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ABSTRACTIntroductionCrohn’s disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient’s unique risk factors, clinical representations, and preferences.Areas coveredThis comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation.Expert opinionAntibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.

The realization of efficient optical devices depends on the ability to harness strong nonlinearities, which are challenging to achieve with standard photonic systems. Exciton–polaritons formed in hybrid organic–inorganic perovskites offer a promising alternative, exhibiting strong interactions at room temperature (RT). Despite recent demonstrations showcasing a robust nonlinear response, further progress is hindered by an incomplete understanding of the microscopic mechanisms governing polariton interactions in perovskite-based strongly coupled systems. Here, we investigate the nonlinear properties of quasi-2D dodecylammonium lead iodide perovskite (n3-C12) crystals embedded in a planar microcavity. Polarization-resolved pump–probe measurements reveal the contribution of indirect exchange interactions assisted by dark states formation. Additionally, we identify a strong dependence of the unique spin-dependent interaction of polaritons on sample detuning. The results are pivotal for the advancement of polaritonics, and the tunability of the robust spin-dependent anisotropic interaction in n3-C12 perovskites makes this material a powerful choice for the realization of polaritonic circuits.

Directed cell migration is driven by the front–back polarization of intracellular signalling1–3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4–6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7–9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum–plasma membrane (ER–PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER–PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER–PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER–PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front–back ER–PM contact gradient. Together, our study suggests that the structural polarity mediated by ER–PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.

AbstractThe Earned Value Management (EVM) methodology provides an index-based Estimate at Completion (EAC) formula to forecast the final cost of an ongoing project. However, neither the EVM methodology nor the literature in cost forecasting considers the occurrence of risks and how the cost contingency reserve (CC) is used to mitigate them. This study proposes a risk-adjusted cost EAC methodology based on nonlinear regression that captures the CC spending profile and exploits it to improve the EAC forecasting performance. The CC spending profile reflects the preventive, neutral, or reactive risk management strategy (RMS) adopted, which dictates how the CC reserve is depleted throughout the project execution. The framework was tested on a dataset comprising 79 constructions and engineering projects to evaluate its performance across the projects’ early, mid, and late stages. Results show that the proposed methodology provides timely forecasts—mean absolute percentage error (MAPE) improves as the project progresses—and that a proactive RMS is the most reliable one in all stages, with MAPE values of 14.57%, 12.28%, and 11.42%, respectively.

In recent years, new methods of generating continuum mid-infrared pulses through filamentation in gases have been developed for ultrafast time-resolved infrared vibrational spectroscopy. The generated infrared pulses can have thousands of wavenumbers of bandwidth, spanning the entire mid-IR region while retaining pulse length below 100 fs. This technology has had a significant impact on problems involving ultrafast structural dynamics in congested spectra with broad features, such as those found in aqueous solutions and molecules with strong intermolecular interactions. This study describes the recent advances in generating and characterizing these pulses and the practical aspects of implementing these sources for broadband detection in transient absorption and 2D IR spectroscopy.

Optoelectronic and spinoptronic technologies benefit from flexible and tunable coherent light sources combining the best properties of nano- and material-engineering to achieve favorable properties such as chiral lasing and low threshold nonlinearities. In this work we demonstrate an electrically wavelength- and polarization-tunable room temperature polariton laser due to emerging photonic spin–orbit coupling. For this purpose, we design an optical cavity filled with both birefringent nematic liquid crystal and an inorganic perovskite. Our versatile growth method of single CsPbBr3inorganic perovskite crystals in polymer templates allows us to reach strong light–matter coupling and pump-induced condensation of exciton–polaritons resulting in coherent emission of light. The sensitivity of the liquid crystal to external voltage permits electrical tuning of the condensate energy across 7 nm; its threshold power, allowing us to electrically switch it on and off; and its state of polarization sweeping from linear to locally tilted circularly polarized emission.

This work highlights the importance of dehydration in natural gas production, especially in offshore units, and tackles the challenges associated with adsorption processes. The main contribution is implementing digital solutions to monitor a Brazilian operational offshore natural gas dehydration unit. Bayesian inference and robust regression are utilized to determine the Remaining Useful Life (RUL) of the adsorbent in fixed beds. Furthermore, a mass balance in fixed beds provides valuable process insights, such as the adsorbed volume of water, a crucial variable for assessing the fixed bed’s performance. Bayesian inference and the logistic function yielded the most accurate predictions for the end of the fixed bed’s useful life. The proposed methodologies have been successfully integrated into a real-time monitoring dashboard at a Brazilian oil and gas plant.

Objectives: While studies examining the effectiveness of virtual reality (VR) systems in autism spectrum disorder (ASD) intervention have seen significant growth, research on their application as tools to improve assessment and diagnosis remains limited. This systematic review explores the potential of VR systems in speeding-up and enhancing the assessment process for ASD. Methods: We conducted a systematic search of peer-reviewed research to identify studies that compared characteristics of autistic and neurotypical participants performing tasks in virtual environments. Pubmed and IEE Xplore databases were searched and screened using predetermined keywords and inclusion criteria related to ASD and virtual reality, resulting in the inclusion of 20 studies. Results: Studies reviewed revealed that VR technologies may serve as a booster of ASD “traits” that might otherwise go unnoticed when using traditional tools. Specifically, results indicated that ASD individuals exhibited distinct behavioral nuances compared to typically developing participants across four main domains: communication and social interaction skills, cognitive functioning and neurological pattern, sensory and physiological processing, and motor behavior and body movements. Also, recent studies analyzed here underscored the potential of integrating machine learning with VR technologies to enhance accuracy in identifying ASD based on motor behavior, eye gaze, and electrodermal activity. Conclusions: The integration of VR technologies can complement traditional tools in ASD diagnosis, providing more objective and reliable assessment within a controlled, ecological, and motivating virtual environment. In addition, the reviewed literature suggests machine learning models combined with VR technologies may support phenotypic diagnosis, offering a more refined classification of ASD subgroups within immersive virtual contexts.

Endovascular interventions are minimally invasive procedures that utilize the vascular system to access anatomical regions deep within the body. Image-guided assistance provides valuable real-time information about the dynamic state of the vascular environment. However, the reliance on intraoperative 2-D fluoroscopy images limits depth perception, prompting the demand for intraoperative 3-D imaging. Existing image registration methods face difficulties in accurately incorporating tissue deformations compared to the preoperative 3-D model, particularly in a weakly supervised manner. Additionally, reconstructing deformations from 2-D to 3-D space and presenting this intraoperative model visually to clinicians poses further complexities. To address these challenges, this study introduces a novel deformable model-to-image registration framework using deep learning. Furthermore, this research proposes a visualization method through augmented reality to guide endovascular interventions. This study utilized image data collected from nine patients who underwent transcatheter aortic valve implantation (TAVI) procedures. The registration results in 2-D indicate that the proposed deformable model-to-image registration framework achieves a modified dice similarity coefficient (MDSC) value of $0.89~\pm ~0.02$ and a penalization of deformations in spare space (PDSS) value of $0.04~\pm ~0.01$ , offering an improvement of 3.5%–98.6% over the state-of-the-art image registration approach. Additionally, the accuracy of registration in 3-D was evaluated using a dataset obtained from an intervention simulator, resulting in a mean absolute error (MAE) of $1.51~\pm ~1.02$ mm within the region of interest. Overall, the study validates the feasibility and accuracy of the proposed weakly supervised deformable model-to-image registration framework, demonstrating its potential to provide intraoperative 3-D imaging as intervention assistance in dynamic vascular environments.

Purpose: The presence of different polymorphic or pseudo-polymorphic forms in active pharmaceutical ingredients may affect the performance of the formulated products. Pseudo-polymorphs, especially hydrates, present a differential dissolution rate. In such a scenario, pseudo-polymorphism should be strictly controlled due to its impact on the bio-availability of formulates products. Methods: In order to determine solid forms of cefadroxil present in commercial capsules, anhydrous and monohydrate pure the solid forms were prepared and fully characterized by optical microscopy, vibrational spectroscopy (middle and near infrared), calorimetric techniques (differential scanning calorimetry and thermogravimetry). Nuclear magnetic resonance was used to corroborate structural integrity. Two sets of synthetic samples for calibration (N = 12) and validation (N = 12) were prepared following a binary-mixtures design of monohydrate/anhydrous cefadroxil in the presence of the excipient matrix. NIR spectra were acquired and used as input of partial least squares (PLS) model. Results: Three PLS-factors, mean scattering correction and MIN–MAX normalization demonstrated to be the optimal parameters on full range spectra (750–2500 nm). The method was validated for linearity/range, accuracy and precision by evaluation of validation set recovery. Once method validated, a commercial lot of capsules was analyzed and acceptable recovery results and low deviations were obtained. Conclusion: Near infrared spectroscopy (NIR) emerged as the technique of choice to determine pseudopolymorphic-purity. Cefadroxil monohydrate was determined in a fast and accurate way in presentence of cefadroxil anhydrous and excipients by NIR–PLS methodology. The developed analytical methodology, arise as a general strategy for hydrates determination, making a direct determination of pseudopolymorphic form.

Introduction: Hyperkalemia, one of the most important electrolyte abnormalities of chronic kidney disease (CKD), often limits the use of renin–angiotensin–aldosterone system inhibitors and can increase in the postprandial period. In this study we report a real-world experience with the new non-adsorbed potassium binder patiromer in stage 3b-4 CKD patients. Moreover, we performed a cross-sectional analysis to evaluate, for the first time, the efficacy of patiromer in the control of postprandial potassium concentrations. Methods: We retrospectively collected data of 40 patients at the time of patiromer initiation (T0), and after 2 (T2), 6 (T6) and 12 (T12) months of treatment. For cross sectional analysis, a blood sample was collected 2 h after the main meal for the evaluation of postprandial potassium concentrations. Results: Eighty-two point five percent of patients (33/40) reached normal potassium concentrations at T2. Serum potassium significantly decreased at T2 compared to T0 (5.13 ± 0.48 vs 5.77 ± 0.41 mmol/L, respectively; p< 0.001) and the reduction remained significant during the follow-up (5.06 ± 0.36 at T6 and 5.77 ± 0.41 at T12; p< 0.001 vsT0). Renin–angiotensin–aldosterone system inhibitors were continued by 93% of patients (27/29). Adverse events were reported in 27.5% of patients and were all mild-to-moderate. Postprandial potassium concentrations did not significantly change compared to fasting state potassium measured at T12 (4.53 ± 0.33 vs 5.06 ± 0.36 mmol/L; p= 0.15). Conclusions: In a real-world setting of advanced CKD patients, patiromer is a useful treatment for hyperkalemia, since it significantly reduces serum potassium levels over the long term and is able to maintain potassium concentrations in the normal range even in the post-prandial period. Graphical abstract:

Grating-based X-ray phase-contrast and in particular dark-field radiography are promising new imaging modalities for medical applications. Currently, the potential advantage of dark-field imaging in early-stage diagnosis of pulmonary diseases in humans is being investigated. These studies make use of a comparatively large scanning interferometer at short acquisition times, which comes at the expense of a significantly reduced mechanical stability as compared to tabletop laboratory setups. Vibrations create random fluctuations of the grating alignment, causing artifacts in the resulting images. Here, we describe a novel maximum likelihood method for estimating this motion, thereby preventing these artifacts. It is tailored to scanning setups and does not require any sample-free areas. Unlike any previously described method, it accounts for motion in between as well as during exposures.

X-ray dark-field imaging enables a spatially-resolved visualization of ultra-small-angle X-ray scattering. Using phantom measurements, we demonstrate that a material’s effective dark-field signal may be reduced by modification of the visibility spectrum by other dark-field-active objects in the beam. This is the dark-field equivalent of conventional beam-hardening, and is distinct from related, known effects, where the dark-field signal is modified by attenuation or phase shifts. We present a theoretical model for this group of effects and verify it by comparison to the measurements. These findings have significant implications for the interpretation of dark-field signal strength in polychromatic measurements.

This letter introduces a new design for a 2-D electronically steerable parasitic array radiator based on a 3 × 3 microstrip patch array. The proposed configuration enables conical beam steering by using nine radiating elements, one active U-slot patch antenna, and eight parasitic elements. To validate the proposed design, a prototype was manufactured and experimentally validated. The reported results show a continuous steering range of 75° on the E-plane (ϕ = 0°), ranging from − 45° to +30°, 74° on the H-plane (ϕ = 90°) from − 37° to +37°, and 60° on the D-plane (ϕ = 51°), from − 36° to +25°. The operational bandwidth is about 1.8 %, including the band reduction due to beam scanning. The measured aperture efficiency is equal to 38% with a maximum gain of 8.2 dB.

Perovskite crystals—with their exceptional nonlinear optical properties, lasing and waveguiding capabilities—offer a promising platform for integrated photonic circuitry within the strong-coupling regime at room temperature. Here we demonstrate a versatile template-assisted method to efficiently fabricate large-scale waveguiding perovskite crystals of arbitrarily predefined geometry such as microwires, couplers and splitters. We non-resonantly stimulate a condensate of waveguided exciton–polaritons resulting in bright polariton lasing from the transverse interfaces and corners of our perovskite microstructures. Large blueshifts with excitation power and high mutual coherence between the different edge and corner lasing signals are detected in the far-field photoluminescence, implying that a spatially extended condensates of coherent polaritons has formed. The condensate polaritons are found to propagate over long distances in the wires from the excitation spot and can couple to neighbouring wires through large air gaps, making our platform promising for integrated polaritonic circuitry and on-chip optical devices with strong nonlinearities.

The classification of medical interventions as either invasive or non-invasive is commonly regarded to be morally important. On the most commonly endorsed account of invasiveness, a medical intervention is invasive if and only if it involves either breaking the skin (‘incision’) or inserting an object into the body (‘insertion’). Building on recent discussions of the concept of invasiveness, we show that this standard account fails to capture three aspects of existing usage of the concept of invasiveness in relation to medical interventions—namely, (1) usage implying that invasiveness comes in degrees, (2) that the invasiveness of an intervention can depend on the characteristics of the salient alternative interventions, and (3) that medical interventions can be invasive in non-physical ways. We then offer the beginnings of a revised account that, we argue, is able to capture a wider range of existing usage. Central to our account is a distinction between two properties: basic invasivenessand threshold invasiveness. We end by assessing what the standard account gets right, and what more needs to be done to complete our schematic account.

Imaging large fields of view at a high magnification requires tiling. Transmission electron microscopes typically have round beam profiles; therefore, tiling across a large area is either imperfect or results in uneven exposures, a problem for dose-sensitive samples. Here, we introduce a square electron beam that can easily be retrofitted in existing microscopes, and demonstrate its application, showing that it can tile nearly perfectly and deliver cryo-electron microscopy imaging with a resolution comparable to conventional set-ups.

The application of radar technology in indoor people monitoring has opened up new avenues, such as localization and tracking, vital signs monitoring, and fall detection. Nevertheless, one of the significant challenges facing radar systems is the issue of indoor multipath propagation, which results in radar ghosts that can diminish the detection accuracy or even compromise the monitoring process entirely. This study delves into the utilization of reconfigurable intelligent surfaces (RISs) in radar-based indoor people localization. Thanks to the use of RIS, targets can be tracked from multiple orientations, achieving a more precise estimation of the propagation channel and in turn mitigating the effects of indoor multipath propagation. As a result, the detection performance of the radar system can be improved without increasing the radar's complexity. Empirical evidence gathered from experiments conducted in a laboratory environment has demonstrated the feasibility of the proposed approach in accurately locating multiple subjects in a two-dimensional (2-D) space while being able to reject radar ghosts. Practical implications of this novel approach include the development of smart building systems, Internet of Things (IoT), telemedicine, Hospital 4.0, automated nurse call solutions, ambient assisted living, firefighter tracking, and security applications.

Odonata species live through their immature development in aquatic habitats, where the eggs are adapted to survive the initial stages. The survival of the eggs is linked to the layers that make up the eggshell. These layers are common to all odonate species, but show variations among them, depending on the oviposition method. For example, endophytic eggs (laid in plant tissues) and exophytic eggs (laid on the water surface) have different morphologies, which may reveal egg adaptations to environmental conditions and stresses. The differences in the egg morphologies could be shown in the length of the egg layers, their histochemical composition, and in the ultrastructure. The histochemical composition can reveal several features that could lead us to a better understanding of its function, for example, how glycoproteins and total proteins could regulate the humidity and water retention in the eggs according to the environments in which the eggs are placed.

La última generación de válvulas cardiacas expandibles con balón y autoexpandibles para implante percutáneo no se han comparado en valvulopatía aórtica bicúspide (VAB).

Nephroangiosclerosis (NAS) associated with hypertension continues to be one of the most causes of end stage renal diseases in Europe, but it is still poorly studied. The prevalence of NAS shows a large variability due to the difference among different countries regarding clinical presentations and the indication to perform renal biopsy. The study aimed to investigate the prevalence in biopsy-proven NAS patients and the association with hypertension and/or glomerulonephritis (GN). We included all patients referred for native kidney biopsy between 2003–2021 at Policlinic Umberto I of Rome. From 837 patients who underwent renal biopsy NAS was diagnosed in 80 (10.5%) patients. Serum creatinine was significantly higher in NAS [2.07 mg/dl (IQR 1.13–5.2) vs 1.1 mg/dl (IQR 0.8–2.1), p< 0.001] compared to patients without NAS. Hypertension was present in 45% of patients with NAS. Proteinuria was significantly higher in patients with mild-moderate NAS compared to patients with severe NAS [2.6 g/die (IQR 1–5) vs 1.5 g/die (IQR 0.86–2.3), p< 0.05]. We did not find any significant differences, including histological features, between NAS patients with hypertension and NAS patients without hypertension (p> 0.05). IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy were the most frequent GN associated. In conclusion no specific histological features are reported in NAS with and without hypertension. More information on the phenotype, clinical presentation and markers are needed to improve histological and clinical diagnostics.

Nanostructured photonic pigments exhibiting structural colors hold promises to replace conventional pigments for several applications. One emerging challenge in the field consists in integrating additional functionalities to the pigments beyond colors. For instance, integrating phase changing materials, such as VO2, would enable the emergence of a new generation of photonic pigments that regulate autonomously the flow of light in the infrared range while conserving their color in the visible range. Yet, developing those self-regulating pigments requires designing VO2periodic nanostructures and developing a robust and scalable fabrication approach based on low-cost chemical methods. It is well known that synthetizing and shaping vanadium-based compounds in a reliable way represents a longstanding challenge in the domain. Herein, we demonstrate the fabrication of self-regulating photonic pigments made of VO2micrometric spheres with inverse opal architectures. We developed a chemical route based on the sol–gel process and colloidal self-assembly coupled with high-throughput spray-drying. Importantly, the key to achieve a robust synthetic approach relies on the controlled pseudomorphic transformation between V2O3and VO2during thermal annealing. A set of in situand ex situmicroscopy and spectroscopy techniques were used to characterize the VO2pigment behavior during phase transition in the visible and infrared range, revealing that these pigments modulate IR radiation while maintaining their structural color in the visible region. We demonstrate that these pigments can be easily integrated into paints and coating or embedded into elastomeric objects, opening interesting perspectives for applications in textile or architecture.

In this work, a new dual-band dual-polarized transmitarray (TA) antenna element based on multilayer frequency selective surfaces is introduced. This novel configuration has been successfully tested for K/Ka satellite communication (SatCom) frequency bands and is composed of a single low-profile printed circuit board incorporating five metal layers without any vertical transitional elements. In contrast to existing solutions, this proposal eliminates the need for vertical interconnections, air gaps, or spacers between the metal layers, resulting in a cost-effective board with an overall thickness of $0.24 \lambda $ at 30 GHz. The proposed unit cell operates at 20 and 30 GHz exploiting an interleaved lattice configuration. It affords independent control of the transmitted field phase within a range of 300°, at both frequency bands while maintaining a transmission loss not exceeding 3.5 dB. To substantiate the proposed design, an $87\times87$ mm2 TA has been prototyped and experimentally validated. The measured results indicate a peak gain of 20.6 and 22.8 dB at 20 and 30 GHz, respectively. Furthermore, the −1 dB gain bandwidth has been found to be 5% in the first band and 4.5% in the second band.

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

Many patients who access in the emergency department for acute bleeding are on anticoagulants; before specific reversal agents were developed, bleeding on anticoagulants was burdened with a substantial increase in morbidity and mortality. Clinical trials demonstrated favourable risk-benefit profiles of direct-acting oral anticoagulants compared with vitamin K antagonists in patients with atrial fibrillation and compared with low molecular weight heparin in patients treated and prevented from venous thromboembolism. Even if they drastically reduced some types of bleeding, particularly intracranial haemorrhage, they have not completely eliminated this risk. The arrival of a patient with active bleeding in the emergency department is always a critical scenario that involves resources and costs. In critical setting, the diagnosis and treatment of bleeding should occurred simultaneously. Understanding the pathophysiological mechanisms that occur during bleeding is essential for establish the most appropriate therapies and improve the standard of care of the haemorrhagic patients.

ABSTRACTEndoplasmic reticulum stress is an emerging significant player in the molecular pathology of connective tissue disorders. In response to endoplasmic reticulum stress, cells can upregulate macroautophagy/autophagy, a fundamental cellular homeostatic process used by cells to degrade and recycle proteins or remove damaged organelles. In these scenarios, autophagy activation can support cell survival. Here we demonstrated by in vitroand in vivoapproaches that megakaryocytes derived from col6a1−⁄−(collagen, type VI, alpha 1) null mice display increased intracellular retention of COL6 polypeptides, endoplasmic reticulum stress and apoptosis. The unfolded protein response is activated in col6a1−⁄−megakaryocytes, as evidenced by the upregulation of molecular chaperones, by the increased splicing of Xbp1mRNA and by the higher level of the pro-apoptotic regulator DDIT3/CHOP. Despite the endoplasmic reticulum stress, basal autophagy is impaired in col6a1−⁄−megakaryocytes, which show lower BECN1 levels and reduced autophagosome maturation. Starvation and rapamycin treatment rescue the autophagic flux in col6a1−⁄−megakaryocytes, leading to a decrease in intracellular COL6 polypeptide retention, endoplasmic reticulum stress and apoptosis. Furthermore, megakaryocytes cultured from peripheral blood hematopoietic progenitors of patients affected by Bethlem myopathy and Ullrich congenital muscular dystrophy, two COL6-related disorders, displayed increased apoptosis, endoplasmic reticulum stress and impaired autophagy. These data demonstrate that genetic disorders of collagens, endoplasmic reticulum stress and autophagy regulation in megakaryocytes may be interrelated.Abbreviations:7-AAD: 7-amino-actinomycin D; ATF: activating transcriptional factor; BAX: BCL2 associated X protein; BCL2: B cell leukemia/lymphoma 2; BCL2L1/Bcl-xL: BCL2-like 1; BM: bone marrow; COL6: collagen, type VI; col6a1−⁄−: mice that are null for Col6a1; DDIT3/CHOP/GADD153: DNA-damage inducible transcript 3; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; reticulophagy: endoplasmic reticulum-selective autophagy; HSPA5/Bip: heat shock protein 5; HSP90B1/GRP94: heat shock protein 90, beta (Grp94), member 1; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; Mk: megakaryocytes; MTOR: mechanistic target of rapamycin kinase; NIMV: noninvasive mechanical ventilation; PI3K: phosphoinositide 3-kinase; PPP1R15A/GADD34: protein phosphatase 1, regulatory subunit 15A; RT-qPCR: reverse transcription-quantitative real-time PCR; ROS: reactive oxygen species; SERPINH1/HSP47: serine (or cysteine) peptidase inhibitor, clade H, member 1; sh-RNA: short hairpin RNA; SOCE: store operated calcium entry; UCMD: Ullrich congenital muscular dystrophy; UPR: unfolded protein response; WIPI2: WD repeat domain, phosphoinositide-interacting 2; WT: wild type; XBP1: X-box binding protein 1.

Enhancing charge-carrier dynamics is imperative to achieve efficient photoelectrodes for practical photoelectrochemical devices. However, a convincing explanation and answer for the important question which has thus far been absent relates to the precise mechanism of charge-carrier generation by solar light in photoelectrodes. Herein, to exclude the interference of complex multi-components and nanostructuring, we fabricate bulky TiO2photoanodes through physical vapor deposition. Integrating photoelectrochemical measurements and in situ characterizations, the photoinduced holes and electrons are transiently stored and promptly transported around the oxygen-bridge bonds and 5-coordinated Ti atoms to form polarons on the boundaries of TiO2grains, respectively. Most importantly, we also find that compressive stress-induced internal magnetic field can drastically enhance the charge-carrier dynamics for the TiO2photoanode, including directional separation and transport of charge carriers and an increase of surface polarons. As a result, bulky TiO2photoanode with high compressive stress displays a high charge-separation efficiency and an excellent charge-injection efficiency, leading to 2 orders of magnitude higher photocurrent than that produced by a classic TiO2photoanode. This work not only provides a fundamental understanding of the charge-carrier dynamics of the photoelectrodes but also provides a new paradigm for designing efficient photoelectrodes and controlling the dynamics of charge carriers.

Single-molecule localization microscopy (SMLM) generates data in the form of coordinates of localized fluorophores. Cluster analysis is an attractive route for extracting biologically meaningful information from such data and has been widely applied. Despite a range of cluster analysis algorithms, there exists no consensus framework for the evaluation of their performance. Here, we use a systematic approach based on two metrics to score the success of clustering algorithms in simulated conditions mimicking experimental data. We demonstrate the framework using seven diverse analysis algorithms: DBSCAN, ToMATo, KDE, FOCAL, CAML, ClusterViSu and SR-Tesseler. Given that the best performer depended on the underlying distribution of localizations, we demonstrate an analysis pipeline based on statistical similarity measures that enables the selection of the most appropriate algorithm, and the optimized analysis parameters for real SMLM data. We propose that these standard simulated conditions, metrics and analysis pipeline become the basis for future analysis algorithm development and evaluation.

ObjectivePulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance–compliance (RC) time, the product of PAC and pulmonary vascular resistance, is reported to be a physiological constant. We investigated if differences in PAC and RC time exist between pulmonary hypertension (PH) subgroups and examined whether PAC is an independent predictor of transplant-free survival in PAH.MethodsThis was a retrospective analysis of adult PAH (n=532) and chronic thromboembolic PH (CTEPH, n=84) patients enrolled in the US Pulmonary Hypertension Association Registry from 2015 to 2019. PAC and RC time were compared between PH subgroups (connective tissue disease-PAH (CTD-PAH), idiopathic/heritable-PAH (i/h-PAH), drug/toxin-PAH (d/t-PAH)). Cox proportional hazards models were constructed for transplant-free survival, adjusting for REVEAL 2.0 risk score.ResultsThere were no differences in estimated PAC between PAH subgroups, nor between PAH and CTEPH. RC time was shorter in CTEPH compared with PAH (median 0.55 (IQR 0.45–0.64) vs 0.62 (0.52–0.73) s, p<0.0001). RC time was shortest in CTD-PAH when compared with i/h-PAH and d/t-PAH ((0.59±0.18) vs (0.65±0.20) vs (0.73±0.25) s, p=0.0001). PAC was associated with transplant-free survival (HR 0.72, 95% CI 0.55 to 0.94, p=0.02) but was not an independent predictor of outcome after adjustment for REVEAL 2.0 score.ConclusionPAC was similar between PH groups and was not an independent predictor of transplant-free survival in PAH. RC time was different between PH subgroups, challenging RC time constancy.Trial registration numberNCT04071327

ObjectiveThis literature review aimed to identify the most efficacious current interventions for dactylitis and provide up-to-date scientific evidence to support the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations on the management of psoriatic arthritis.MethodsOriginal articles published from 2013 to 2020, registered in MEDLINE, Embase, and Cochrane Library, describing interventional trials and reporting dactylitis-related outcomes were included. The 20 members of the GRAPPA dactylitis group were divided into 9 subgroups according to treatment, and members of each group independently extracted data from articles/abstracts corresponding to their group by using a standardized data extraction form.ResultsForty-nine publications were analyzed, representing 40 randomized clinical trials (RCTs) and including 16,752 patients. Dactylitis was assessed as a secondary outcome in 97.5% of these trials and more than 40% of RCTs did not employ a specific dactylitis measure or instrument.ConclusionThe emergence of agents with novel mechanisms of action in recent years, such as interleukin 17 (IL-17), IL-12/23, IL-23, and Janus kinase inhibitors, has significantly expanded the available treatment options for dactylitis. This article points out the lack of consensus regarding dactylitis assessment and the paucity of data concerning the effect of local steroid injections, nonsteroidal antiinflammatory drugs, and conventional disease-modifying antirheumatic drugs. Clinical trials evaluating the effect of these traditional and low-cost medications used to treat dactylitis should be encouraged.

Novel techniques to capture carbon dioxide (CO2) from gas mixtures include physical adsorption on pelleted solid substrates. In this paper, the behaviour of spherical zeolite pellets is modelled, by resorting to one-dimensional partial differential equations, along the pellet radial direction, to express CO2mass and energy conservation inside the porous material. One of the innovative contributions is that a dynamic description is adopted also for adsorption/desorption kinetics. The uncertain parameters in the model can be identified with a two-step procedure thanks to real data collected in two different sets of experiments. First, static isothermal tests carried out on few pellets by means of a gas adsorption analyzer allow to identify the available sorbent active sites (saturation capacities) and the ratio of the desorption and adsorption kinetic coefficients. Then, dynamic tests carried out with the same analyzer with small progressive CO2injections allow to estimate desorption and adsorption kinetic coefficients separately. The pellet dynamic model thus tuned can be adopted in future work as a core element to mathematically describe a whole adsorption column filled with many pellets.

Exciton–polaritons derived from the strong light–matter interaction of an optical bound state in the continuum with an excitonic resonance can inherit an ultralong radiative lifetime and significant nonlinearities, but their realization in two-dimensional semiconductors remains challenging at room temperature. Here we show strong light–matter interaction enhancement and large exciton–polariton nonlinearities at room temperature by coupling monolayer tungsten disulfide excitons to a topologically protected bound state in the continuum moulded by a one-dimensional photonic crystal, and optimizing for the electric-field strength at the monolayer position through Bloch surface wave confinement. By a structured optimization approach, the coupling with the active material is maximized here in a fully open architecture, allowing to achieve a 100 meV photonic bandgap with the bound state in the continuum in a local energy minimum and a Rabi splitting of 70 meV, which results in very high cooperativity. Our architecture paves the way to a class of polariton devices based on topologically protected and highly interacting bound states in the continuum.

Neuroblastoma (NB) is a heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, viaβ-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of β3-adrenergic receptor (β3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the β3-AR modulation influenced the host immune system response against tumor. Results demonstrated that β3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, β3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression, caused by TILs infiltration, on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates with worse clinical outcome compared to the low expression group, and that ADRB3 gene expression affects different immune-related pathways. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.

Adenoid ameloblastoma is a very rare benign epithelial odontogenic tumor characterized microscopically by epithelium resembling conventional ameloblastoma, with additional duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid deposits, clusters of clear cells, and ghost-cell keratinization may also be present. These tumors do not harbor BRAFor KRASmutations and their molecular basis appears distinct from conventional ameloblastoma but remains unknown. We assessed CTNNB1(beta-catenin) exon 3 mutations in a cohort of 11 samples of adenoid ameloblastomas from 9 patients. Two of the 9 patients were female and 7 male and in 7/9 patients the tumors occurred in the maxilla. Tumors of 4 of these 9 patients harbored CTNNB1mutations, specifically p.Ser33Cys, p.Gly34Arg, and p.Ser37Phe. Notably, for one patient 3 samples were analyzed including the primary tumour and two consecutive recurrences, and results were positive for the mutation in all three tumors. Therefore, 6/11 samples tested positive for the mutation. In the 6 mutation-positive samples, ghost cells were present in only 2/6, indicating beta-catenin mutations are not always revealed by ghost cell formation. Dentinoid matrix deposition was observed in 5/6 mutation-positive samples and clear cells in all 6 cases. None of the cases harbored either BRAFor KRASmutations. Beta-catenin immunoexpression was assessed in the samples of 8 patients. Except for one wild-type case, all cases showed focal nuclear expression irrespective of the mutational status. Together with the absence of BRAFmutation, the detection of beta-catenin mutation in adenoid ameloblastomas supports its classification as a separate entity, and not as a subtype of ameloblastoma. The presence of this mutation may help in the diagnosis of challenging cases.