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Abstract The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole‐exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild‐type, PlxnB2 in CUP stem cells resulted in the impairment of self‐renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C‐PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C‐PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR‐dependent manner.

Background: Recent studies have highlighted the recognition of diaphragmatic dysfunction as a significant factor contributing to respiratory disturbances in severely ill COVID-19 patients. In the field of noninvasive respiratory support, high-flow nasal cannula (HFNC) has shown effectiveness in relieving diaphragm dysfunction. This study aims to investigate the diaphragmatic response to HFNC in patients with COVID-19 pneumonia by utilizing ultrasound. Methods: This retrospective study was conducted in a medical-surgical intensive care unit (ICU) at a tertiary care center in Buenos Aires, Argentina (Sanatorio de Los Arcos) over a 16-month period (January 2021–June 2022). The study included patients admitted to the ICU with a diagnosis of COVID-19 pneumonia who were deemed suitable candidates for HFNC therapy by the attending physician. Diaphragm ultrasound was conducted, measuring diaphragmatic excursion (DE) both before and during the utilization of HFNC for these patients. Results: A total of 10 patients were included in the study. A statistically significant decrease in respiratory rate was observed with the use of HFNC (p = 0.02), accompanied by a significant increase in DE (p = 0.04). Conclusion: HFNC leads to a reduction in respiratory rate and an increase in DE as observed by ultrasound in patients with COVID-19 pneumonia, indicating promising enhancements in respiratory mechanics. However, further research is required to validate these findings. [ABSTRACT FROM AUTHOR]

Purpose: The passive leg raising test (PLR) is a noninvasive method widely adopted to assess fluid responsiveness. We propose to explore if changes in the carotid flow assessed by echo-Doppler can predict fluid responsiveness after a PLR. Methods: We conducted a performance diagnostic study in two intensive care units from Argentina between February and April 2022. We included patients with signs of tissular hypoperfusion that required fluid resuscitation. We labeled the patients as fluid responders when we measured, after a fluid bolus, an increase greater than 15% in the left ventricle outflow tract (LVOT) VTI in an apical 5-chamber view and we compared those results with the carotid flow (CF) velocity–time integral (VTI) from the left supraclavicular region in a semi-recumbent position and during the PLR. Results: Of the 62 eligible patients, 50 patients (80.6%) were included. The area under the ROC curve for a change in CF VTI during the PLR test was 0.869 (95% CI 0.743–0.947). An increase of at least of 11% in the CF VTI with the PLR predicted fluid-responsiveness with a sensitivity of 77.3% (95% CI 54.6–92.2%) and specificity of 78.6% (95% CI 59–91.7%). The positive predictive value was 73.9% (95% CI 57.4–85.6%) and the negative predictive value was 81.5% (95% CI 66.5–90.7%). The positive likelihood ratio was 3.61 and the negative likelihood ratio was 0.29. Conclusion: An increase greater than 11% in CF VTI after a PLR may be useful to predict fluid responsiveness among critically ill patients. [ABSTRACT FROM AUTHOR]

Prone position has shown beneficial hemodynamic effects in patients with right ventricular dysfunction associated with acute respiratory distress syndrome decreasing the right ventricle afterload. We describe the case of a 57-year-old man with right ventricular dysfunction associated with pulmonary thromboembolism with severe hypoxemia that required mechanical ventilation in prone position. With this maneuver, we verified an improvement not only in his oxygenation, but also in his right ventricular function assessed with speckle tracking echocardiography. Our case shows the potential beneficial effect of the prone position maneuver in severely hypoxemic patients with right ventricular dysfunction associated with pulmonary thromboembolism. [ABSTRACT FROM AUTHOR]

Purpose: There is evidence that COVID-19 can have a clinically significant effect on the right ventricle (RV). Our objective was to enhance the efficiency of assessing RV dilation for diagnosing ACP by utilizing both linear measurements and qualitative assessment and its usefulness as an independent predictor of mortality. Methods: This is an observational, retrospective and single-center study of the Intensive Care Unit of the Sanatorio de Los Arcos in Buenos Aires, Argentina from March 2020 to January 2022. All patients admitted with acute respiratory distress syndrome due to COVID-19 pneumonia (C-ARDS) on mechanical ventilation who were assessed by transthoracic echocardiography (TTE) were included. Results: A total of 114 patients with C-ARDS requiring invasive mechanical ventilation were evaluated by echocardiography. 12.3% had RV dilation defined as a RV basal diameter greater than 41 mm, and 87.7% did not. Acute cor pulmonale (ACP) defined as RV dilation associated with paradoxical septal motion was found in 6.1% of patients. 7% had right ventricular systolic dysfunction according to qualitative evaluation. The different RV echocardiographic variables were studied with a logistic regression model as independent predictors of mortality. In the multivariate analysis, both the RV basal diameter and the presence of ACP showed to be independent predictors of in-hospital mortality with OR of 3.16 (95% CI 1.36–7.32) and 3.64 (95% CI 1.05–12.65) respectively. Conclusion: An increase in the RV basal diameter and the presence of ACP measured by TTE are independent predictors of in-hospital mortality in patients with C-ARDS. [ABSTRACT FROM AUTHOR]

This article discusses the use of color M-mode in transcranial duplex sonography as a novel approach for diagnosing right-to-left shunt (RLS). RLS is a condition where there is abnormal blood flow from the right side to the left side of the heart, bypassing the lungs. Early detection and treatment of RLS are important to prevent complications such as stroke or brain abscess. The article describes a case study where the diagnosis of RLS was confirmed using transesophageal echocardiography. The authors propose that color M-mode could be a valuable technique for screening and monitoring patients with signs of RLS. [Extracted from the article]

Abstract Secreted class 3 semaphorins (Sema3), which signal through plexin receptors and mostly use neuropilins (Nrps) as co‐receptors, were initially identified for their ability to steer navigating axons in the developing embryo. They were later found to control angiogenesis in physiological and pathological settings as well (Serini et al, 2013). Indeed, the development of a novel and aberrant vasculature is central to the pathogenesis of several human diseases, including cancer and vascular retinopathies (Goel et al, 2011). A large body of evidence demonstrates that in cancer, a massive regression of angiogenesis may trigger hypoxia‐driven genetic programs, which in turn can overcome drug inhibitory mechanisms and ultimately favour cancer cell invasion and dissemination. Thus, an emerging concept in molecular medicine is to devise therapeutic strategies that, rather than simply inhibiting angiogenesis, can foster the re‐establishment of a structural and functional normal network, a phenomenon often referred to as “vessel normalization” (Goel et al, 2011) (Fig 1). Of note, and in this context, Sema3A (Maione et al, 2009) and Sema3F (Wong et al, 2012) have been reported to favour the normalization of cancer vasculature and impair metastatic dissemination.

The epidermal growth factor receptor (EGFR) is one of the main tumor drivers and is an important therapeutic target for many cancers. Calcium is important in EGFR signaling pathways. Sorcin is one of the most important calcium sensor proteins, overexpressed in many tumors, that promotes cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, malignant progression and resistance to chemotherapeutic drugs. The present work elucidates a functional mechanism that links calcium homeostasis to EGFR signaling in cancer. Sorcin and EGFR expression are significantly correlated and associated with reduced overall survival in cancer patients. Mechanistically, Sorcin directly binds EGFR protein in a calcium-dependent fashion and regulates calcium (dys)homeostasis linked to EGF-dependent EGFR signaling. Moreover, Sorcin controls EGFR proteostasis and signaling and increases its phosphorylation, leading to increased EGF-dependent migration and invasion. Of note, silencing of Sorcin cooperates with EGFR inhibitors in the regulation of migration, highlighting calcium signaling pathway as an exploitable target to enhance the effectiveness of EGFR-targeting therapies. [ABSTRACT FROM AUTHOR]

Purpose: The velocity time integral (VTI) of the left ventricular outflow tract (LVOT) obtained in the apical view by echocardiography can be regarded as a surrogate for the stroke volume. In critically ill patients it is often difficult to obtain an appropriate apical view to assess the VTI. The subcostal view is more accessible, but while it allows a qualitative assessment of the heart, is not adequate for estimating a reliable LVOT VTI, given the inappropriate angle between the Doppler signal and the flow through the LVOT. We present a new modified subcostal view that allows a proper LVOT VTI measurement. Methods: This is a single-centre experimental, retrospective, and observational study using data from patients in a tertiary-care centre. We included adult patients admitted to the intensive care unit in the period from June 2020 to January 2022, who were evaluated by echocardiography and whose LVOT VTI was measured aligned with the Doppler signal in both the apical five-chamber view and the modified subcostal view. Results: A total of 30 patients were evaluated in the study period by ultrasonography. The Bland–Altman method analysis of the LVOT VTI measured in the apical view compared with that obtained in the subcostal view showed a bias of 0.8 (95% CI 0.39–1.21) with a 95% limit of agreement between − 1.35 (95% CI − 2.06 to − 0.64) and 2.96 (95% CI 2.25–3.67). The percentage error was calculated to be 23%. The Pearson correlation coefficient for the two forms of measurements showed an R value of 0.98 (95% CI 0.96–0.99). Conclusion: The LVOT VTI measured in a modified subcostal view is useful for estimating the value of the LVOT VTI obtained in an apical view. [ABSTRACT FROM AUTHOR]

Background: Serum albumin has been demonstrated as prognostic parameter in non-Hodgkin lymphoma (NHL). Primary central nervous system lymphoma (PCNSL) is a rare extranodal NHL with highly aggressive behavior. In this study, we aimed at creating a novel prognostic model for PCNSL based on serum albumin levels. Methods: We compared several commonly used laboratory nutritional parameters for predicting the survival of PCNSL patients using overall survival (OS) for outcome analysis and receiver operating characteristic curve analysis to determine the optimal cut-off values. Parameters associated with OS were evaluated by univariate and multivariate analyses. Independent prognostic parameters for OS were selected for risk stratification, including albumin ≤ 4.1 g/dL, ECOG PS > 1, and LLR > 166.8, which were associated with shorter OS; albumin > 4.1 g/dL, ECOG PS 0–1 and LLR ≤ 166.8, which were associated with longer OS, and five-fold cross-validation was used for evaluating predictive accuracy of identified prognostic model. Results: By univariate analysis, age, ECOG PS, MSKCC score, Lactate dehydrogenase-to-lymphocyte ratio (LLR), total protein, albumin, hemoglobin, and albumin to globulin ratio (AGR) resulted statistically associated with the OS of PCNSL. By multivariate analysis, albumin ≤ 4.1 g/dL, ECOG PS > 1, and LLR > 166.8 were confirmed to be significant predictors of inferior OS. We explored several PCNSL prognostic models based on albumin, ECOG PS and LLR with 1 point assigned to each parameter. Eventually, a novel and effective PCNSL prognostic model based on albumin and ECOG PS successfully classified patients into three risk groups with 5-year survival rates of 47.5%, 36.9%, and 11.9%, respectively. Conclusions: The novel two-factor prognostic model based on albumin and ECOG PS we propose represents a simple but significant prognostic tool for assessing newly diagnosed patients with PCNSL. [ABSTRACT FROM AUTHOR]

Transmembrane semaphorins are signaling molecules, controlling axonal wiring and embryo development, which are increasingly implicated in human diseases. Semaphorin 6C (Sema6C) is a poorly understood family member and its functional role is still unclear. Upon targeting Sema6C expression in a range of cancer cells, we observed dramatic growth suppression, decreased ERK phosphorylation, upregulation of cell cycle inhibitor proteins p21, p27 and p53, and the onset of cell senescence, associated with activation of autophagy. These data are consistent with a fundamental requirement for Sema6C to support viability and growth in cancer cells. Mechanistically, we unveiled a novel signaling pathway elicited by Sema6C, and dependent on its intracellular domain, mediated by tyrosine kinases c-Abl and Focal Adhesion Kinase (FAK). Sema6C was found in complex with c-Abl, and induced its phosphorylation, which in turn led to FAK activation, independent of cell–matrix adhesion. Sema6C-induced FAK activity was furthermore responsible for increased nuclear localization of YAP transcriptional regulator. Moreover, Sema6C conferred YAP signaling-dependent long-term cancer cell survival upon nutrient deprivation. In conclusion, our findings demonstrate that Sema6C elicits a cancer promoting-signaling pathway sustaining cell viability and self-renewal, independent of growth factors and nutrients availability. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a worldwide public health concern given its significant morbidity and mortality, years of potential life lost, reduced quality of life and elevated healthcare costs. The primary injury occurs at the moment of impact, but secondary injuries might develop as a result of brain hemodynamic abnormalities, hypoxia, and hypotension. The cerebral edema and hemorrhage of the injured tissues causes a decrease in cerebral perfusion pressure (CPP), which leads to higher risk of cerebral ischemia, herniation and death. In this setting, our role as physicians is to minimize damage by the optimization of the CPP and therefore to reduce mortality and improve neurological outcomes. Performing a transcranial doppler ultrasound (TCD) allows to estimate cerebral blood flow velocities and identify states of low flow and high resistance. We propose to include TCD as an initial assessment and further monitoring tool for resuscitation guidance in patients with severe TBI. We present an Ultrasound-Guided Cardio-cerebral Resuscitation (UGCeR) protocol in Patients with Severe TBI. [ABSTRACT FROM AUTHOR]

Transthoracic echocardiography (TTE) is a fundamental tool for hemodynamic monitoring in critical patients. It allows evaluating the left ventricle's stroke volume based on the measurement of the velocity-time integral (VTI) of the left ventricle outflow tract (LVOT). However, in the intensive care unit obtaining adequate echocardiographic views may present a challenge. We propose to measure, as a surrogate of the stroke volume, the carotid flow with a novel technique. This is an observational, prospective, and simple blind study, conducted in the intensive care unit of Sanatorio de los Arcos and Hospital Aleman, in Buenos Aires, Argentina. We measured the carotid systodiastolic flow (CSD) VTI and the carotid systolic flow (CS) VTI at the level of the left supraclavicular fossa and we compared it with the LVOT VTI obtained by TTE. We evaluated 43 subjects. Spearman's correlation coefficient between LVOT VTI and CS VTI was 0.81 (95% CI 0.67–0.89) and between LVOT VTI and CSD VTI was 0.89 (95% CI 0.81–0.94). The Bland–Altman method analysis of the 5-chamber apical window LVOT VTI compared to the CSD VTI showed a bias of − 0.2 (95% CI − 0.82 to 0.43), with a concordance interval between − 4.2 (95% CI − 5.2 to − 3.1) and 3.8 cm (95% CI 2.7 to 4.9). The percentage error was 37.9%. Almost 100% of the values fell within the concordance limits, and no trend was observed in bias across the spectrum of mean variables. Although the CSD VTI could not be interchangeable with the LVOT VTI, it could be considered as its surrogate. [ABSTRACT FROM AUTHOR]

The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole‐exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild‐type, PlxnB2 in CUP stem cells resulted in the impairment of self‐renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C‐PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C‐PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFR‐dependent manner. Synopsis: Genetic changes sustaining the development of Cancers of Unknown Primary (CUP) remain elusive. Here we report a novel activating mutation of the axon guidance gene PLXNB2 that sustains proliferative autonomy and confers invasive properties to CUP stem cells, in EGFR‐dependent manner. The genomic profiling of 14 rigorously selected Cancer of Unknown Primary (CUP) samples revealed a consistent enrichment of changes in axon guidance genes, compared to other human tumor types.G842C mutation in the IPT3 domain of PlexinB2 (PlxnB2) was predicted to be damaging by structural modeling in silico, and showed a putative gain‐of‐function phenotype by triggering ligand‐independent cellular collapse.Knocking down the mutated, but not the wild‐type, PlxnB2 in CUP stem cells resulted in the impairment of self‐renewal and proliferation in culture, as well as tumorigenic capacity in mice.Conversely, the genetic transfer of G842C‐PlxnB2 was sufficient to promote CUP stem cell proliferation, invasiveness, and tumorigenesis in mice.G842C‐PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation. Moreover, CUP cells carrying the mutated receptor were dependent on EGFR signaling, as demonstrated by treatment with inhibitors. [ABSTRACT FROM AUTHOR]

The ultrasonography of carotid arteries plays a key role in evaluating cerebrovascular disease. There are some useful considerations to perform it correctly in the intensive care unit, such as using different kind of transducer, Doppler mode optimization, and the correct interpretation of the findings. [ABSTRACT FROM AUTHOR]

Purpose: Severe Covid-19 pneumonia frequently presents with infective complications as bacterial and fungal infections, nosocomial maxillary sinusitis is one of them. We describe the role of ultrasonography in the diagnosis of nosocomial maxillary sinusitis in patients undergoing mechanical ventilation due to severe Covid-19 pneumonia. Methods: Patients with severe pneumonia due to Covid-19 requiring mechanical ventilation and had maxillary sinus occupation by ultrasonography were retrospectively enrolled at intensive care unit of Sanatorio De los Arcos, Buenos Aires, Argentina, between March 2020 and May 2021. Results: We evaluated a total of 171 patients with severe Covid-19 pneumonia requiring mechanical ventilation during the study period. We included 26 patients that had maxillary sinus occupation by ultrasonography (15.2%). Out of the 26 patients, in 17 the diagnosis was confirmed by surgical drainage of the maxillary sinus with positive cultures with a positive predictive value of 85%. In 34.6% of the cases the maxillary sinus disease was unilateral and in 38.4% bilateral. A sinus computed tomography (CT) was performed in 30.7% of the patients. Most of the patients underwent to surgical drainage without a CT scan (66.7%). Conclusions: Ultrasonography is a useful tool for the detection of maxillary sinus infection in patients with severe Covid-19 pneumonia and avoids to perform a CT scan and, therefore, unnecessary transfers. [ABSTRACT FROM AUTHOR]

Mechanical ventilation in prone position is a strategy that increases oxygenation and reduces mortality in severe ARDS. The hemodynamic and cardiovascular assessment of these patients is essential. Transthoracic echocardiography (TTE) is a widely used tool to assess hemodynamics in critical care, but the prone position is thought to limit adequate TTE views and goal-oriented measurements. The aim of this study is to show the feasibility of the hemodynamic assessment by transthoracic echocardiography during prone position ventilation (PPV). This is a retrospective, observational study, carried out in the intensive care unit (ICU) of a tertiary-care center in Buenos Aires, Argentina. We included all the adult patients admitted to the ICU between March 2020 and August 2021 who had a TTE examination in PPV due to ARDS. During the study period, we evaluated by TTE a total of 35 patients requiring PPV. The vast majority of the patients had COVID-19 pneumonia (91.4%). In 33 out of 35 (94.3%) cases, it was able to achieve an adequate apical four chamber view. We assessed qualitatively the systolic function of left ventricle (LV) and right ventricle (RV) in all of the successfully evaluated patients. We measured the RV basal diameter (94.3%), RV/LV ratio (77.1%), tricuspid annular plane systolic excursion (TAPSE) (91.4%), and septal mitral annular plane systolic excursion (MAPSE) (88.5%) in most of them. Also, we quantified the left ventricle outflow tract velocity time integral (LVOT VTI) in a large part (68.5%) of the examinations. Transthoracic echocardiography is a useful tool for the hemodynamic assessment of patients in prone position under mechanical ventilation. [ABSTRACT FROM AUTHOR]

Recent advances in wavefront shaping have enabled complex classes of Structured Light which carry spin and orbital angular momentum, offering new tools for light-matter interaction, communications, and imaging. Controlling both components of angular momentum along the propagation direction can potentially extend such applications to 3D. However, beams of this kind have previously been realized using bench-top setups, requiring multiple interaction with light of a fixed input polarization, thus impeding their widespread applications. Here, we introduce two classes of metasurfaces that lift these constraints, namely: i) polarization-switchable plates that couple any pair of orthogonal polarizations to two vortices in which the magnitude and/or sense of vorticity vary locally with propagation, and ii) versatile plates that can structure both components of angular momentum, spin and orbital, independently, along the optical path while operating on incident light of any polarization. Compact and integrated devices of this type can advance light-matter interaction and imaging and may enable applications that are not accessible via other wavefront shaping tools. Creating complex forms of structured light typically requires bulky optics and multiple interactions with incident light. Here the authors demonstrate versatile control over light's polarization and orbital angular momentum along the propagation direction with a single metasurface. [ABSTRACT FROM AUTHOR]

Tailored nanostructures provide at-will control over the properties of light, with applications in imaging and spectroscopy. Active photonics can further open new avenues in remote monitoring, virtual or augmented reality and time-resolved sensing. Nanomaterials with χ(2) nonlinearities achieve highest switching speeds. Current demonstrations typically require a trade-off: they either rely on traditional χ(2) materials, which have low non-linearities, or on application-specific quantum well heterostructures that exhibit a high χ(2) in a narrow band. Here, we show that a thin film of organic electro-optic molecules JRD1 in polymethylmethacrylate combines desired merits for active free-space optics: broadband record-high nonlinearity (10-100 times higher than traditional materials at wavelengths 1100-1600 nm), a custom-tailored nonlinear tensor at the nanoscale, and engineered optical and electronic responses. We demonstrate a tuning of optical resonances by Δλ = 11 nm at DC voltages and a modulation of the transmitted intensity up to 40%, at speeds up to 50 MHz. We realize 2 × 2 single- and 1 × 5 multi-color spatial light modulators. We demonstrate their potential for imaging and remote sensing. The compatibility with compact laser diodes, the achieved millimeter size and the low power consumption are further key features for laser ranging or reconfigurable optics. Spatial light modulators (SLM) provide tailored light fields for many applications. Here, the authors present an SLM device based on an organic electro-optic material that manipulates the properties of individual pixels by electronic signals at speeds up to 50 MHz. [ABSTRACT FROM AUTHOR]

Metasurfaces are arrays of subwavelength spaced nanostructures that can manipulate the amplitude, phase, and polarization of light to achieve a variety of optical functions beyond the capabilities of 3D bulk optics. However, they suffer from limited performance and efficiency when multiple functions with large deflection angles are required because the non-local interactions due to optical coupling between nanostructures are not fully considered. Here we introduce a method based on supercell metasurfaces to demonstrate multiple independent optical functions at arbitrary large deflection angles with high efficiency. In one implementation the incident laser is simultaneously diffracted into Gaussian, helical and Bessel beams over a large angular range. We then demonstrate a compact wavelength-tunable external cavity laser with arbitrary beam control capabilities – including beam shaping operations and the generation of freeform holograms. Our approach paves the way to novel methods to engineer the emission of optical sources. The angular dependence is a well-known issue in metasurface engineering. Here the authors introduce a supercell metasurface able to implement multiple independent functions under large deflection angles with high efficiency, leading to a wavelength tunable laser with arbitrary wavefront control. [ABSTRACT FROM AUTHOR]

Polarization plays a key role in science; hence its versatile manipulation is crucial. Existing polarization optics, however, can only manipulate polarization in a single transverse plane. Here we demonstrate a new class of polarizers and wave plates—based on metasurfaces—that can impart an arbitrarily chosen polarization response along the propagation direction, regardless of the incident polarization. The underlying mechanism relies on transforming an incident waveform into an ensemble of pencil-like beams with different polarization states that beat along the optical axis thereby changing the resulting polarization at will, locally, as light propagates. Remarkably, using form-birefringent metasurfaces in combination with matrix-based holography enables the desired propagation-dependent polarization response to be enacted without a priori knowledge of the incident polarization—a behaviour that would require three polarization-sensitive holograms if implemented otherwise. Our work expands the use of polarization in the design of multifunctional metasurfaces and may find application in tunable structured light, optically switchable devices and versatile light–matter interactions. Using a metasurface that allows shaping of the polarization state of a light beam independently at each point of space along its propagation direction, longitudinally variable polarization optical components are demonstrated, inspiring new directions in structured light, polarization-switchable devices and light–matter interaction. [ABSTRACT FROM AUTHOR]

Plexins receive guidance cues from semaphorin ligands and transmit their signal through the plasma membrane. This family of proteins is unique amongst single-pass transmembrane receptors as their intracellular regions interact directly with several small GTPases, which regulate cytoskeletal dynamics and cell adhesion. Here, we characterize the GTPase Activating Protein (GAP) function of Plexin-B1 and find that a cooperative GAP activity towards the substrate GTPase, Rap1b, is associated with the N-terminal Juxtamembrane region of Plexin-B1. Importantly, we unveil an activation mechanism of Plexin-B1 by identifying a novel functional loop which partially blocks Rap1b entry into the plexin GAP domain. Consistent with the concept of allokairy developed for other systems, Plexin-B activity is increased by an apparent substrate-mediated cooperative effect. Simulations and mutagenesis suggest the repositioned JM conformation is stabilized by the new activation switch loop when the active site is occupied, giving rise to faster enzymatic turnover and cooperative behavior. The biological implications, essentially those of a threshold behavior for cell migration, are discussed. [ABSTRACT FROM AUTHOR]

Wave instability—the process that gives rise to turbulence in hydrodynamics1—represents the mechanism by which a small disturbance in a wave grows in amplitude owing to nonlinear interactions. In photonics, wave instabilities result in modulated light waveforms that can become periodic in the presence of coherent locking mechanisms. These periodic optical waveforms are known as optical frequency combs2–4. In ring microresonator combs5,6, an injected monochromatic wave becomes destabilized by the interplay between the resonator dispersion and the Kerr nonlinearity of the constituent crystal. By contrast, in ring lasers instabilities are considered to occur only under extreme pumping conditions7,8. Here we show that, despite this notion, semiconductor ring lasers with ultrafast gain recovery9,10 can enter frequency comb regimes at low pumping levels owing to phase turbulence11—an instability known to occur in hydrodynamics, superconductors and Bose–Einstein condensates. This instability arises from the phase–amplitude coupling of the laser field provided by linewidth enhancement12, which produces the needed interplay of dispersive and nonlinear effects. We formulate the instability condition in the framework of the Ginzburg–Landau formalism11. The localized structures that we observe share several properties with dissipative Kerr solitons, providing a first step towards connecting semiconductor ring lasers and microresonator frequency combs13. Wave destabilization is demonstrated in semiconductor ring lasers operating at low pumping levels, where ultrafast gain recovery leads to the emergence of a frequency comb regime owing to phase turbulence. [ABSTRACT FROM AUTHOR]

Engineers have shaped the environment across the centuries in order to improve the quality and safety of human life. The unrestrained invasion of nature led to significant environmental problems, for this reason nowadays engineering projects should be based on ecological concepts to protect our environment. This paper presents an integrated methodology that involves GIS tools, hydraulic numerical models, and landscape metrics to investigate ecological consequences caused by river restoration activities. The combined use of these different tools represents a bridge to connect the field of engineering with ecological techniques. The proposed method was tested to predict and assess the influence of a river restoration plan on a reach of the Orco river located in the northwest of Italy. Morphological alterations were simulated to reconnect remnant meanders and provide water to the floodplain, enhancing the ecological value of riparian ecosystems. The application of the hydraulic model permitted to evaluate the distribution of water inside the study area before and after the restoration plan. Thereafter, spatial configuration and temporal dynamics of the landscape structures were quantified using landscape metrics. The increase of patch density (PD) by 9% and edge density (ED) up to 10% highlights that restoration activities lead to a new configuration characterized by a higher level of fragmentation and heterogeneity. The characteristics of versatility, repeatability, and the possibility to predict the outcomes of a specific plan make the proposed method a useful tool that could help decision-makers to manage the territory while safeguarding natural ecosystems. [ABSTRACT FROM AUTHOR]

Recent studies have shown that long non-coding RNAs (lncRNAs) have key functions during breast cancer development. Considering the complexity of IncRNAs regulatory network, the identification of novel and functional lncRNAs associated with breast cancer is thus very important. By using Agilent LncRNA Human Gene Expression Microarray, we identified a number of lncRNAs that were differentially expressed in breast cancer compared to their corresponding adjacent tissues. According to the microarray, the expression of p10247, henceforth named as lncRNA-BCHE (standing for lncRNA high expressed in breast cancer), was found to be uniformly higher in all the five breast cancer tissues tested, and this was further confirmed in 56 breast cancer tissues by real-time RT-PCR. The function of lncRNA-BCHE in breast cancer cells was tested by knockdown and over-expression experiments in vitro. We also analyzed the public cohorts of breast cancer patients on the Kaplan Meier plotter platform. Clinical analysis revealed that the expression of lncRNA-BCHE was significantly correlated with advanced clinical stage and lymph node metastasis. Our data indicate that lncRNA-BCHE regulates the growth, migration and invasion of breast cancer cells. In addition, we found that these functions are mediated, at least in part, by the regulation of integrin subunit beta 1 (ITGB1) levels. The expression of ITGB1 serves as a negative prognostic factor and metastasis risk predictor in breast cancer, irrespective of subtype and therapeutic regimen. In summary, our results suggest that lncRNA-BCHE is an oncogenic lncRNA enhancing the growth and metastatic potential of breast cancer cells, and a potential predictor of breast cancer metastatic progression. [ABSTRACT FROM AUTHOR]

Semaphorins are signaling molecules playing pivotal roles not only as axon guidance cues, but are also involved in the regulation of a range of biological processes, such as immune response, angiogenesis and invasive tumor growth. The main functional receptors for semaphorins are plexins, which are large single-pass transmembrane molecules. Semaphorin signaling through plexins-the 'classical' forward signaling-affects cytoskeletal remodeling and integrin-dependent adhesion, consequently influencing cell migration. Intriguingly, semaphorins and plexins can interact not only in trans, but also in cis, leading to differentiated and highly regulated signaling outputs. Moreover, transmembrane semaphorins can also mediate a so-called 'reverse' signaling, by acting not as ligands but rather as receptors, and initiate a signaling cascade through their own cytoplasmic domains. Semaphorin reverse signaling has been clearly demonstrated in fruit fly Sema1a, which is required to control motor axon defasciculation and target recognition during neuromuscular development. Sema1a invertebrate semaphorin is most similar to vertebrate class-6 semaphorins, and examples of semaphorin reverse signaling in mammalians have been described for these family members. Reverse signaling is also reported for other vertebrate semaphorin subsets, e.g. class-4 semaphorins, which bear potential PDZ-domain interaction motifs in their cytoplasmic regions. Therefore, thanks to their various signaling abilities, transmembrane semaphorins can play multifaceted roles both in developmental processes and in physiological as well as pathological conditions in the adult. [ABSTRACT FROM AUTHOR]

Semaphorins are extracellular signals known to guide migrating cells during developmental morphogenesis and in adult tissues. Semaphorin receptors, that is plexins and neuropilins, have been found in association with diverse receptor tyrosine kinases (RTKs), such as Met, ErbB2 and VEGFR2. These receptor complexes are formed in a cell-specific manner and can mediate distinctive signalling cascades, sometimes leading to divergent functional outcomes. This is particularly intriguing in cancer, since the same semaphorin has been found to mediate either tumor-promoting or tumor-suppressing functions, depending on the cancer type and cellular context. We will therefore review the current understanding about the role of RTKs in neuropilin and plexin signalling, putatively accounting for the multifaceted role of semaphorins in cancer. [ABSTRACT FROM AUTHOR]

The potential of graphene for photonic applications was evidenced by recent demonstrations of modulators, polarization rotators and isolators. These promising yet preliminary results raise crucial questions: what is the optimal performance achievable by more complex designs and how can this optimum be achieved in practice? We answer by first demonstrating that the relevant figures of merit for the devices above are subject to absolute theoretical upper bounds. Strikingly, these limits are related only to the conductivity tensor of graphene; thus, we can provide essential roadmap information such as the best possible device performance versus wavelength and graphene quality. Second, based on the theory developed, physical insight and detailed simulations, we demonstrate how structures closely approaching these fundamental limits can be designed, demonstrating the possibility of significant improvement. These results are believed to be of paramount importance for the design of modulators, rotators and isolators using graphene or other two-dimensional materials. [ABSTRACT FROM AUTHOR]

Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading. See accompanying article [ABSTRACT FROM AUTHOR]

The semaphorins constitute a large family of molecular signals with regulatory functions in neuronal development, angiogenesis, cancer progression and immune responses. Accumulating data indicate that semaphorins might trigger multiple signalling pathways, and mediate different and sometimes opposing effects, depending on the cellular context and the particular plexin-associated subunits of the receptor complex, which can include receptor-type or cytoplasmic tyrosine kinases such as MET, ERBB2, VEGFR2, FYN, FES, PYK2 and SRC. It has also been shown that a specific plexin can alternatively associate with different tyrosine kinase receptors, eliciting divergent signalling pathways and functional outcomes. Tyrosine phosphorylation is a pivotal post-translational protein modification that regulates intracellular signalling. Therefore, phosphorylation of tyrosines in the intracellular domain of plexins could determine or modify their interactions with additional signal transducers. Here, we discuss the potential relevance of tyrosine phosphorylation in semaphorin-induced signalling, with an emphasis on its probable role in dictating the choice between multiple pathways and functional outcomes. The identification of implicated tyrosine kinases will pave the way to target individual semaphorin-mediated functions. [ABSTRACT FROM AUTHOR]

The original version of this paper was unfortunately published with an error. The online visualization of the paper is correct; instead, the printed version (page 5) reports strange lines into the vectors of Eq. (2), and the G is divided from its expression (see Fig. 1). [ABSTRACT FROM AUTHOR]

Semaphorins are a large family of molecular cues implicated in neural development and in a variety of functions outside the nervous system. Semaphorin 5A (Sema5A) is a transmembrane semaphorin, containing seven thrombospondin type-1 repeats, which was recently found to control axon guidance. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). In addition, Sema5A can trigger the intracellular signalling of the hepatocyte growth factor/scatter factor receptor, Met, associated in a complex with plexin-B3. We thus conclude that Sema5A is able to elicit multiple functional responses through its receptor plexin-B3. [ABSTRACT FROM AUTHOR]

Semaphorins were discovered 11 years ago as molecular cues for axon guidance that are conserved from invertebrates to humans. More than 20 semaphorin genes have been identified in mammals and their protein products are now known to be involved in a range of processes from the guidance of cell migration to the regulation of the immune response, angiogenesis and cancer. Plexins, either alone or in association with neuropilins, constitute high-affinity semaphorin receptors. However, other transmembrane molecules have been implicated in semaphorin receptor complexes, and interactions between plexins and a range of intracellular effectors have been reported. These data indicate that semaphorins might be able to elicit responses through more than one signalling pathway. Interestingly, according to recent findings, the semaphorin-dependent control of cell migration crucially involves integrin-based adhesive structures through which polarized cell-membrane protrusion is coupled to cytoskeletal dynamics. This review focuses on the mechanisms whereby semaphorins are thought to regulate cell migration. [ABSTRACT FROM AUTHOR]

The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function. [ABSTRACT FROM AUTHOR]

Semaphorins are cell surface and soluble signals that control axonal guidance. Recently, semaphorin receptors (plexins) have been discovered and shown to be widely expressed. Their biological activities outside the nervous system and the signal transduction mechanism(s) they utilize are largely unknown. Here, we show that in epithelial cells, Semaphorin 4D (Sema 4D) triggers invasive growth, a complex programme that includes cell?cell dissociation, anchorage-independent growth and branching morphogenesis. Interestingly, the same response is also controlled by scatter factors through their tyrosine kinase receptors, which share striking structural homology with plexins in their extracellular domain . We found that in cells expressing the endogenous proteins, Plexin B1 (the Sema 4D Receptor) and Met (the Scatter Factor 1/ Hepatocyte Growth Factor Receptor) associate in a complex. In addition, binding of Sema 4D to Plexin B1 stimulates the tyrosine kinase activity of Met, resulting in tyrosine phosphorylation of both receptors. Finally, cells lacking Met expression do not respond to Sema 4D unless exogenous Met is expressed. This work identifies a novel biological function of semaphorins and suggests the involvement of an unexpected signalling mechanism, namely, the coupling of a plexin to a tyrosine kinase receptor. [ABSTRACT FROM AUTHOR]

Secreted class 3 semaphorins (Sema3), which signal through plexin receptors and mostly use neuropilins (Nrps) as co-receptors, were initially identified for their ability to steer navigating axons in the developing embryo. They were later found to control angiogenesis in physiological and pathological settings as well (Serini et al, ). Indeed, the development of a novel and aberrant vasculature is central to the pathogenesis of several human diseases, including cancer and vascular retinopathies (Goel et al, ). A large body of evidence demonstrates that in cancer, a massive regression of angiogenesis may trigger hypoxia-driven genetic programs, which in turn can overcome drug inhibitory mechanisms and ultimately favour cancer cell invasion and dissemination. Thus, an emerging concept in molecular medicine is to devise therapeutic strategies that, rather than simply inhibiting angiogenesis, can foster the re-establishment of a structural and functional normal network, a phenomenon often referred to as 'vessel normalization' (Goel et al, ) (Fig [Sema3 prot]). Of note, and in this context, Sema3A (Maione et al, ) and Sema3F (Wong et al, ) have been reported to favour the normalization of cancer vasculature and impair metastatic dissemination. [ABSTRACT FROM AUTHOR]

Mutations in the genes encoding for Met, Ret and Kit receptor tyrosine kinases invariably result in increased kinase activity and in the acquisition of transforming potential. However, the requirement of receptor ligands for the transformation process is still unclear. We have investigated the role of hepatocyte growth factor (HGF), the high-affinity ligand for Met, in mutant Met-mediated cell transformation. We provide evidence that the transforming potential displayed by mutant forms of Met found in human cancer is not only sensitive but entirely dependent on the presence of HGF, by showing that mutant Met transforms NIH3T3 fibroblasts, which produce endogenous HGF, but is not able to transform epithelial cells, unless exogenous HGF is supplied. Accordingly, mutant Met-induced transformation of NIH3T3 cells can be inhibited by HGF antagonists and increased by HGF stimulation. We also show that an engineered Met receptor which contains an oncogenic mutation but is impaired in its ability to bind HGF completely loses its transforming activity, which can be rescued by causing receptor dimerization using a monoclonal antibody. These results indicate that point mutations resulting in Met kinase activation are necessary but not sufficient to cause cell transformation, the latter being dependent on ligand-induced receptor dimerization. They also suggest that mutant Met-driven tumour growth depends on the availability and tissue distribution of active HGF, and provide proof-of-concept for the treatment of mutant-Met related pathologies by HGF-antagonizing drugs. [ABSTRACT FROM AUTHOR]

Presents research which showed that the third phase of the response of epithelial cells to hepatocyte growth factor (HGF) is dependent on the STAT pathway. Role of HGF; HGF receptor tyrosine kinase; First two phases; Electroporation of a tyrosine-phosphorylated peptide; Activation of signal transduction required for morphogenesis.

When vesicular-arbuscular mycorrhizal (VAM) fungi colonize the cortical cells of their host plant roots, the hyphae are separated from the host cytoplasm by the invaginated host plasmalemma and interfacial material. The presence of hydroxyproline rich glycoproteins (HRGPs) at the interface was investigated with a polyclonal antibody obtained against melon callus HRGP. By using a combination of cytochemical methods, antigens were detected in pea, in both the presence and absence of Glomus versiforme, a mycorrhizal fungus. For comparison, observations were performed in parallel with leek as a monocot host. Antigens were localized over the pea cell wall in root tissues. At the ultrastructural level, gold granules were mostly present in the periplasmic space. In mycorrhizal plants, the most substantial deposition occurred at the interface between the fungal wall and the host membrane. Dot blot experiments revealed HRGP antigens in soluble root fractions from both uninfected and mycorrhizal samples. The results demonstrate that HRGP antigens can be localized over the cell wall of both dicot and monocot hosts, although they mostly occur in the contact zone in infected samples. Their presence-in the company of localized glucans and pectins-means that the contact zone can be regarded as an apoplastic space presenting a structural response to the symbiotic mycorrhizal status. [ABSTRACT FROM AUTHOR]

Direct visualization of nanometer-scale properties of moiré superlattices in van der Waals heterostructure devices is a critically needed diagnostic tool for study of the electronic and optical phenomena induced by the periodic variation of atomic structure in these complex systems. Conventional imaging methods are destructive and insensitive to the buried device geometries, preventing practical inspection. Here we report a versatile scanning probe microscopy employing infrared light for imaging moiré superlattices of twisted bilayers graphene encapsulated by hexagonal boron nitride. We map the pattern using the scattering dynamics of phonon polaritons launched in hexagonal boron nitride capping layers via its interaction with the buried moiré superlattices. We explore the origin of the double-line features imaged and show the mechanism of the underlying effective phase change of the phonon polariton reflectance at domain walls. The nano-imaging tool developed provides a non-destructive analytical approach to elucidate the complex physics of moiré engineered heterostructures. Direct visualization of moiré superlattices in van der Waals heterostructures is a needed diagnostic tool for the study of periodicity-induced electronic and optical phenomena. Here, the authors demonstrate that the moiré pattern in twisted bilayer graphene can be indirectly imaged by imaging the phonon polariton interference on the top hexagonal boron nitride encapsulation layer. [ABSTRACT FROM AUTHOR]

Semaphorins regulate a variety of biological processes, including axon guidance, neuronal migration, angiogenesis, cardiogenesis and immune responses. Semaphorin 6D is now shown to regulate osteoclast function during bone development, through its association with its receptor plexinA1. This activity implicates a signalling pathway known to transcriptionally regulate cell differentiation and involves the receptor Trem2 and the adaptor DAP12. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that semaphorins-known to provide directional cues during axon guidance-also provide regulatory signals for cell migration during tissue morphogenesis. During heart development, it is crucial that semaphorins can signal bidirectionally, functioning as both a ligand and a receptor. Through these distinct signalling pathways, semaphorins can provide both 'stop' and 'go' signals for cell motility and invasive growth. [ABSTRACT FROM AUTHOR]

Polaritons formed by the coupling of light and material excitations enable light-matter interactions at the nanoscale beyond what is currently possible with conventional optics. However, novel techniques are required to control the propagation of polaritons at the nanoscale and to implement the first practical devices. Here we report the experimental realization of polariton refractive and meta-optics in the mid-infrared by exploiting the properties of low-loss phonon polaritons in isotopically pure hexagonal boron nitride interacting with the surrounding dielectric environment comprising the low-loss phase change material Ge3Sb2Te6. We demonstrate rewritable waveguides, refractive optical elements such as lenses, prisms, and metalenses, which allow for polariton wavefront engineering and sub-wavelength focusing. This method will enable the realization of programmable miniaturized integrated optoelectronic devices and on-demand biosensors based on high quality phonon resonators. Here, the authors experimentally demonstrate a platform for tunable polariton refractive and meta-optics based on hexagonal boron nitride and phase change Ge3Sb2Te6. This combination has the advantage of the long-lived phonon-polariton with switchable refractive index of the phase change material. [ABSTRACT FROM AUTHOR]