Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation.

OBJECTIVE: Increased apoptotic shedding has been linked to intestinal barrier dysfunction and development of inflammatory bowel diseases (IBD). In contrast, physiological cell shedding allows the renewal of the epithelial monolayer without compromising the barrier function. Here, we investigated the role of live cell extrusion in epithelial barrier alterations in IBD. DESIGN: Taking advantage of conditional GGTase and RAC1 knockout mice in intestinal epithelial cells (Pggt1b iΔIEC and Rac1 iΔIEC mice), intravital microscopy, immunostaining, mechanobiology, organoid techniques and RNA sequencing, we analysed cell shedding alterations within the intestinal epithelium. Moreover, we examined human gut tissue and intestinal organoids from patients with IBD for cell shedding alterations and RAC1 function. RESULTS: Epithelial Pggt1b deletion led to cytoskeleton rearrangement and tight junction redistribution, causing cell overcrowding due to arresting of cell shedding that finally resulted in epithelial leakage and spontaneous mucosal inflammation in the small and to a lesser extent in the large intestine. Both in vivo and in vitro studies (knockout mice, organoids) identified RAC1 as a GGTase target critically involved in prenylation-dependent cytoskeleton dynamics, cell mechanics and epithelial cell shedding. Moreover, inflamed areas of gut tissue from patients with IBD exhibited funnel-like structures, signs of arrested cell shedding and impaired RAC1 function. RAC1 inhibition in human intestinal organoids caused actin alterations compatible with arresting of cell shedding. CONCLUSION: Impaired epithelial RAC1 function causes cell overcrowding and epithelial leakage thus inducing chronic intestinal inflammation. Epithelial RAC1 emerges as key regulator of cytoskeletal dynamics, cell mechanics and intestinal cell shedding. Modulation of RAC1 might be exploited for restoration of epithelial integrity in the gut of patients with IBD.

Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.

BACKGROUND: Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON. METHODS: Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies. RESULTS: All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG-seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast-enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy. CONCLUSIONS: MOG-seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD.

Retinal Ganglion Cell Topography in Patients With Visual Pathway Pathology.

BACKGROUND: To investigate and quantify the impact of intracranial lesions at different locations within the visual pathway on the ganglion cell layer-inner plexiform layer (GCL-IPL) complex and the retinal nerve fiber layer (RNFL). METHODS: Patients with intracranial lesions affecting the optic chiasm (Group I) or the optic tract and/or lateral geniculate nucleus (Group II) were included. All patients received kinetic visual field assessment and underwent spectral domain optical coherence tomography. Peripapillary and papillomacular bundle (PMB) RNFL and macular GCL-IPL thickness in 4 perifoveal areas were measured and compared with normal values derived from 52 age-matched healthy control subjects. Z-scores for each parameter of every patient were calculated and compared with the normative data. Z-scores less than -2.0 (e.g., -2.5) were considered as being statistically significant. RESULTS: Twenty-two patients (Group I and II: 13 and 9, respectively) were included. Ten of 13 patients in Group I showed significant binasal GCL-IPL thinning, with associated temporal sector thinning in 8 patients. In Group II, all 9 patients showed significant reduction of the GCL-IPL corresponding to the homonymous visual field defect, but only 4 demonstrated RNFL thinning. Contralateral RNFL thinning within the PMB clinically similar to bow-tie atrophy was evident in all patients in Group II. GCL-IPL and RNFL thinning varied in severity from mild (isolated PMB RNFL thickness reduction) to severe (bilateral asymmetrical reduction of PMB RNFL associated with asymmetric, predominantly nasal reduction of GCL-IPL) in Group I. CONCLUSION: Clinical abnormalities in patients with visual pathway lesions are more likely to demonstrate abnormalities of GCL-IPL than global peripapillary RNFL thickness. However, PMB thickness measurement appears to be a valuable tool to detect abnormalities of the anterior visual pathways. If peripapillary RNFL measurements are performed in such patients, PMB thickness should be considered the most useful quantitative parameter.

Optical Coherence Tomography in Multiple Sclerosis.

Retinal optical coherence tomography (OCT) has recently become a vital tool for clinicians and researchers in ophthalmology and, increasingly, in neurology. Optical coherence tomography is quickly and easily performed, well-tolerated by patients, and allows high-resolution viewing of unmyelinated axons and other retinal structures in vivo. These factors have led OCT to find favor as a method of quantifying neuroaxonal loss in multiple sclerosis (MS), and the increasing acceptance of the anterior visual pathway as a model to investigate MS in humans.In this short review, the authors discuss OCT findings in MS research, and the relationships of these structural findings with established functional outcome measures such as visual acuity and electrophysiological examinations. The utility of OCT in patients with acute optic neuritis is emphasized. Optical coherence tomography is a particularly powerful tool when the individual retinal layers are visualized and quantified following the segmentation of scans; this technique shows promise as a method for defining novel MS phenotypes.

An overview of current assessment techniques for evaluating cutaneous perfusion in reconstructive surgery.

This article provides a comprehensive analysis of modern techniques used in the assessment of cutaneous flaps in reconstructive surgery. It emphasizes the importance of preoperative planning and intra- and perioperative assessment of flap perfusion to ensure successful outcomes. Despite technological advancements, direct clinical assessment remains the gold standard. We categorized assessment techniques into non-invasive and invasive modalities, discussing their strengths and weaknesses. Non-invasive methods, such as acoustic Doppler sonography, near-infrared spectroscopy, hyperspectral imaging thermal imaging, and remote-photoplethysmography, offer accessibility and safety but may sacrifice specificity. Invasive techniques, including contrast-enhanced ultrasound, computed tomography angiography, near-infrared fluorescence angiography with indocyanine green, and implantable Doppler probe, provide high accuracy but introduce additional risks. We emphasize the need for a tailored decision-making process based on specific clinical scenarios, patient characteristics, procedural requirements, and surgeon expertise. It also discusses potential future advancements in flap assessment, including the integration of artificial intelligence and emerging technologies.

First standardized assessment of perforators and perforasomes of the occipital artery - An anatomical study.

BACKGROUND: Flaps have become an integral part of plastic and reconstructive surgery. The robust blood supply of such flaps is a prerequisite to reduce flap failure. Despite the reported versatility of the occipital flap, comprehensive anatomical studies on its perforators and perforasomes are lacking. Hence, we examined the perforators originating from the occipital artery and their associated perforasomes, aiming to fill this knowledge gap for reconstructive surgery techniques. METHODS: 39 of 40 occipital arteries of 20 fresh anatomical head specimens were dissected. Perforators with a least an outer diameter of 0.50 mm were identified and injected with dye to color their respective perforasomes. Location and size of the colored skin areas were determined as well as the location of their perforators were documented and analyzed. RESULTS: In total, 183 perforators were found and described. The mean diameter of these vessels was 0.88 ± 0.27 mm (0.5-2.1 mm). The mean area of the perforasomes was 1288.26 ± 662.51 mm2 (144.60-3890.60 mm2). They were localized over the whole nuchal and occipital area. Lastly, perforator diameters were significantly associated with the size of their resulting perforasomes. CONCLUSION: This study is the first comprehensive overview of perforators and associated perforasomes of the occipital artery on a respectable amount of specimen. The arterial supply of big portions of the occipital and nuchal area is provided solely by the perforators of the occipital artery. For flap surgery, perforator diameter is a crucial detail to be considered in the decision-making process.

Button shear testing for adhesion measurements of 2D materials.

Two-dimensional (2D) materials are considered for numerous applications in microelectronics, although several challenges remain when integrating them into functional devices. Weak adhesion is one of them, caused by their chemical inertness. Quantifying the adhesion of 2D materials on three-dimensional surfaces is, therefore, an essential step toward reliable 2D device integration. To this end, button shear testing is proposed and demonstrated as a method for evaluating the adhesion of 2D materials with the examples of graphene, hexagonal boron nitride (hBN), molybdenum disulfide, and tungsten diselenide on silicon dioxide and silicon nitride substrates. We propose a fabrication process flow for polymer buttons on the 2D materials and establish suitable button dimensions and testing shear speeds. We show with our quantitative data that low substrate roughness and oxygen plasma treatments on the substrates before 2D material transfer result in higher shear strengths. Thermal annealing increases the adhesion of hBN on silicon dioxide and correlates with the thermal interface resistance between these materials. This establishes button shear testing as a reliable and repeatable method for quantifying the adhesion of 2D materials.

Two-Dimensional Platinum Diselenide Waveguide-Integrated Infrared Photodetectors.

Low-cost, easily integrable photodetectors (PDs) for silicon (Si) photonics are still a bottleneck for photonic-integrated circuits (PICs), especially for wavelengths above 1.8 µm. Multilayered platinum diselenide (PtSe2) is a semi-metallic two-dimensional (2D) material that can be synthesized below 450 °C. We integrate PtSe2-based PDs directly by conformal growth on Si waveguides. The PDs operate at 1550 nm wavelength with a maximum responsivity of 11 mA/W and response times below 8.4 µs. Fourier-transform IR spectroscopy in the wavelength range from 1.25 to 28 µm indicates the suitability of PtSe2 for PDs far into the IR wavelength range. Our PtSe2 PDs integrated by direct growth outperform PtSe2 PDs manufactured by standard 2D layer transfer. The combination of IR responsivity, chemical stability, selective and conformal growth at low temperatures, and the potential for high carrier mobility makes PtSe2 an attractive 2D material for optoelectronics and PICs.

Stacking Polymorphism in PtSe2 Drastically Affects Its Electromechanical Properties.

PtSe2 is one of the most promising materials for the next generation of piezoresistive sensors. However, the large-scale synthesis of homogeneous thin films with reproducible electromechanical properties is challenging due to polycrystallinity. It is shown that stacking phases other than the 1T phase become thermodynamically available at elevated temperatures that are common during synthesis. It is shown that these phases can make up a significant fraction in a polycrystalline thin film and discuss methods to characterize them, including their Seebeck coefficients. Lastly, their gauge factors, which vary strongly and heavily impact the performance of a nanoelectromechanical device are estimated.

Soft palate resection and secondary healing not to impair the velopharyngeal function? - Diagnosis and treatment of an intraoral schwannoma: A case report.

INTRODUCTION: Schwannomas are benign lesions arising from the nerve sheath, commonly located in the head and neck. Intraoral schwannomas mostly occur in tongue and lips and are rarely located in the soft palate. PRESENTATION OF CASE: We describe the diagnostic assessment and treatment of 18-year old male presenting with an intraoral mass on the soft palate. DISCUSSION: The treatment of choice in peripheral nerve sheath tumors is conservative resection and due to location and impairment, reconstruction. Secondary healing of soft palate defects is rarely described in the literature. CONCLUSION: With this case report, we demonstrate the feasibility of secondary healing after resection of a 3,0 × 1,9 × 2,1 cm schwannoma in the soft palate, resulting in no postoperative impairments, especially due to velopharyngeal function in a follow-up period of 2 months.

Nanoelectromechanical Sensors Based on Suspended 2D Materials.

The unique properties and atomic thickness of two-dimensional (2D) materials enable smaller and better nanoelectromechanical sensors with novel functionalities. During the last decade, many studies have successfully shown the feasibility of using suspended membranes of 2D materials in pressure sensors, microphones, accelerometers, and mass and gas sensors. In this review, we explain the different sensing concepts and give an overview of the relevant material properties, fabrication routes, and device operation principles. Finally, we discuss sensor readout and integration methods and provide comparisons against the state of the art to show both the challenges and promises of 2D material-based nanoelectromechanical sensing.

Gate-tunable graphene-based Hall sensors on flexible substrates with increased sensitivity.

We demonstrate a novel concept for operating graphene-based Hall sensors using an alternating current (AC) modulated gate voltage, which provides three important advantages compared to Hall sensors under static operation: (1) The sensor sensitivity can be doubled by utilizing both n- and p-type conductance. (2) A static magnetic field can be read out at frequencies in the kHz range, where the 1/f noise is lower compared to the static case. (3) The off-set voltage in the Hall signal can be reduced. This significantly increases the signal-to-noise ratio compared to Hall sensors without a gate electrode. A minimal detectable magnetic field Bmin down to [Formula: see text] and sensitivity up to 0.55 V/VT was found for Hall sensors working on flexible polyimide (PI) substrates. This clearly outperforms state-of-the-art flexible Hall sensors and is comparable to the values obtained by the best rigid III/V semiconductor Hall sensors.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

OBJECTIVE: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. METHODS: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. RESULTS: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. CONCLUSIONS: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study.

BACKGROUND: Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. METHODS: In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. FINDINGS: 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 µm or less than or equal to 88 µm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume. INTERPRETATION: Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. FUNDING: Instituto de Salud Carlos III.

Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography.

OBJECTIVE: To investigate whether patients with moyamoya angiopathy without obvious retinal pathologies such as retinal infarctions or the congenital morning glory anomaly may have subtle subclinical retinal changes. METHODS: In this cross-sectional study, spectral domain optical coherence tomography was used to analyze the retinal morphology of 25 patients with idiopathic moyamoya angiopathy and 25 age- and sex-matched healthy controls. We analyzed the retinal vasculature with blue laser autofluorescence, lipofuscin deposits with MultiColor confocal scanning laser ophthalmoscopy, and the optic nerve head (ONH) volume with a custom postprocessing algorithm. In addition to the total retinal thickness, semiautomated segmentation was used for segmentation of retinal layers in macular cross scans, macular volume scans, and peripapillary ring scans. RESULTS: The main finding was a pronounced reduction of the ONH volume in moyamoya angiopathy compared with controls (0.76 ± 0.45 mm(3) and 1.47 ± 0.50 mm(3), respectively; p < 0.0001), which was associated with a less pronounced reduction of the retinal nerve fiber layer in macular volume scans (0.97 ± 0.11 mm(3) and 1.10 ± 0.10 mm(3), respectively; p < 0.001). Autofluorescence and MultiColor confocal scanning laser ophthalmoscopy images revealed no pathologies except for one branch retinal artery occlusion. CONCLUSION: Our results indicate that even patients with moyamoya angiopathy who do not have obvious retinal abnormalities have retinal abnormalities. These can be detected by spectral domain optical coherence tomography, and the association of ONH abnormalities with the vascular changes may suggest that idiopathic moyamoya angiography is a systemic disease involving abnormalities of the early mesodermal development.