julilili42/papers huggingface dataset:
Microglia-neuron interactions in schizophrenia
2024-03-06

Multiple lines of evidence implicate increased neuroinflammation mediated by glial cells to play a key role in neurodevelopmental disorders such as schizophrenia. Microglia, which are the primary innate immune cells of the brain, are crucial for the refinement of the synaptic circuitry during early brain development by synaptic pruning and the regulation of synaptic plasticity during adulthood. Schizophrenia risk factors as genetics or environmental influences may further be linked to increased activation of microglia, an increase of pro-inflammatory cytokine levels and activation of the inflammasome resulting in an overall elevated neuroinflammatory state in patients. Synaptic loss, one of the central pathological hallmarks of schizophrenia, is believed to be due to excess removal of synapses by activated microglia, primarily affecting glutamatergic neurons. Therefore, it is crucial to investigate microglia-neuron interactions, which has been done by multiple studies focusing on post-mortem brain tissues, brain imaging, animal models and patient iPSC-derived 2D culture systems. In this review, we summarize the major findings in patients and in vivo and in vitro models in the context of neuron-microglia interactions in schizophrenia and secondly discuss the potential of anti-inflammatory treatments for the alleviation of positive, negative, and cognitive symptoms.
Immunocytokines with target cell–restricted IL-15 activity for treatment of B cell malignancies
2024-03-06

Despite the advances in cancer treatment achieved, for example, by the CD20 antibody rituximab, an urgent medical need remains to optimize the capacity of such antibodies to induce antibody-dependent cellular cytotoxicity (ADCC) that determines therapeutic efficacy. The cytokine IL-15 stimulates proliferation, activation, and cytolytic capacity of NK cells, but broad clinical use is prevented by short half-life, poor accumulation at the tumor site, and severe toxicity due to unspecific immune activation. We here report modified immunocytokines consisting of Fc-optimized CD19 and CD20 antibodies fused to an IL-15 moiety comprising an L45E-E46K double mutation (MIC + format). The E46K mutation abrogated binding to IL-15Rα, thereby enabling substitution of physiological trans-presentation by target binding and thus conditional IL-15Rβγ stimulation, whereas the L45E mutation optimized IL-15Rβγ agonism and producibility. In vitro analysis of NK activation, anti-leukemia reactivity, and toxicity using autologous and allogeneic B cells confirmed target-dependent function of MIC + constructs. Compared with Fc-optimized CD19 and CD20 antibodies, MIC + constructs mediated superior target cell killing and NK cell proliferation. Mouse models using luciferase-expressing human NALM-6 lymphoma cells, patient acute lymphoblastic leukemia (ALL) cells, and murine EL-4 lymphoma cells transduced with human CD19/CD20 as targets and human and murine NK cells as effectors, respectively, confirmed superior and target-dependent anti-leukemic activity. In summary, MIC + constructs combine the benefits of Fc-optimized antibodies and IL-15 cytokine activity and mediate superior NK cell immunity with potentially reduced side effects. They thus constitute a promising new immunotherapeutic approach shown here for B cell malignancies.
Addressing psychosocial needs in patients with Long-COVID (PsyLoCo-Study): study protocol of a pilot-study of a specialized modular intervention
2024-03-06

Introduction After an acute infection with the corona virus 10-20% of those affected suffer from ongoing or new symptoms. A causal therapy for the phenomenon known as Long/Post-COVID is still lacking and specific therapies addressing psychosocial needs of these patients are imperatively needed. The aim of the PsyLoCo-study is developing and piloting a psychotherapeutic manual, which addresses Long/Post-COVID-related psychosocial needs and supports in coping with persistent bodily symptoms as well as depressive or anxiety symptoms. Methods and analysis This pilot trial implements a multi-centre, 2-arm (N=120; allocation ratio: 1:1), parallel group, randomised controlled design. The pilot trial is designed to test the feasibility and estimate the effect of 1) a 12-session psychotherapeutic intervention compared to 2) a wait-list control condition on psychosocial needs as well as bodily and affective symptoms in patients suffering from Long/Post-COVID. The intervention uses an integrative, manualized, psychotherapeutic approach. The primary study outcome is health-related quality of life. Outcome variables will be assessed at three timepoints, pre-intervention (t1), post-intervention (t2) and three months after completed intervention (t3). To determine the primary outcome, changes from t1 to t2 are examined. The analysis will be used for the planning of the RCT to test the efficacy of the developed intervention. Discussion The pilot study will evaluate a 12-session treatment manual for Long/Post-COVID sufferers and the therapy components it contains. The analysis will provide insights into the extent to which psychotherapeutic treatment approaches improve the symptoms of Long/Post-COVID sufferers. The treatment manual is designed to be carried out by psychotherapists as well as people with basic training in psychotherapeutic techniques. This approach was chosen to enable a larger number of practitioners to provide therapeutic support for Long/Post-COVID patients. After completion of the pilot study, it is planned to follow up with a randomized controlled study and to develop a treatment guideline for general practitioners and interested specialists. Trial registration The pilot trial has been registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien; Trial-ID: DRKS00030866; URL: https://drks.de/search/de/trial/DRKS00030866 ) on March 7, 2023.
Sleep-slow oscillation-spindle coupling precedes spindle-ripple coupling during development
2024-03-06

Abstract Study Objectives Sleep supports systems memory consolidation through the precise temporal coordination of specific oscillatory events during slow-wave sleep, i.e. the neocortical slow oscillations (SOs), thalamic spindles, and hippocampal ripples. Beneficial effects of sleep on memory are also observed in infants, although the contributing regions, especially hippocampus and frontal cortex, are immature. Here, we examined in rats the development of these oscillatory events and their coupling during early life. Methods EEG and hippocampal local field potentials were recorded during sleep in male rats at postnatal days (PD)26 and 32, roughly corresponding to early (1–2 years) and late (9–10 years) human childhood, and in a group of adult rats (14–18 weeks, corresponding to ~22–29 years in humans). Results SO and spindle amplitudes generally increased from PD26 to PD32. In parallel, frontocortical EEG spindles increased in density and frequency, while changes in hippocampal ripples remained nonsignificant. The proportion of SOs co-occurring with spindles also increased from PD26 to PD32. Whereas parietal cortical spindles were phase-locked to the depolarizing SO-upstate already at PD26, over frontal cortex SO-spindle phase-locking emerged not until PD32. Co-occurrence of hippocampal ripples with spindles was higher during childhood than in adult rats, but significant phase-locking of ripples to the excitable spindle troughs was observed only in adult rats. Conclusions Results indicate a protracted development of synchronized thalamocortical processing specifically in frontocortical networks (i.e. frontal SO-spindle coupling). However, synchronization within thalamocortical networks generally precedes synchronization of thalamocortical with hippocampal processing as reflected by the delayed occurrence of spindle-ripple phase-coupling.
Ecology of arboviruses and their potential mosquito vectors in Benin, Côte d’Ivoire and Gabon: a mini review
2024-03-06

Mosquito-borne arboviral zoonoses are an increasingly (re-)emerging threat for millions of people in endemic countries of Africa. Aedes-transmitted yellow fever (YF), dengue (DEN), chikungunya (CHIK), and Zika (ZIK) viruses, as well as Aedes- and Culex transmitted Rift Valley fever virus (RVFV) infections often go undiagnosed and as a result, accurate clinical reports for these viral diseases are lacking. The absence of evidence-based risk maps for arbovirus infections hinders the implementation of more suitable prevention/surveillance and control strategies in both non-endemic and endemic African countries. The vectorial capacity of arbovirus-transmitting vectors is highly complex mainly due to the interplay between biotic and abiotic factors that vary in time and space, explaining the differential patterns of arbovirus diseases between countries. Mapping the influential factors of arbovirus transmission, such as vector ecology, behavior, and biology in countries with different outcomes of arboviral diseases, will strongly help improve our understanding of local epidemiology and circulation of these diseases. Herein, we review up-to-date data on the distribution of arboviruses and their respective vectors from three sub-Saharan African countries (Benin, Côte d’Ivoire, and Gabon) presenting different patterns of arbovirus diseases. We pinpointed major knowledge gaps and potential research interests to increase knowledge of the distribution of arboviral diseases and their vectors through African countries to improve the strategies to successfully prevent, monitor, and control the disease outbreak.
A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan
2024-03-06

ABSTRACT Objectives Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.
Efficacy and safety of everolimus plus exemestane in patients with hormone receptor‐positive, HER‐2‐negative advanced breast cancer: Results from the open‐label, multicentre, non‐interventional BRAWO study
2024-03-06

Abstract BRAWO, a real‐world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2– advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2‐ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate‐analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012–December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second‐line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression‐free survival (mPFS) reported as 6.6 months (95%CI: 6.3–7.0). Multivariate‐analysis in a subset of patients ( n = 1837) found higher body mass index (BMI) and non‐visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to &lt;25 had a mPFS of 6.0 (95%CI: 5.4–6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9–9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real‐world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2− ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.
Bimodal volcanism in the Hegau region (SW Germany): Differentiation of primitive melilititic to nephelinitic rocks produces evolved nosean phonolites
2024-03-06

Peculiar bimodal volcanism in the Hegau region (SW Germany) comprises two contrasting SiO2-undersaturated rock suites. Primitive olivine melilitites and melilite-bearing olivine nephelinites (12–9 Ma) are characterized by high MgO, CaO, Fe2O3, TiO2, Ni, V, F, moderate alkalis, Al2O3, P2O5, Ba, Nb, Zr, and low SiO2, Rb, Pb, and U concentrations. The rocks are composed of forsteritic olivine, diopsidic clinopyroxene, melilite, perovskite, Cr-bearing oxyspinel, F- and Ba-rich mica, and fluorapatite. In rare cases, they contain coeval coarse-grained ijolite schlieren generated by rapid in-situ fractionation in small melt pockets. Evolved nosean phonolites (14–11 Ma) comprise high alkalis, Al2O3, SiO2, Rb, Nb, Zr, U, Pb, S, and low MgO, CaO, Fe2O3, TiO2, P2O5, Ba, Ni, and V concentrations, and contain abundant Ba-bearing alkali feldspar and nosean-haüyne-sodalitess macrocrysts, aegirine-augitic clinopyroxene, as well as accessory apatite, titanite, zircon, and pyrochlore. The melilititic–nephelinitic rocks formed by low degrees of partial melting of a carbonated amphibole ± phlogopite-bearing garnet wehrlite in the uppermost asthenosphere or in the thermal boundary layer and occur also in neighbouring regions. However, their coexistence with evolved nosean phonolites is a unique and so far, unexplained feature in the southern Central European Volcanic Province. Thermodynamic modelling implies that removal of 11–19% oxyspinel, 4–10% olivine, 42–57% clinopyroxene, <3% mica, <9% feldspathoids, <8% feldspar from melilititic–nephelinitic parental melts at upper crustal conditions (~200 MPa) results in significant amounts of phonolitic residues that are compositionally similar to the exposed nosean phonolites. Strongly negative P and Ti anomalies and a trough of MREE in primitive mantle-normalized trace element patterns of phonolites indicate additional fractionation of titanite and apatite, consistent with the mineralogy of coarse-grained (nepheline) syenitic cumulates, which are present as enclaves in both rock suites. The modelling results suggest crystallization of the (nepheline) syenite cumulates between 1050 and 800 °C and ascent and eruption of the phonolite residues at no less than ~900 °C with complete solidification of the observed assemblage at >750 °C. Significant crustal assimilation during fractionation appears unnecessary to explain the mineralogical, mineral chemical, and geochemical characteristics of the phonolites. Prolonged upper crustal differentiation of the magmas in one case (nosean phonolites) and fast ascent of primitive melts in the other (olivine melilitites and melilite-bearing olivine nephelinites) can be explained by stress field changes from an extensional to a more compressive regime, the magma ascent becoming thereby increasingly structurally controlled and supported by brittle deformation.
What Does It Mean to Be Human Today?
2024-03-06

Abstract With the progress of artificial intelligence, the digitalization of the lifeworld, and the reduction of the mind to neuronal processes, the human being appears more and more as a product of data and algorithms. Thus, we conceive ourselves “in the image of our machines,” and conversely, we elevate our machines and our brains to new subjects. At the same time, demands for an enhancement of human nature culminate in transhumanist visions of taking human evolution to a new stage. Against this self-reification of the human being, the present book defends a humanism of embodiment: our corporeality, vitality, and embodied freedom are the foundations of a self-determined existence, which uses the new technologies only as means instead of submitting to them. The book offers an array of interventions directed against a reductionist naturalism in various areas of science and society. As an alternative, it offers an embodied and enactive account of the human person: we are neither pure minds nor brains, but primarily embodied, living beings in relation with others. This general concept is applied to issues such as artificial intelligence (AI), transhumanism and enhancement, virtual reality, neuroscience, embodied freedom, psychiatry, and finally to the accelerating dynamics of current society which lead to an increasing disembodiment of our everyday life. The book thus applies cutting-edge concepts of embodiment and enactivism to current scientific, technological, and cultural tendencies that will crucially influence our society’s development in the twenty-first century.
Effects of maternal separation on adult vocal communication: A Mongolian gerbil (<i>Meriones unguiculatus</i>) study
2024-03-06

Child neglect increases the risk of developing social communication disorders in adulthood. This study measured how maternal separation affects vocal communication in adult Mongolian gerbils, which produce a rich vocal repertoire during social interactions. The vocalizations produced by the two adult animals when they first met were recorded and analyzed. The results showed that MS-received gerbils vocalized significantly more, and the effect was more prominent in aggressive vocalizations than in non-aggressive vocalizations. These changes suggest that MS affects social interactions, and demonstrates the potential of the gerbil as a model animal for early stress-related social communication disorders.
Venomics and Peptidomics of Palearctic vipers: Clade-wide analysis of seven taxa of the generaVipera,Montivipera,MacroviperaandDaboiaacross Türkiye
2024-03-06

ABSTRACT Snake venom variations are a crucial factor to understand the consequences of snakebite envenoming worldwide and therefore it’s important to know about toxin composition alterations between taxa. Palearctic vipers of the genera Vipera , Montivipera , Macrovipera and Daboia have high medical impacts across the Old World. One hotspot for their occurrence and diversity is Türkiye on the border between the continents, but many of their venoms remain still understudied. Here, we present the venom compositions of seven Turkish viper taxa. By complementary mass spectrometry-based bottom-up and top-down workflows, the venom profiles were investigated on proteomics and peptidomics level. This study includes the first venom descriptions of Vipera berus barani , Vipera darevskii , Montivipera bulgardaghica albizona and Montivipera xanthina , as well as first snake venomics profiles of Turkish Macrovipera lebetinus obtusa and Daboia palaestinae , including an in-depth reanalysis of Montivipera bulgardaghica bulgardaghica venom. Additionally, we identified the modular consensus sequence pEXW(PZ 1– 2P (EI)/(KV)PPLE for bradykinin-potentiating peptides (BPP) in viper venoms. For better insights into variations and potential impacts of medical significance the venoms were compared against other Palearctic viper proteomes, including the first genus-wide Montivipera venom comparison. This will help the risk assessment of snakebite envenoming by these vipers and aid in predicting the venoms pathophysiology and clinical treatments.
An Unbeloved Heir? A Reassessment of Louis the Stammerer's Role in the Last Years of Charles the Bald's Reign and its Implications for Understanding Carolingian Rule
2024-03-06

The father–son relationship between Charles the Bald and his eldest son Louis the Stammerer is generally understood as one of hostility and distrust. This article takes several episodes from the final decades of Charles the Bald's reign to question this, re-examining how royal Carolingian fathers and royal Carolingian sons could take steps to overcome previous conflicts and arguing that political ties within the royal family were more robust, and consequently of different significance for our understanding of Carolingian politics, than is usually understood.
Reflection confocal microscopy for quantitative assessment of airway surface liquid dysregulation and pharmacological rescue in cystic fibrosis under near-physiological conditions
2024-03-06

ABSTRACT Proper regulation of airway surface liquid (ASL) is essential for effective mucociliary clearance (MCC) in healthy airways, and ASL depletion due to deficient cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion/fluid secretion plays an important role in the pathogenesis of mucociliary dysfunction and chronic muco-obstructive lung disease in patients with cystic fibrosis (CF). The current standard for quantitative measurements of ASL height is confocal fluorescence microscopy that has the disadvantage that it requires apical addition of volume for fluorescent staining, and hence perturbation of the ASL. Therefore, our aim was to develop a method that enables studies of ASL regulation under unperturbed conditions using reflected light by confocal microscopy of primary airway epithelial cultures grown at air-liquid interface (ALI). After apical volume addition to primary tracheal mouse cultures, confocal reflection microscopy yielded comparable ASL height as confocal fluorescence microscopy on cultures of wild-type mice, and was sensitive to detect ASL depletion on cultures of βENaC-Tg mice. Under unperturbed conditions, ASL determined by confocal reflection microscopy was significantly higher in wild-type and βENaC-Tg mice compared to values obtained by confocal fluorescence microscopy. Studies in normal and CF primary human airway epithelial cultures showed that confocal reflection microscopy was sensitive to detect effects of low temperature rescue and pharmacological modulation including improvement of CFTR function by VX-809 and VX-770 in cultures from CF patients with the F508del mutation. Our results support confocal reflection microscopy as a novel sensitive technique for quantitative studies of ASL regulation and response to therapeutic intervention under unperturbed near-physiological conditions in healthy and CF airways. NEW &amp; NOTEWORTHY Measurement of airway surface liquid (ASL) height by confocal fluorescence microscopy is an important tool to investigate ASL dysregulation and effects of therapeutic strategies aiming at restoring ASL volume to improve mucociliary clearance and lung function in patients with cystic fibrosis. However, confocal fluorescence microscopy has the disadvantage that it requires apical addition of volume for fluorescent staining of the ASL leading to perturbation of its height and composition. Here, we developed confocal reflection microscopy as a new method that enables quantitative assessment of ASL on highly-differentiated primary airway epithelial cultures under unperturbed near-physiological conditions by detection of refracted light.