be considered individually. Careful patient selection with special consideration to existing comorbidities and preoperative anesthesiologic evaluation is essential.
Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range of diseases is associated with impaired Ub modification. In this light, the Ub system offers an attractive, yet underexplored route to the development of novel targeted treatments. A promising strategy for small molecule intervention is posed by the final components of the enzymatic ubiquitination cascade, E3 ligases, as they determine the specificity of the protein ubiquitination pathway. Here, we present UbSRhodol, an autoimmolative Ub-based probe, which upon E3 processing liberates the pro-fluorescent dye, amenable to profile the E3 transthiolation activity for recombinant and in cell-extract E3 ligases. UbSRhodol enabled detection of changes in transthiolation efficacy evoked by enzyme key point mutations or conformational changes, and offers an excellent assay reagent amenable to a high-throughput screening setup allowing the identification of small molecules modulating E3 activity.
Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (BMEM) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. Whereas selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
Objective In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking.
Methods In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280).
Results 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia.
Conclusion Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA.
Trial registration number It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).
Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy.
Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected.
Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI.
Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics.
However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
We report a case of a 2-day-old neonate with bilious vomiting and abdominal distension. A small bowel obstruction with ileal perforation due to a misplaced clamping of the umbilical cord was apparent before laparotomy. This complication was a sequala after clamping the cord too close to the abdominal wall in a case where there was a hernia into the cord with intestinal content. A herniation of abdominal contents due to an omphalocele minor or a hernia must be taken into consideration during the inspection of the umbilical cord before clamping.
Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and psoriasis (Ps), represent autoinflammatory and autoimmune disorders, as well as conditions that have an overlap of both categories. Understanding the underlying pathogeneses, making diagnoses, and choosing individualized treatments remain challenging due to heterogeneous disease phenotypes and the lack of reliable biomarkers that drive the treatment choice. In this review, we provide an overview of the low-molecular-weight metabolites that might be employed as biomarkers for various applications, e.g., early diagnosis, disease activity monitoring, and treatment-response prediction, in RA, PsA, and Ps. The literature was evaluated, and putative biomarkers in different matrices were identified, categorized, and summarized. While some of these candidate biomarkers appeared to be disease-specific, others were shared across multiple IMIDs, indicating common underlying disease mechanisms. However, there is still a long way to go for their application in a routine clinical setting. We propose that studies integrating omics analyses of large patient cohorts from different IMIDs should be performed to further elucidate their pathomechanisms and treatment options. This could lead to the identification and validation of biomarkers that might be applied in the context of precision medicine to improve the clinical outcomes of these IMID patients.