ICAM-1 nanoclusters regulate hepatic epithelial cell polarity by leukocyte adhesion-independent control of apical actomyosin

Epithelial intercellular adhesion molecule (ICAM)-1 is apically polarized, interacts with, and guides leukocytes across epithelial barriers. Polarized hepatic epithelia organize their apical membrane domain into bile canaliculi and ducts, which are not accessible to circulating immune cells but that nevertheless confine most of ICAM-1. Here, by analyzing ICAM-1_KO human hepatic cells, liver organoids from ICAM-1_KO mice and rescue-of-function experiments, we show that ICAM-1 regulates epithelial apicobasal polarity in a leukocyte adhesion-independent manner. ICAM-1 signals to an actomyosin network at the base of canalicular microvilli, thereby controlling the dynamics and size of bile canalicular-like structures. We identified the scaffolding protein EBP50/NHERF1/SLC9A3R1, which connects membrane proteins with the underlying actin cytoskeleton, in the proximity interactome of ICAM-1. EBP50 and ICAM-1 form nano-scale domains that overlap in microvilli, from which ICAM-1 regulates EBP50 nano-organization. Indeed, EBP50 expression is required for ICAM-1-mediated control of BC morphogenesis and actomyosin. Our findings indicate that ICAM-1 regulates the dynamics of epithelial apical membrane domains beyond its role as a heterotypic cell– cell adhesion molecule and reveal potential therapeutic strategies for preserving epithelial architec-ture during inflammatory stressWe gratefully acknowledge the expert technical advice of the Confocal Microscopy, Electron Microscopy, and Genomic facilities of the CBM Severo Ochoa, especially the contribution of Milagros Guerra, from the electron microscopy facility. We thank the staff of the Advanced Light Microscopy and cryo-EM facilities of the CNB-CSIC for their expert technical assistance with the correlative Cryo-SXT. We also thank Dr. Eva Pereiro at ALBA Synchrotron Light Source (Cerdanyola del Vall\u00E8s, Spain) for her expert technical advice, Prof. Nancy Hogg at the Francis Crick Institute (London, UK) for generating and sharing the Icam1_KO mouse, Dr. Luc\u00EDa Cordero Espinoza at the Gurdon Institute (Cambridge, UK) for her technical support in generating liver organoids, and Ana L\u00F3pez Sancha for her technical support with isolating the PBMCs. The work was supported by grants PID2020-119881RB-I00 from AEI (to CC-N, CL-P, NC-A, SB, GdR, JF, and JM) and P2022/BMD-7232 TomoXliver2 (to AC, SB, JMC, and JM), and IND2019/BMD-17139 (to JM) from Comunidad de Madrid. This research work was also funded by the European Commission\u2500NextGenerationEU (Regulation EU 2020/2094), through CSIC\u2019s Global Health Platform (PTI Salud Global). SB is supported by Endocornea, Convenio Colaboraci\u00F3n CSIC, funded by Instituto de Investigaci\u00F3n Fundaci\u00F3n Jim\u00E9nez D\u00EDaz. CM acknowledges support through the grant PID2021-125386NB-I00 funded by MCIN/AEI/10.13039/501100011033/and FEDER 'ERDF A way of making Europe'. CC-N is a recipient of FPI fellowships from MINECO. NC-A is a recipient of an FPU fellowship from MECD. NR-R is supported by funding from the People Programme (Marie Curie Actions) of the European Union\u2019s Seventh Framework Programme (FP7/2007\u20132013) under REA grant agreement no. 608765 and also by Ram\u00F3n y Cajal program, grant RYC2021-031221-I and grant PID2022-137552OA-I00 from AE

Assessing the relationship between microwave vegetation optical depth and gross primary production

At the global scale, the uptake of atmospheric carbon dioxide by terrestrial ecosystems through photosynthesis is commonly estimated through vegetation indices or biophysical properties derived from optical remote sensing data. Microwave observations of vegetated areas are sensitive to different components of the vegetation layer than observations in the optical domain and may therefore provide complementary information on the vegetation state, which may be used in the estimation of Gross Primary Production (GPP). However, the relation between GPP and Vegetation Optical Depth (VOD), a biophysical quantity derived from microwave observations, is not yet known. This study aims to explore the relationship between VOD and GPP. VOD data were taken from different frequencies (L-, C-, and X-band) and from both active and passive microwave sensors, including the Advanced Scatterometer (ASCAT), the Soil Moisture Ocean Salinity (SMOS) mission, the Advanced Microwave Scanning Radiometer for Earth Observation System (AMSR-E) and a merged VOD data set from various passive microwave sensors. VOD data were compared against FLUXCOM GPP and Solar-Induced chlorophyll Fluorescence (SIF) from the Global Ozone Monitoring Experiment-2 (GOME-2). FLUXCOM GPP estimates are based on the upscaling of flux tower GPP observations using optical satellite data, while SIF observations present a measure of photosynthetic activity and are often used as a proxy for GPP. For relating VOD to GPP, three variables were analyzed: original VOD time series, temporal changes in VOD (ΔVOD), and positive changes in VOD (ΔVOD≥0). Results show widespread positive correlations between VOD and GPP with some negative correlations mainly occurring in dry and wet regions for active and passive VOD, respectively. Correlations between VOD and GPP were similar or higher than between VOD and SIF. When comparing the three variables for relating VOD to GPP, correlations with GPP were higher for the original VOD time series than for ΔVOD or ΔVOD≥0 in case of sparsely to moderately vegetated areas and evergreen forests, while the opposite was true for deciduous forests. Results suggest that original VOD time series should be used jointly with changes in VOD for the estimation of GPP across biomes, which may further benefit from combining active and passive VOD data

A method for the analysis of the oligomerization profile of the Huntington’s disease-associated, aggregation-prone mutant huntingtin protein by isopycnic ultracentrifugation

Conformational diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases as well as ataxias and fronto-temporal disorders, are part of common class of neurological disorders characterised by the aggregation and progressive accumulation of mutant proteins which display aberrant conformation. In particular, Huntington’s disease (HD) is caused by mutations leading to an abnormal expansion in the polyglutamine (poly-Q) tract of the huntingtin protein (HTT), leading to the formation of inclusion bodies in neurons of affected patients. Furthermore, recent experimental evidence is challenging the conventional view of the disease by revealing the ability of mutant HTT to be transferred between cells by means of extracellular vesicles (EVs), allowing the mutant protein to seed oligomers involving both the mutant and wild type forms of the protein. There is still no successful strategy to treat HD. In addition, the current understanding of the biological processes leading to the oligomerization and aggregation of proteins bearing the poly-Q tract has been derived from studies conducted on isolated poly-Q monomers and oligomers, whose structural properties are still unclear and often inconsistent. Here we describe a standardised biochemical approach to analyse by isopycnic ultracentrifugation the oligomerization of the N-terminal fragment of mutant HTT. The dynamic range of our method allows one to detect large and heterogeneous HTT complexes. Hence, it could be harnessed for the identification of novel molecular determinants responsible for the aggregation and the prion-like spreading properties of HTT in the context of HD. Equally, it provides a tool to test novel small molecules or bioactive compounds designed to inhibit the aggregation of mutant HTT

Management of acute diverticulitis with pericolic free gas (ADIFAS). an international multicenter observational study

Background: There are no specific recommendations regarding the optimal management of this group of patients. The World Society of Emergency Surgery suggested a nonoperative strategy with antibiotic therapy, but this was a weak recommendation. This study aims to identify the optimal management of patients with acute diverticulitis (AD) presenting with pericolic free air with or without pericolic fluid. Methods: A multicenter, prospective, international study of patients diagnosed with AD and pericolic-free air with or without pericolic free fluid at a computed tomography (CT) scan between May 2020 and June 2021 was included. Patients were excluded if they had intra-abdominal distant free air, an abscess, generalized peritonitis, or less than a 1-year follow-up. The primary outcome was the rate of failure of nonoperative management within the index admission. Secondary outcomes included the rate of failure of nonoperative management within the first year and risk factors for failure. Results: A total of 810 patients were recruited across 69 European and South American centers; 744 patients (92%) were treated nonoperatively, and 66 (8%) underwent immediate surgery. Baseline characteristics were similar between groups. Hinchey II-IV on diagnostic imaging was the only independent risk factor for surgical intervention during index admission (odds ratios: 12.5, 95% CI: 2.4-64, P =0.003). Among patients treated nonoperatively, at index admission, 697 (94%) patients were discharged without any complications, 35 (4.7%) required emergency surgery, and 12 (1.6%) percutaneous drainage. Free pericolic fluid on CT scan was associated with a higher risk of failure of nonoperative management (odds ratios: 4.9, 95% CI: 1.2-19.9, P =0.023), with 88% of success compared to 96% without free fluid ( P <0.001). The rate of treatment failure with nonoperative management during the first year of follow-up was 16.5%. Conclusion: Patients with AD presenting with pericolic free gas can be successfully managed nonoperatively in the vast majority of cases. Patients with both free pericolic gas and free pericolic fluid on a CT scan are at a higher risk of failing nonoperative management and require closer observation

Cultural Perception of Accessibility and the Role of Heritage: The Havelis in Shahjahanabad (Old Delhi)

In the Western context accessibility is a quality achieved through several steps, where the physical dimension is usually the first one, addressing people with disabilities. Changing the perspective, in a context such as the historic city of old Delhi, the removal of architectural barriers might not be the first concern, also referring to the diverse socio-economic situation and different cultural perception about disabilities. This paper reverses priorities, foregrounding the cultural accessibility, followed then by all the other dimensions. The case study of Shahjahanabad, one of the most significant historic areas of New Delhi, is analysed according to several aspects and dimensions of accessibility, with specific reference to the hundreds of havelis, the typical courtyard dwellings built during the Mughal era. Recognizing the heritage as a carrier of an identity value will allow us to enlarge the view and then pursue the other forms of inclusion

The multilayered complexity of the chemokine receptor system

The chemokines receptor family are membrane-expressed class A-specific seven-transmembrane receptors linked to G proteins. Through interaction with the corresponding ligands, the chemokines, they induce a wide variety of cellular responses including cell polarization, movement, immune and inflammatory responses, as well as the prevention of HIV-1 infection. Like a Russian matryoshka doll, the chemokine receptor system is more complex than initially envisaged. This review focuses on the mechanisms that contribute to this dazzling complexity and how they modulate the signaling events triggered by chemokines. The chemokines and their receptors exist as monomers, dimers and oligomers, their expression pattern is highly regulated, and the ligands can bind distinct receptors with similar affinities. The use of novel imaging-based technologies, particularly real-time imaging modalities, has shed new light on the very dynamic conformations that chemokine receptors adopt depending on the cellular context, and that affect chemokine-mediated responses. This complex scenario presents both challenging and exciting opportunities for drug Discovery

COVID-19 Neuromuscular Involvement in Post-Acute Rehabilitation

Background: Coronavirus disease 2019 (COVID-19) is associated with muscle and nerve injuries as a consequence of prolonged critical illness or the infection itself. In this study, we evaluated neuromuscular involvement in patients who underwent post-acute intensive rehabilitation after COVID-19. Methods: Clinical and neurophysiological evaluations, including nerve conduction studies and electromyography, were performed on 21 consecutive patients admitted for rehabilitation after COVID-19. Results: Clinical signs suggesting muscle or nerve involvement (weakness, reduced deep tendon reflexes, impaired sensitivity, abnormal gait) were found in 19 patients. Neurophysiological examinations confirmed neuromuscular involvement in 17 patients: a likely association of critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) was found in 5 patients; CIM alone was found in 4 patients; axonal sensory-motor polyneuropathy was found in 4 patients (CIP in 2 patients, metabolic polyneuropathy in 2 patients); Guillain-Barré syndrome was found in 2 patients (classical demyelinating sensory-motor polyneuropathy and acute motor axonal neuropathy, respectively); peroneal nerve injury was found in 1 patient; and pre-existing L4 radiculopathy was found in 1 patient. Conclusions: Neuromuscular involvement is a very common finding among patients admitted for rehabilitation after COVID-19, and proper investigation should be conducted when muscle or nerve injury is suspected for adequate rehabilitative strategy planning