Structural Models of Cortical Networks with Long-Range Connectivity

Most current studies of neuronal activity dynamics in cortex are based on network models with completely random wiring. Such models are chosen for mathematical convenience, rather than biological grounds, and additionally reflect the notorious lack of knowledge about the neuroanatomical microstructure. Here, we describe some families of new, more realistic network models and explore some of their properties. Specifically, we consider spatially embedded networks and impose specific distance-dependent connectivity profiles. Each of these network models can cover the range from purely local to completely random connectivity, controlled by a single parameter. Stochastic graph theory is then used to describe and analyze the structure and the topology of these networks

Synthesis and Characterization of Novel Isosorbide‐Based Polyester Derivatives Decorated with α ‐Acyloxy Amides

The synergy of multicomponent reactions (MCRs) and metathesis chemistry is applied for the synthesis of bio-based functional isosorbide polymers (i.e., polyesters) decorated with α-acyloxy amide motif. The chemical structure of the polyesters that are not accessible by any other conventional methodologies is characterized in-depth via nuclear magnetic resonance, size-exclusion chromatography, and attenuated total reflectance infrared spectroscopy. It is also observed that the “biomass-derived” carbon % of the polymers varied between 66.2 and 76.9. Moreover, the thermal properties of the novel isosorbide-based polymers are investigated via thermogravimetric analysis and differential scanning calorimetry, revealing that the polymers are in the amorphous state, identified by the glass transition temperature (T$_g$) values below the human body temperature. The mechanical properties and the biocompatibility of the functional novel polyester derivative with the highest “biomass-derived” carbon % are evaluated via dynamic mechanical analysis and cytotoxicity test. The exemplary polymer is biocompatible with chondrocyte cells in the conditions used in the tests. In summary, the complementary nature of isosorbide derivatives with MCRs and metathesis chemistry is utilized to illustrate the potential utility of isosorbide as a building block for polymers with prospective biomedical application (namely, as novel cartilage materials)

Enhanced cellular migration and prolonged chondrogenic differentiation in decellularized cartilage scaffolds under dynamic culture conditions

Lesions of aural, nasal and tracheal cartilage are frequently reconstructed by complex surgeries which are based on harvesting autologous cartilage from other locations such as the rib. Cartilage tissue engineering (CTE) is regarded as a promising alternative to attain vital cartilage. Nevertheless, CTE with nearly natural properties poses a significant challenge to research due to the complex reciprocal interactions between cells and extracellular matrix which have to be imitated and which are still not fully understood. Thus, we used a custom-made glass bioreactor to enhance cell migration into decellularized porcine cartilage scaffolds (DECM) and mimic physiological conditions. The DECM seeded with human nasal chondrocytes (HPCH) were cultured in the glass reactor for 6 weeks and examined by histological and immunohistochemical staining, biochemical analyses and real time-PCR at 14, 28 and 42 days. The migration depth and the number of migrated cells were quantified by computational analysis. Compared to the static cultivation, the dynamic culture (DC) fostered migration of HPCH into deeper tissue layers. Furthermore, cultivation in the bioreactor enhanced differentiation of the cells during the first 14 days, but differentiation diminished in the course of further cultivation. We consider the DC in the presented bioreactor as a promising tool to facilitate CTE and to help to better understand the complex physiological processes during cartilage regeneration. Maintaining differentiation of chondrocytes and improving cellular migration by further optimizing culture conditions is an important prerequisite for future clinical application

Patient Benefit Following Bimodal CI-provision: Self-reported Abilities vs. Hearing Status

Objectives: Patient-reported outcomes gain importance for the assessment of auditory abilities in cochlear implant users and for the evaluation of auditory rehabilitation. Aims of the study were to explore the interrelation of self-reported improvements in auditory ability with improvements in speech comprehension and to identify factors other than audiological improvement that affect self-reported auditory ability.Study Design: Explorative prospective analysis using a within-subjects repeated measures design.Setting: Academic tertiary care center.Participants: Twenty-seven adult participants with bilateral sensorineural hearing loss who received a HiRes 90K CI and continued use of a HA at the non-implanted ear (bimodal hearing).Intervention: Cochlear implantation.Main Outcome Measures: Self-reported auditory ability/disability assessed by the comparative version of the Speech, Spatial and Qualities of Hearing Scale (SSQ-B), and monosyllable as well as sentence comprehension in quiet and within speech modulated noise from different directions assessed pre- as well as 3 and 6 months post-implantation.Results: Data of 17 individuals were analyzed. At the endpoint of the study, improvement of self-reported auditory ability was significant. Regarding audiometric measures, significant improvement was seen for CI-aided pure tone thresholds, for monaural CI-assisted and bimodal sentence comprehension in quiet and in speech-modulated noise that was presented from the same source or at the side of the HA-ear. Correlations between self-reported and audiometric improvements remained weak, with the exception of the improvement seen for monaural CI-aided sentence comprehension in quiet and self-perceived improvement of sound quality. Considerable correlations existed between self-reported improvements and current level of depression and anxiety, and with general self-efficaciousness. Regression analyses substantiated a positive influence of self-efficaciousness on self-reported improvement in speech comprehension and between the improvement of monaural CI-aided sentence comprehension in quiet and perceived sound quality as well as a negative influence of anxiety on self-reported improvement in spatial hearing. Self-reported improvements were significantly better in the subgroup with intensive as compared to regular rehabilitation.Conclusions: Self-reported auditory ability/disability represents an important measure for the success of bimodal CI-provision. It is influenced by personal and mental health factors that may improve CI-rehabilitation results if addressed during rehabilitation

Synthesis and Characterization of Novel Isosorbide‐Based Polyester Derivatives Decorated with α ‐Acyloxy Amides

The synergy of multicomponent reactions (MCRs) and metathesis chemistry is applied for the synthesis of bio-based functional isosorbide polymers (i.e., polyesters) decorated with α-acyloxy amide motif. The chemical structure of the polyesters that are not accessible by any other conventional methodologies is characterized in-depth via nuclear magnetic resonance, size-exclusion chromatography, and attenuated total reflectance infrared spectroscopy. It is also observed that the “biomass-derived” carbon % of the polymers varied between 66.2 and 76.9. Moreover, the thermal properties of the novel isosorbide-based polymers are investigated via thermogravimetric analysis and differential scanning calorimetry, revealing that the polymers are in the amorphous state, identified by the glass transition temperature (T$_g$) values below the human body temperature. The mechanical properties and the biocompatibility of the functional novel polyester derivative with the highest “biomass-derived” carbon % are evaluated via dynamic mechanical analysis and cytotoxicity test. The exemplary polymer is biocompatible with chondrocyte cells in the conditions used in the tests. In summary, the complementary nature of isosorbide derivatives with MCRs and metathesis chemistry is utilized to illustrate the potential utility of isosorbide as a building block for polymers with prospective biomedical application (namely, as novel cartilage materials)

Characterization of Distinct Chondrogenic Cell Populations of Patients Suffering from Microtia Using Single-Cell Micro-Raman Spectroscopy

Microtia is a congenital condition of abnormal development of the outer ear. Tissue engineering of the ear is an alternative treatment option for microtia patients. However, for this approach, the identification of high regenerative cartilage progenitor cells is of vital importance. Raman analysis provides a novel, non-invasive, label-free diagnostic tool to detect distinctive biochemical features of single cells or tissues. Using micro-Raman spectroscopy, we were able to distinguish and characterize the particular molecular fingerprints of differentiated chondrocytes and perichondrocytes and their respective progenitors isolated from healthy individuals and microtia patients. We found that microtia chondrocytes exhibited lower lipid concentrations in comparison to healthy cells, thus indicating the importance of fat storage. Moreover, we suggest that collagen is a useful biomarker for distinguishing between populations obtained from the cartilage and perichondrium because of the higher spectral contributions of collagen in the chondrocytes compared to perichondrocytes from healthy individuals and microtia patients. Our results represent a contribution to the identification of cell markers that may allow the selection of specific cell populations for cartilage tissue engineering. Moreover, the observed differences between microtia and healthy cells are essential for gaining better knowledge of the cause of microtia. It can be useful for designing novel treatment options based on further investigations of the discovered biochemical substrate alterations

Risk factors for immune-related adverse effects during CPI therapy in patients with head and neck malignancies – a single center study

IntroductionCheckpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications.Material and methodsData from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs.ResultsIrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels.DiscussionEven though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out

Rethinking commonality in refugee status determination in Europe: Legal geographies of asylum appeals

The Common European Asylum System aims to establish common standards for refugee status determination among EU Member States. Combining insights from legal and political geography we bring the depth and scale of this challenge into sharp relief. Drawing on interviews and a detailed ethnography of asylum adjudication involving over 850 in-person asylum appeal observations, we point towards practical differences in the spatio-temporality, materiality and logistics of asylum appeal processes as they are operationalised in seven European countries. Our analysis achieves three things. Firstly, we identify a key zone of differences at the level of concrete, everyday implementation that has largely escaped academic attention, which allows us to critically assess the notion of harmonisation of asylum policies in new ways. Secondly, drawing on legal- and political-geographical concepts, we offer a way to conceptualise this zone by paying attention to the spatio-temporality, materiality and logistics it involves. Thirdly, we offer critical legal logistics as a new direction for scholarship in legal geography and beyond that promises to prise open the previously obscured mechanics of contemporary legal systems

Organotypic Co-Cultures as a Novel 3D Model for Head and Neck Squamous Cell Carcinoma

Background: Head and neck squamous cell carcinomas (HNSCC) are phenotypically and molecularly heterogeneous and frequently develop therapy resistance. Reliable patient-derived 3D tumor models are urgently needed to further study the complex pathogenesis of these tumors and to overcome treatment failure. Methods: We developed a three-dimensional organotypic co-culture (3D-OTC) model for HNSCC that maintains the architecture and cell composition of the individual tumor. A dermal equivalent (DE), composed of healthy human-derived fibroblasts and viscose fibers, served as a scaffold for the patient sample. DEs were co-cultivated with 13 vital HNSCC explants (non-human papillomavirus (HPV) driven, n = 7; HPV-driven, n = 6). Fractionated irradiation was applied to 5 samples (non-HPV-driven, n = 2; HPV-driven n = 3). To evaluate expression of ki-67, cleaved caspase-3, pan-cytokeratin, p16INK4a, CD45, ∝smooth muscle actin and vimentin over time, immunohistochemistry and immunofluorescence staining were performed Patient checkup data were collected for up to 32 months after first diagnosis. Results: All non-HPV-driven 3D-OTCs encompassed proliferative cancer cells during cultivation for up to 21 days. Proliferation indices of primaries and 3D-OTCs were comparable and consistent over time. Overall, tumor explants displayed heterogeneous growth patterns (i.e., invasive, expansive, silent). Cancer-associated fibroblasts and leukocytes could be detected for up to 21 days. HPV DNA was detectable in both primary and 3D-OTCs (day 14) of HPV-driven tumors. However, p16INK4a expression levels were varying. Morphological alterations and radioresistant tumor cells were detected in 3D-OTC after fractionated irradiation in HPV-driven and non-driven samples. Conclusions: Our 3D-OTC model for HNSCC supports cancer cell survival and proliferation in their original microenvironment. The model enables investigation of invasive cancer growth and might, in the future, serve as a platform to perform sensitivity testing upon treatment to predict therapy response

What’s missing from legal geography and materialist studies of law? Absence and the assembling of asylum appeal hearings in Europe

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: Due to the ethical and legally sensitive nature of the research, ethnographic notes taken in court could not be made openly available. Appellant interviewees were not asked for their permission to share their interview transcripts in an online open archive because of concerns that they could misunderstand what was being asked for, or feel obliged to agree but subsequently feel less able to conduct free conversation in research interviews as a result, thereby negatively impacting on the quality of the data generated. Additional details relating to, and data resulting from, to a survey taken during observations of British asylum appeals between 2013 and 2016 are available from the UK Data Archive (persistent identifier: 10.5255/UKDA-SN-852032).There is an absence of absence in legal geography and materialist studies of the law. Drawing on a multi‐sited ethnography of European asylum appeal hearings, this paper illustrates the importance of absences for a fully‐fledged materiality of legal events. We show how absent materials impact hearings, that non‐attending participants profoundly influence them, and that even when participants are physically present, they are often simultaneously absent in other, psychological registers. In so doing we demonstrate the importance and productivity of thinking not only about law's omnipresence but also the absences that shape the way law is experienced and practiced. We show that attending to the distribution of absence and presence at legal hearings is a way to critically engage with legal performance.Economic and Social Research Council (ESRC)European Research Council (ERC