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Effects of Transcranial Alternating Current Stimulation over the Dorsolateral Prefrontal Cortex on Implicit Learning in Older Adults
No full textDer demografische Wandel führt zu einem zunehmenden Bedarf an Diagnostik und Behandlungsoptionen für eine alternde Bevölkerung, wobei nicht-invasive Hirnstimulation als potenzielles Verfahren zur Modulation kognitiver Prozesse im höheren Lebensalter zunehmend an Bedeutung gewonnen hat. Während sich bisherige Forschung vor allem auf explizite Gedächtnisleistungen und das Arbeitsgedächtnis konzentriert hat, ist die nicht-deklarative Kognition, einschließlich impliziter Lernprozesse, in der Literatur vergleichsweise unterrepräsentiert. Insbesondere die Rolle des dorsolateralen präfrontalen Kortex (DLPFC) beim impliziten sequenziellen Lernen sowie dessen Modulierbarkeit durch transkranielle Wechselstromstimulation (tACS) sind bislang nicht ausreichend verstanden. Ziel der vorliegenden Studie war es daher zu untersuchen, ob eine Theta-Gamma-Cross-Frequency-tACS über dem DLPFC in Kombination mit einem computerbasierten kognitiven Training (CCT) das implizite Sequenz-spezifische Lernen bei älteren Erwachsenen beeinflusst. In einem randomisierten, dreifach verblindeten, Sham-kontrollierten Studiendesign erhielten 35 ältere Teilnehmende im Alter zwischen 55 und 82 Jahren insgesamt 16 Sitzungen entweder aktiver bilateraler Theta-Gamma-Cross-Frequency-tACS oder Sham-Stimulation, jeweils in Kombination mit CCT. Das implizite Lernen wurde mithilfe des Alternating Serial Reaction Time (ASRT)-Tests erfasst, wodurch sowohl das Visuomotorische Lernen als auch das Sequenz-spezifische Lernen untersucht werden konnten. Die Ergebnisse wurden mittels Messwiederholungs-ANOVA analysiert. Zusätzlich wurden demografische und klinisch erhobene Variablen wie Alter, kognitiver Status, depressive Symptomatik, Angstsymptomatik und Bildungsdauer in die Analysen einbezogen. Die Ergebnisse zeigten keine signifikanten Effekte der tACS-Intervention auf das Sequenz-spezifische implizite Lernen. Obwohl im Visuomotorischen Lernen Offline-Effekte über die Sitzungen hinweg beobachtet werden konnten, zeigten sich keine signifikanten Unterschiede zwischen aktiver tACS- und Sham-Stimulation. Darüber hinaus fanden sich keine signifikanten Modulationen durch Alter, Bildungsdauer, depressive Symptome oder Angstsymptomatik. Im Gegensatz dazu zeigte eine zuvor publizierte Analyse desselben Datensatzes mittels linear gemischter Modelle, dass aktive tACS im Vergleich zur Sham-Stimulation zu Verbesserungen der visuomotorischen Fähigkeiten unmittelbar nach der Intervention führte, die auch drei Monate später anhielten, insbesondere bei jüngeren älteren Teilnehmenden sowie bei Personen mit geringerer kognitiver Performance beim Baseline-Assessment. Zusammenfassend zeigten die Ergebnisse, basierend auf den in der vorliegenden Studie angewandten statistischen Analysen, keine signifikanten Effekte einer Theta-Gamma-tACS im Vergleich zu Sham-tACS über dem DLPFC unter den vorliegenden Studienbedingungen auf das implizite Sequenz-spezifische Lernen bei älteren Erwachsenen. Zukünftige Studien sollten daher individualisierte Stimulationsprotokolle, neurophysiologische Messungen sowie adaptive Stimulationsdesigns berücksichtigen, um die Rolle von tACS bei der Modulation impliziter Lernprozesse im Alter weiter zu untersuchen.Demographic changes lead to an increasing demand for diagnosis and treatment targeting an aging population, and non-invasive brain stimulation has gained increasing attention as a potential tool to modulate cognitive processes in later life. While previous research has primarily focused on explicit and working memory, non-declarative cognition, including implicit learning, has been comparatively underrepresented in the literature. In particular, the role of the dorsolateral prefrontal cortex (DLPFC) in implicit sequence learning and its modulation by transcranial alternating current stimulation (tACS) remain insufficiently understood. The aim of the present study was therefore to investigate whether theta–gamma cross-frequency tACS applied over the DLPFC, in combination with computerized cognitive training (CCT), influences implicit sequence learning in older adults. In a randomized, triple-blind, sham-controlled design, 35 participants aged between 55 and 82 years received 16 sessions of either active bilateral theta–gamma cross-frequency tACS or sham stimulation, both combined with CCT. Implicit learning was assessed using the Alternating Serial Reaction Time (ASRT) task, allowing the evaluation of visuomotor skill learning and probabilistic sequence learning. The outcomes were analyzed using repeated-measures ANOVA. Additional analyses included demographic and clinically assessed variables such as age, cognitive status, depressive symptoms, anxiety, and education level. The findings revealed no significant effects of the tACS intervention on sequence-specific implicit learning. Although visuomotor learning showed offline effects across sessions, no significant group differences between active tACS and sham stimulation were observed. Furthermore, no significant modulation by age, education level, depressive symptoms, or anxiety was found. In contrast, a previously published analysis of the same dataset using linear mixed models demonstrated superior visuomotor performance following active tACS compared to sham stimulation, with effects evident immediately after the intervention and still present at three-month follow-up, particularly in relatively younger older adults and individuals with lower baseline cognitive performance. In conclusion, the findings suggest that theta–gamma tACS applied over the DLPFC does not enhance implicit sequence learning in older adults compared to sham-tACS under the present study conditions and the employed statistical analyses. Future studies should therefore incorporate individualized stimulation protocols, neurophysiological measures, and adaptive stimulation designs to further investigate the role of tACS in modulating implicit learning processes in aging.2026-03-0
The impact of brentuximab vedotin on the regulation of mitochondrial apoptosis in peripheral T-cell lymphomas
No full textPeriphere T-Zell-Lymphome (PTCL) stellen eine seltene und biologisch heterogene Gruppe aggressiver lymphatischer Neoplasien dar, die trotz intensiver Therapieansätze mit einer ungünstigen Prognose assoziiert sind. Mit dem CD30-gerichteten Antikörper-Wirkstoff-Konjugat Brentuximab Vedotin (BV) wurde eine zielgerichtete Therapie etabliert, die insbesondere beim anaplastisch-großzelligen Lymphom (ALCL) zu verbesserten klinischen Ergebnissen geführt hat. Dennoch entwickeln viele Patientinnen und Patienten eine primäre oder sekundäre Therapieresistenz.
Ziel dieser Arbeit war es, die zytotoxischen Effekte von Brentuximab Vedotin in CD30-positiven PTCL-Zelllinien zu charakterisieren und die zugrunde liegenden Mechanismen der mitochondrialen Apoptoseregulation sowie potenzielle Resistenzmechanismen zu untersuchen. Hierzu wurden verschiedene PTCL-Zelllinien mit BV behandelt und hinsichtlich Zellviabilität, Zellzyklusverteilung und Apoptoseinduktion analysiert. Ergänzend erfolgte eine funktionelle Charakterisierung der mitochondrialen Apoptose mittels dynamischem BH3-Profiling. Darüber hinaus wurden Kombinationstherapien mit selektiven Inhibitoren antiapoptotischer Mitglieder der BCL-2-Proteinfamilie evaluiert.
Die Ergebnisse zeigen, dass Brentuximab Vedotin in den meisten untersuchten CD30-positiven ALCL-Zelllinien eine ausgeprägte zytotoxische Wirkung entfaltet, die mit einem G2/M-Zellzyklusarrest und der Induktion mitochondrialer Apoptose einhergeht. Allerdings konnte in allen Zelllinien eine residuale, vitale Zellpopulation nachgewiesen werden, die gegenüber der BV-Therapie resistent blieb. Diese residuellen Zellen wiesen ein vermindertes mitochondriales Priming auf und zeigten funktionelle Veränderungen der Abhängigkeit von antiapoptotischen Proteinen der BCL-2-Familie, insbesondere von BCL-xL und MCL-1. In Kombinationstestungen führte die gleichzeitige Inhibition von BCL-xL zu signifikanten synergistischen Effekten mit Brentuximab Vedotin in ausgewählten Zelllinien.
Zusammenfassend liefert diese Arbeit neue Erkenntnisse zur funktionellen Regulation der mitochondrialen Apoptose und zu möglichen Mechanismen der Therapieresistenz gegenüber Brentuximab Vedotin in peripheren T-Zell-Lymphomen. Die Ergebnisse unterstreichen das Potenzial funktioneller Apoptoseanalysen als Grundlage für die Entwicklung rationaler kombinatorischer Therapiestrategien.Peripheral T-cell lymphomas (PTCL) represent a rare and biologically heterogeneous group of aggressive lymphoid malignancies that are associated with poor clinical outcomes despite intensive therapeutic approaches. The CD30-directed antibody–drug conjugate brentuximab vedotin (BV) has been established as a targeted treatment option and has significantly improved clinical outcomes, particularly in anaplastic large cell lymphoma (ALCL). Nevertheless, primary and acquired resistance to BV therapy remains a major clinical challenge.
The aim of this study was to characterize the cytotoxic effects of brentuximab vedotin in CD30-positive PTCL cell lines and to investigate the underlying mechanisms of mitochondrial apoptosis regulation and potential resistance pathways. PTCL cell lines were treated with BV and analyzed with respect to cell viability, cell cycle distribution, and apoptosis induction. Functional regulation of mitochondrial apoptosis was further assessed using dynamic BH3 profiling. In addition, combination treatments with selective inhibitors targeting anti-apoptotic members of the BCL-2 protein family were evaluated.
The results demonstrate that brentuximab vedotin induces pronounced cytotoxic effects in most CD30-positive ALCL cell lines, accompanied by G2/M cell cycle arrest and activation of mitochondrial apoptosis. However, in all investigated cell lines, a residual viable cell population persisted after BV treatment, indicating incomplete tumor cell eradication. These residual cells exhibited reduced mitochondrial priming and functional alterations in their dependency on anti-apoptotic BCL-2 family proteins, particularly BCL-xL and MCL-1. Combination experiments revealed significant synergistic effects of brentuximab vedotin with selective BCL-xL inhibition in selected cell lines.
In conclusion, this study provides new insights into the functional regulation of mitochondrial apoptosis and identifies potential mechanisms of resistance to brentuximab vedotin in peripheral T-cell lymphomas. The findings highlight the value of functional apoptosis profiling as a tool to better understand therapy resistance and to support the development of rational combination treatment strategies in PTCL.2026-04-0
- Analysis and Ethical Assessment
No full textHintergrund:
Obwohl in Deutschland etwa 90.000 wohnungslose Frauen leben, existiert nur wenig medizinische Forschung zu dieser Bevölkerungsgruppe. Ziel dieser Studie war es, einen umfassenden Überblick über die medizinische Situation wohnungsloser Frauen in Deutschland zu geben und ihre spezifischen Versorgungsbedarfe zu identifizieren. Anschließend wurde die Situation unter medizinethischen Gesichtspunkten bewertet.
Methoden:
Die Studie wurde in zwei Teilen durchgeführt. Zunächst erfolgte eine systematische Literaturrecherche, die sich anfänglich auf nicht geschlechtsspezifische Publikationen aus Deutschland konzentrierte und anschließend auf geschlechtsspezifische Studien aus anderen westlichen Industrienationen ausgedehnt wurde. Eine zusätzliche Literaturrecherche befasste sich mit medizinethischer Fachliteratur zum Thema Wohnungslosigkeit.
Im zweiten Teil wurden qualitative Expert*inneninterviews mit medizinischem Fachpersonal durchgeführt, das in niedrigschwelligen medizinischen Einrichtungen für wohnungslose Menschen tätig ist.
Ergebnisse:
Wohnungslose Frauen stellen eine hoch vulnerable und zugleich unterversorgte Patientinnengruppe dar. Im Vergleich sowohl zur Allgemeinbevölkerung als auch zu wohnungslosen Männern weisen sie deutlich schlechtere Gesundheitsoutcomes auf. Es zeigten sich ausgeprägte geschlechtsspezifische Unterschiede hinsichtlich Morbiditätsmustern und Inanspruchnahme von Versorgungsangeboten. Psychische Erkrankungen und Traumafolgestörungen sind unter wohnungslosen Frauen besonders häufig, und sowohl Mortalitäts- als auch Suizidraten sind alarmierend hoch.
Trotz dieser Risiken bieten nur sehr wenige niedrigschwellige Einrichtungen geschlechtsspezifische oder gynäkologische Versorgung an. Barrieren wie Misstrauen, Scham sowie strukturelle Einschränkungen erschweren zusätzlich den Zugang zu adäquater medizinischer Versorgung.
Insbesondere die ethischen Prinzipien der Fürsorge (Benefizienz) und der Gerechtigkeit sind im Kontext der Wohnungslosenmedizin von zentraler Bedeutung. Unter den derzeitigen Bedingungen werden diese ethischen Ziele jedoch nicht erreicht.
Insgesamt werden die spezifischen Bedürfnisse wohnungsloser Frauen sowohl in der Forschung als auch in der klinischen Praxis weiterhin unzureichend berücksichtigt.
Schlussfolgerung:
Es besteht ein dringender Bedarf an mehr geschlechtersensibler Forschung zu Wohnungslosigkeit und Gesundheitsversorgung in Deutschland. Zukünftige Studien sollten konsequent geschlechtsbezogene Analysen einbeziehen, um einen männlich dominierten Datenbias zu vermeiden. Versorgungsmodelle müssen traumasensibel gestaltet und an die komplexen sozialen und gesundheitlichen Lebensrealitäten wohnungsloser Frauen angepasst werden, um Zugang, Gerechtigkeit und Versorgungsergebnisse nachhaltig zu verbessern.Background:
Although approximately 90,000 homeless women live in Germany, there is only limited medical research on this population group. The aim of this study was to provide a comprehensive overview of the medical situation of homeless women in Germany and to identify their specific healthcare needs. The situation was subsequently evaluated from a medical-ethical perspective.
Methods:
The study was conducted in two parts. First, a systematic literature review was performed, initially focusing on non–gender-specific publications from Germany and subsequently extended to gender-specific studies from other Western industrialized countries. An additional literature review examined medical-ethical literature on the topic of homelessness.
In the second part, qualitative expert interviews were conducted with medical professionals working in low-threshold healthcare facilities for homeless individuals.
Results:
Homeless women constitute a highly vulnerable and at the same time underserved patient population. Compared both to the general population and to homeless men, they exhibit significantly poorer health outcomes. Marked gender-specific differences were identified with regard to morbidity patterns and utilization of healthcare services. Mental illnesses and trauma-related disorders are particularly prevalent among homeless women, and both mortality and suicide rates are alarmingly high.
Despite these risks, only very few low-threshold facilities offer gender-specific or gynecological care. Barriers such as mistrust, shame, and structural limitations further impede access to adequate medical care.
In particular the ethical principles of beneficence and justice are of central importance in the context of healthcare for the homeless. Under current conditions these ethical goals are not being met.
Overall, the specific needs of homeless women continue to be insufficiently addressed in both research and clinical practice.
Conclusion:
There is an urgent need for more gender-sensitive research on homelessness and healthcare in Germany. Future studies should consistently incorporate sex- and gender-based analyses in order to avoid male-dominated data bias. Care models must be trauma-informed and adapted to the complex social and health realities of homeless women in order to sustainably improve access, equity, and health outcomes.2026-03-2
Quantitative cerebral T1 mapping and quantitative CSF flow measurements in patients with idiopathic normal pressure hydrocephalus and idiopathic intracranial hypertension
No full textIdiopathic normal pressure hydrocephalus (iNPH) and idiopathic intracranial hypertension (IIH) are important cerebral disorders with impaired production, circulation or resorption of cerebrospinal fluid (CSF). Despite advances in diagnostic imaging, non-invasive diagnostic tools and disease-specific biomarkers are still rare.
In this study, the diagnostic significance of quantitative cerebral T1 mapping and real-time phase contrast measurements of CSF flow as novel and high-resolution magnetic resonance imaging (MRI) techniques were investigated in 15 patients with suspected iNPH and seven patients with suspected IIH and eleven age-matched healthy controls.
Measurements were performed using 3T MRI. T1 relaxation times were assessed in five or six predefined periventricular regions. CSF flow measurements were performed at three intracranial and two extracranial measurement regions. MRI as well as clinical and neuropsychological testing were performed prior to and after cerebrospinal fluid tap test (CSF-TT) or lumbar puncture (LP).
In our study, periventricular T1 relaxation times were significantly increased in patients with iNPH compared to a healthy control group with most pronounced differences in the anterior (1006 ± 93ms vs. 911 ± 77ms; p= 0.023) and posterior horns (983 ± 103ms vs. 893 ± 68ms; p= 0.037) of the lateral ventricles. Montreal cognitive assessment (MoCA) scores at baseline were negatively correlated with T1 relaxation times (r 0.6 and p < 0.03) after CSF-TT. We found no significant differences in comparing T1 relaxation times before and after the spinal tap test.
Apart from increased relaxation times in the superior anterior horn region we found no significant differences in T1 relaxation times in patients with IIH, compared to the control group, and no significant changes after LP.
Despite improved MRI methods and taking into account the respiratory influence on CSF pulsation, we did not find any predictive value of total CSF flow volumes determined by real-time phase contrast measurements on clinical improvements after LP in either patient group. The severeness of hydrocephalus in patients with iNPH, quantified by the Evans index, correlated with increased intracranial CSF flow volumes, particularly in the aqueduct and 4th ventricle. However, this had no influence on the results after LP.
It can be concluded from our results that T1 mapping represents a new sensitive diagnostic tool for the detection of periventricular tissue changes in iNPH, with a predictive value with regard to an improvement of the gait pattern, in particular gait speed, after the spinal tap test. Analogous findings could not be confirmed in IIH. A conspicuous finding in the superior anterior horn region should be examined in follow-up studies in patients with IIH in earlier stages of the disease, with still elevated CSF pressure.2026-04-0
Enantioselective Electrochemical C–H Activation with Cobalt, Nickel, and Iron
No full textThe enantioselective functionalization of otherwise inert C–H bonds to assemble chiral
molecules has become an increasingly powerful tool in molecular synthesis. In spite of
significant advances in this domain, the reported approaches commonly relied on precious metal
catalysts, while strategies employing 3d transition metal-catalysis remained underexplored,
generally featuring major limitations such as the use of chemical oxidants or organometallic
additives, compromising the overall sustainability. In sharp contrast, this thesis
showcases the enabling potential of the merger of electrosynthesis with enantioselective 3d
transition metal-catalyzed C–H activation. Hence, powerful and resource-economic approaches
for the assembly of versatile chiral compounds were disclosed.2026-03-1
Tau oligomers and stress granules: Molecular insights into slowly and rapidly progressive Alzheimer’s disease
No full textAlzheimer’s disease (AD) exhibits substantial clinical and molecular heterogeneity, with
rapidly progressive AD representing a distinct and aggressive subtype. This study provides an
in-depth characterization of stress granules (SGs) and tau oligomers (TauO) in AD subtypes,
uncovering their molecular interplay and contribution to disease progression. Through
biochemical fractionation, immunoprecipitation, and mass spectrometry we identified distinct
SG proteome in slowly progressive AD (spAD) and rpAD, revealing subtype specific
compositional differences. Transmission electron microscopy (TEM) further demonstrated that
rpAD-associated SGs exhibit increased aggregation, altered morphology and greater
association with lysosomal structures, suggesting impaired clearance mechanisms.
Proteomic analysis of SGs in rpAD highlighted differential enrichment of proteins involved in
cytoskeletal organization, ribonucleoprotein assembly and metabolic processes suggesting
dysfunction of related processes. RNA sequencing of SG-associated transcripts highlighted a
widespread depletion of several crucial RNA species linked to neurodegeneration particularly
in rpAD, including those involved in synaptic function, protein translation and RNA
metabolism. Concurrently, TauO characterization revealed that rpAD cases exhibit distinct
phosphorylation pattern through post translational modifications (PTMs) at serine 396 and
serine 422, and enhanced neurotoxicity in neuronal models compared to spAD. Mass
spectrometry-based interactome analysis showed a significant overlap between SG proteome
and potential TauO interactors, supporting a mechanistic link between tau pathology and SG
dysfunction in AD.
Notably, rpAD exhibited a higher number of unique TauO interactors than spAD, underscoring
the presence of subtype-specific molecular signatures. Functional enrichment analysis
identified shared molecular pathways between SGs and TauO emphasizing RNA-binding,
protein quality control and metabolic dysregulation as key drivers of rapid disease progression.
Ultimately, integration of multi-omics datasets revealed that rpAD is characterized by hyper
aggregated state, defective SG clearance, and toxic tau species that likely accelerate disease
progression. This study provides crucial insights into the molecular signatures distinguishing
AD subtypes.2026-05-1
Structural and functional analyses of the HECT E3 ligase HACE1
No full textMany crucial cellular processes rely on post-translational modifications. In particular, the covalent attachment of ubiquitin molecules, termed ubiquitylation, onto substrates, typically via lysine residues, is most commonly associated with a signal for the proteasomal degradation of the respective modified proteins, among many other roles. Ubiquitylation is mediated by a cascade of enzyme classes: few different ubiquitin-activating enzymes (E1) transfer ubiquitin onto several different ubiquitin-conjugating enzymes (E2), before the final transfer to specific substrates is mediated by many different ubiquitin ligases (E3).
HACE1 (HECT domain and ankyrin repeat containing E3 ubiquitin-protein ligase 1) belongs to the HECT-subclass of E3 ligases and as such employs a catalytic cysteine to accept thioester-linked ubiquitin from E2 enzymes and directly catalyze the isopeptide bond-formation between ubiquitin and substrates. Initially characterized as a tumor suppressor absent in a Wilm’s tumor (kidney cancer) patient, loss of HACE1 function is associated with a broad spectrum of cancers as well as neurodevelopmental and -degenerative diseases.
This dissertation describes the structural and functional elucidation of HACE1.
It demonstrates that recombinantly expressed and purified HACE1 forms a stable homodimer, as shown by size exclusion chromatography, mass photometry, and small-angle X-ray scattering. The physiological relevance of this self-association was furthermore supported in ectopic and near-endogenous cellular co-immunoprecipitation experiments as well as native PAGE analyses of endogenous protein in murine brain homogenates.
Dimerization is mediated by an N-terminal helix contacting the C-terminal HECT domain in trans, as shown by a cryo-EM structure of the full-length dimeric HACE1 complex as well as hydrogen-deuterium exchange mass spectrometry. The N-terminal helix thereby obstructs the canonical E2-binding site of the HECT domain, explaining why the HACE1 dimer represents an inactive, autoinhibited state deficient in accepting thioester-linked ubiquitin from E2 enzymes. Disruption of dimerization by mutating or truncating the helix lifts autoinhibition and induces strong ubiquitylation of the HACE1 model substrate RAC1, both in vitro and in cellular assays. A similar effect was achieved with certain phosphomimetic substitutions, indicating a potential mode of regulation via kinases.
This dissertation provides biochemical and structural insights into the regulation of a HECT E3 ligase. The monomeric HACE1 variants developed here could be used to identify and characterize oligomerization-dependent interactors and regulators of HACE1 and better understand pathologies.2026-03-2
A cross-sectional study on the impact of herbal medicine on the prevalence of bacterial and fungal pathogens in wound infections and surgical site infections in rural Ghana
No full textThis study was performed to get a better understanding about the use of traditional herbal
medicine on wound infection in Ghana, and to analyze possible effects on wound pathogen
composition and pathogen resistance. Our results demonstrate that traditional herbal
medicine is still widely used in rural Ghana. This includes the use of medical plants described
previously, especially Alchornea cordifolia. There was a significant effect on pathogen
prevalence in wounds treated with traditional herbal medicine with regard to key bacterial
and fungal pathogens, but no general difference in pathogen distribution. Herbal medicine
products were often contaminated with bacterial and fungal pathogens, which may trigger
infection of wounds. With 94.6 %, a high prevalence of wound infections resulting from
bacterial and fungal pathogens could be determined. Although infection rates were highest
in chronic wounds, a high prevalence (24.9 %) of hospital-acquired surgical-site infections
was also demonstrated. Infected wounds were mainly of polymicrobial composition. With
more than 60 %, the majority of pathogens were gram-negative bacteria consisting of
Enterobacterales and non-fermenters. Nearly every third wound was infected with grampositive
bacteria. The majority of S. aureus was shown to produce the virulence factor PVL.
Together with the already high rates of combined fluoroquinolone and cephalosporin
resistance in most gram-negative bacterial species found in wound infections, the novel
appearance of PVL-positive MRSA and new emergence and nosocomial spread of
carbapenem-resistant A. baumannii in the study region are worrying. Anaerobic and fungal
pathogens requiring challenging polymicrobial diagnostics were detected in small numbers,
including metronidazole-resistant B. fragilis. While sequence typing has revealed new A.
baumannii strains, it can only be assumed that lack of diagnostics, improper treatment and
widely available over-the-counter antibiotics are contributing factors to the rise of new
antibiotic resistances. Together, these results emphasize the importance of permanent
availability of local microbial diagnostics and continuous surveillance of the local resistance
situation. Still not completely resolved is the precise reason for the emergence of new
antibiotic resistances. Finally, access to effective antibiotic drugs according to specific
resistance profile needs to be established.2026-03-1
Sarcomere signaling in a patient-specific iPSC model of hypertrophic cardiomyopathy
No full textHypertrophic cardiomyopathy (HCM) is a severe cardiac disorder associated with ventricular hypertrophy, diastolic dysfunction, and arrhythmias, which can lead to heart failure. Inherited forms of HCM are frequently caused by mutations in sarcomere proteins, but many of the underlying molecular dysfunctions remain incompletely understood. To elucidate the sarcomere-dependent signaling in HCM, and its regulation by the actin filament network, we generated a patient-specific induced pluripotent stem cell (iPSC)-based model platform of HCM, employing an inherited HCM mutation (HCM1) in a z-disc localized, actin-organizing protein, as well as a well-characterized HCM mutation in a protein of the sarcomere thick filaments (HCM2). We tested the functions of specific actin-organizing proteins and their signaling activities in HCM1 patient-specific iPSC-derived cardiomyocytes (iPSC-CMs), compared to HCM2 iPSC-CMs, as well as WT controls. Alteration of some specific molecular and functional signalling defects was observed only in HCM1 iPSC-CMs, however, altered contractility and force generation defects were found in both HCM1 and HCM2 iPSC-CM models, compared to WT controls. Moreover, the HCM model platform contributed new understanding of the molecular basis of actin-organizing proteins in the organization of sarcomeres and their connections with the plasma membrane, which were found altered in HCM1 iPSC-CMs. Together, these sarcomere- and actin cytoskeleton-dependent dysfunctions in HCM1 iPSC-CMs may modulate disease-specific molecular signalling pathways that contribute to regulation of cardiomyocyte contractility in HCM. Thus, the findings of this study provided initial insights into subcellular disease phenotypes and molecular signaling dysfunctions in human patient-specific iPSC-CMs carrying different HCM mutations. In the future, these findings may assist the development of precision therapies for patients with HCM due to mutations in sarcomere proteins.2026-12-1
The regulation of the transcription factor TFEB in B cells via pathways of the B cell antigen receptor
No full textThe signalling pathways downstream of the BCR are vital for B cell function and previous
to this work, it was shown that TFEB is a transcription factor implicated in the cellular re
sponse of B cells to the stimulation of their BCR. Recent findings suggest that TFEB is
placed at an essential point of B cell biology, at the one hand inducing apoptosis to prevent
autoreactive B cells from causing damage, while on the other hand equipping the B cell with
receptors for costimulatory signals and increasing MHC II-mediated antigen presentation to
provide an escape from the induced cell death. It was also shown that different subsets of B
cells vary in their subcellular localisation of TFEB. For instance, unswitched and switched
memory B cells hold increased amounts of TFEB in their nuclei even in a resting state.
This work was able to provide information on the possible signalling basis of these differ
ences in between different subsets of B cells. By Single Cell Dilution of WEHI-231 B cells
as well as Ramos B cells, subpopulations with differing translocation rates of TFEB could
be generated. Moreover, it was shown that these different subpopulations have a conspicu
ous divergence within one of the identified pathways for TFEB downstream of the BCR.
Whereas the investigated parts of the BCR-PLC-PKC axis displayed no differences in terms
of expression, enzymatic activity or signalling amplitude, this work was able to link the dif
fering translocation rates to a stronger signalling amplitude within the CD19-PI3K-Akt axis.
This was demonstrated by significant disparities of Akt phosphorylation. Subpopulations
with strong nuclear translocation of TFEB also showed strong Akt phosphorylation and in
contrast, subpopulations with low translocation rates also were found to have less phosphor
ylated Akt.
Furthermore, this work was able to implicate multiple phosphorylation sites of TFEB in the
regulation of its subcellular localisation. Constitutive dephosphorylation of these phosphor
ylation sites was mimicked by introducing single amino acid substitutions via site-directed
mutagenesis. The simulation of constitutive dephosphorylation at these sites led to a very
significant increase in nuclear localisation of TFEB, thus indicating the involvement of these
sites in the regulation of TFEB. The phosphorylation sites which were found to be involved
are not exclusively sites that previously have been reported to be phosphorylated by PKC
and GSK3, the kinases responsible for TFEB phosphorylation in B cells according to our
findings. These sites also include phosphorylation sites that are described as being phosphor
ylated by other kinases such as mTOR and Akt. While these findings prove that multiple
phosphorylation sites are involved in the regulation of the subcellular localisation of TFEB,
it was also shown that the regulation does not simply involve all phosphorylation sites of
TFEB. Substituting S3 with alanine and thus mimicking dephosphorylation at this site did
not have any notable influence on the subcellular localisation of TFEB.
Making the targeted phosphorylation sites of PKC and GSK3 unavailable to phosphorylation
was thought to diminish the effect these kinases have on the subcellular localisation of TFEB.
Hence, inhibitors of these enzymes were used to investigate, if their influence on TFEB’s localisation was eliminated. The findings showed that inhibition of PKC and GSK3 still led
to a significant increase of nuclear translocation of TFEB, suggesting that these two kinases
also use other phosphorylation sites which have not been implicated in this process, yet.
In summary, this work was able to shed light on many different aspects of the regulation of
TFEB downstream of the BCR in B cells. The findings of this work verified numerous pre
vious results from our institute regarding the pathways for TFEB regulation and moreover
provided many new information on the possible foundation of different translocation rates
of TFEB in subsets of B cells as well as the role of multiple phosphorylation sites in its
regulation of the subcellular localisation. Since the nuclear translocation of TFEB appears as
a hallmark event of BCR signalling, addressing the new questions this work created as well
as the unresolved ones might prove to be a promising field to future research.2026-04-0