INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.

Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives.

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels-Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure-activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.

Are different countries equally green with envy? A comparison of the everyday concept of envy in the United States, Spain, and Germany.

Using a prototype approach to emotion concepts, we mapped the internal structure and content of the everyday concept of envy (as used in the United States) and its translation equivalents of envidia in Spanish and Neid in German. In Study 1 (total N = 415), the features of the concept of envy, envidia, and Neid were generated via an open-ended questionnaire. In Study 2 (total N = 404), participants rated the degree of typicality of the constitutive features on a forced-choice questionnaire. The prototype analysis of envy, supplemented with network analyses, revealed that the largest connected set of features of envy, envidia, and Neid shared a group of central features, including features related to success or to people with a better appearance. Still, envy, envidia, and Neid did differ with respect to their constituent peripheral features as well as the density of their networks, their structure, and the betweenness centrality of the nodes. These results suggest that a prototype approach combined with network analysis is a convenient approach for studying the internal structure of everyday emotion concepts and the degree of overlap with respect to the translation equivalents in different countries.

Updates from Optics Letters: editorial.

Optics Letters' Editor-in-Chief Miguel Alonso provides a journal update and discusses journal criteria.

Analysis of the Safety of Drug Allergy Workups in a Spanish University Hospital: Drug Characteristics, Type of Reaction, and Patients' Age at the Initial Assessment.

INTRODUCTION: The drug provocation test (DPT) is the gold standard for the drug allergy workup; however, it is not free from severe adverse reactions. Our aim was to obtain robust data that predict a reaction during or after the DPT at the first contact with the patient in the allergy outpatient clinic. METHODS: The population of this cross-sectional study comprised all patients undergoing a drug allergy workup (clinical assessment, specific IgE, or skin tests, or DPT) at University Hospital Fundacion Alcorcon in 2016. DPTs were performed until therapeutic doses were reached, and late reactions were checked. The clinical disorders assessed in our study were classified mainly as absence of allergic reactions, morbilliform rash, urticaria, anaphylaxis, and other cutaneous disorders. RESULTS: Physicians from the Allergy Unit programmed drug allergy workups in 977 patients (median age, 52 years; women, 64.54%). DPTs were not performed for 165 drugs involved in the reactions. Patients who did not undergo DPT were older than patients who did (positive or negative) (p = 0.0001). Positive DPT results were detected in 6.00% of DPTs performed, and most were for amoxicillin and metamizole (15-25% each). Multinomial logistic regression showed that positive reactions were more probable after DPT if the same clinical disorder was diagnosed at the first visit, including the episodes not considered allergic episodes (OR = 0.2, <0.01), except for anaphylaxis, which favored not performing DPTs (OR = 11, p < 0.001). CONCLUSION: We conclude that clinical practice in the diagnosis of drug allergy in our Allergy Department is safe, without over-diagnosis.

Drug Allergy Alert System in a Spanish University Hospital: Description and Dynamics of Use.

INTRODUCTION: The drug allergy alert system reduces the frequency of adverse drug events, although it is subjected to collateral effects, since 80-90% of alerts are not real, and a large percentage of alerts are overridden (46.2-96.2%). We reviewed how the alert system is used at University Hospital Fundación Alcorcon (HUFA). METHODS: Data were obtained from the drug allergy alert and the alert overriding notification forms (both in the period 2011-20). We also recorded drug allergy diagnoses at HUFA, drug consumption in primary care in 2016. We calculated the incidence of drug allergy alert activation, temporal trends in use, and correlations between the number of drugs in several datasets. RESULTS: We collected 15,535 alerts. NSAIDs and penicillins were the drugs with the highest number of drug allergy alerts (36.55% and 26.91%, respectively). A correlation was found between the number of drug alerts and the type of drug allergy in HUFA in 2016. Only 6.83% of the alerts were removed, and, of these, 21.77% were reactivated. Approximately 100 overrides were recorded per year from 2016 (6.8% of 8,434 activated alerts during 2014-2020). CONCLUSIONS: The number of drug allergy alerts recorded via the drug allergy alert system of HUFA correlates with the distribution of drug allergy diagnoses in the hospital, although many of the alerts could be false positives (as per current published evidence). We detected a very low frequency of removed alerts (6.83%), a relevant frequency of reactivations (one quarter), and a very low frequency of overrides (6.8%).

"Frequency of fatal and recurrent anaphylaxis due to COW'S milk: A systematic review and meta-analysis of observational studies".

Cow's milk allergy can result in anaphylactic reactions. The estimated prevalence of cow's milk allergy in developed countries ranges from 0.5% to 3% at age 1 year. Our objective was to perform a systematic review and, if possible, a meta-analysis to assess the frequency of fatal and recurrent anaphylaxis induced by cow's milk. We searched PubMed/MEDLINE, EMBASE, and the Web of Science for studies that had assessed fatal and recurrent anaphylaxis induced by cow's milk for the population of a country or at least an administrative region. Our review included cohort, cross-sectional, and registry studies that had assessed the incidence or prevalence of recurrent anaphylaxis or the incidence of fatal anaphylaxis due to cow's milk. The pooled prevalence of recurrence (PR) for at least an episode of anaphylaxis was 26.98% (3.85-189.1). Teymourpour et al (Iran) reported the highest PR (53.10%); the two studies with the lowest PR were from France (5.2 and 0.42, respectively) (p < .01). Nine studies on fatal anaphylaxis were selected (41 deaths) and found to be highly heterogeneous (I2 = 75.9%). Levy et al and Bassagio et al reported the highest incidence rate (IR 0.15 and 0.6 deaths per million persons-year). The PR of anaphylaxis was approximately one quarter of patients with anaphylaxis due to cow's milk, while deaths from anaphylaxis caused by cow's milk were very rare, although some studies report rates as high as 15 times the lowest IR.

An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

Coherence in the radial degree of freedom.

Coherence quantifies the statistical fluctuations in an optical field and has been extensively studied in the space, time, and polarization degrees of freedom. In the context of space, coherence theory has been formulated between two transverse positions as well as between two azimuthal positions, referred to as transverse spatial coherence and angular coherence, respectively. In this paper, we formulate the theory of coherence for optical fields in the radial degree of freedom and discuss the associated concepts of coherence radial width, radial quasi-homogeneity, and radial stationarity with some physically realizable examples of radially partially coherent fields. Furthermore, we propose an interferometric scheme for measuring radial coherence.

MALL, a membrane-tetra-spanning proteolipid overexpressed in cancer, is present in membraneless nuclear biomolecular condensates.

Proteolipids are proteins with unusual lipid-like properties. It has long been established that PLP and plasmolipin, which are two unrelated membrane-tetra-spanning myelin proteolipids, can be converted in vitro into a water-soluble form with a distinct conformation, raising the question of whether these, or other similar proteolipids, can adopt two different conformations in the cell to adapt their structure to distinct environments. Here, we show that MALL, another proteolipid with a membrane-tetra-spanning structure, distributes in membranes outside the nucleus and, within the nucleus, in membrane-less, liquid-like PML body biomolecular condensates. Detection of MALL in one or other environment was strictly dependent on the method of cell fixation used, suggesting that MALL adopts different conformations depending on its physical environment -lipidic or aqueous- in the cell. The acquisition of the condensate-compatible conformation requires PML expression. Excess MALL perturbed the distribution of the inner nuclear membrane proteins emerin and LAP2ß, and that of the DNA-binding protein BAF, leading to the formation of aberrant nuclei. This effect, which is consistent with studies identifying overexpressed MALL as an unfavorable prognostic factor in cancer, could contribute to cell malignancy. Our study establishes a link between proteolipids, membranes and biomolecular condensates, with potential biomedical implications.

Plasmolipin regulates basolateral-to-apical transcytosis of ICAM-1 and leukocyte adhesion in polarized hepatic epithelial cells.

Apical localization of Intercellular Adhesion Receptor (ICAM)-1 regulates the adhesion and guidance of leukocytes across polarized epithelial barriers. Here, we investigate the molecular mechanisms that determine ICAM-1 localization into apical membrane domains of polarized hepatic epithelial cells, and their effect on lymphocyte-hepatic epithelial cell interaction. We had previously shown that segregation of ICAM-1 into apical membrane domains, which form bile canaliculi and bile ducts in hepatic epithelial cells, requires basolateral-to-apical transcytosis. Searching for protein machinery potentially involved in ICAM-1 polarization we found that the SNARE-associated protein plasmolipin (PLLP) is expressed in the subapical compartment of hepatic epithelial cells in vitro and in vivo. BioID analysis of ICAM-1 revealed proximal interaction between this adhesion receptor and PLLP. ICAM-1 colocalized and interacted with PLLP during the transcytosis of the receptor. PLLP gene editing and silencing increased the basolateral localization and reduced the apical confinement of ICAM-1 without affecting apicobasal polarity of hepatic epithelial cells, indicating that ICAM-1 transcytosis is specifically impaired in the absence of PLLP. Importantly, PLLP depletion was sufficient to increase T-cell adhesion to hepatic epithelial cells. Such an increase depended on the epithelial cell polarity and ICAM-1 expression, showing that the epithelial transcytotic machinery regulates the adhesion of lymphocytes to polarized epithelial cells. Our findings strongly suggest that the polarized intracellular transport of adhesion receptors constitutes a new regulatory layer of the epithelial inflammatory response.

Structure and function of the N-terminal extension of the formin INF2.

In INF2-a formin linked to inherited renal and neurological disease in humans-the DID is preceded by a short N-terminal extension of unknown structure and function. INF2 activation is achieved by Ca2+-dependent association of calmodulin (CaM). Here, we show that the N-terminal extension of INF2 is organized into two α-helices, the first of which is necessary to maintain the perinuclear F-actin ring and normal cytosolic F-actin content. Biochemical assays indicated that this helix interacts directly with CaM and contains the sole CaM-binding site (CaMBS) detected in INF2. The residues W11, L14 and L18 of INF2, arranged as a 1-4-8 motif, were identified as the most important residues for the binding, W11 being the most critical of the three. This motif is conserved in vertebrate INF2 and in the human population. NMR and biochemical analyses revealed that CaM interacts directly through its C-terminal lobe with the INF2 CaMBS. Unlike control cells, INF2 KO cells lacked the perinuclear F-actin ring, had little cytosolic F-actin content, did not respond to increased Ca2+ concentrations by making more F-actin, and maintained the transcriptional cofactor MRTF predominantly in the cytoplasm. Whereas expression of intact INF2 restored all these defects, INF2 with inactivated CaMBS did not. Our study reveals the structure of the N-terminal extension, its interaction with Ca2+/CaM, and its function in INF2 activation.

Transcriptomics of Canine Inflammatory Mammary Cancer Treated with Empty Cowpea Mosaic Virus Implicates Neutrophils in Anti-Tumor Immunity.

Canine inflammatory mammary cancer (IMC) is a highly aggressive and lethal cancer in dogs serving as a valuable animal model for its human counterpart, inflammatory breast cancer (IBC), both lacking effective therapies. Intratumoral immunotherapy (IT-IT) with empty cowpea mosaic virus (eCPMV) nanoparticles has shown promising results, demonstrating a reduction in tumor size, longer survival rates, and improved quality of life. This study compares the transcriptomic profiles of tumor samples from female dogs with IMC receiving eCPMV IT-IT and medical therapy (MT) versus MT alone. Transcriptomic analyses, gene expression profiles, signaling pathways, and cell type profiling of immune cell populations in samples from four eCPMV-treated dogs with IMC and four dogs with IMC treated with MT were evaluated using NanoString Technologies using a canine immune-oncology panel. Comparative analyses revealed 34 differentially expressed genes between treated and untreated samples. Five genes (CXCL8, S100A9, CCL20, IL6, and PTGS2) involved in neutrophil recruitment and activation were upregulated in the treated samples, linked to the IL17-signaling pathway. Cell type profiling showed a significant increase in neutrophil populations in the tumor microenvironment after eCPMV treatment. These findings highlight the role of neutrophils in the anti-tumor response mediated by eCPMV IT-IT and suggest eCPMV as a novel therapeutic approach for IBC/IMC.

Divergent effects of oxytocin on "mind-reading" in healthy males.

The neuropeptide oxytocin (OT) has been associated with a broad range of human behaviors, particularly in the domain of social cognition, and is being discussed to play a role in a range of psychiatric disorders. Studies using the Reading The Mind In The Eyes Test (RMET) to investigate the role of OT in mental state recognition reported inconsistent outcomes. The present study applied a randomized, double-blind, cross-over design, and included measures of serum OT. Twenty healthy males received intranasal placebo or OT (24 IU) before performing the RMET. Frequentist and Bayesian analyses showed that contrary to previous studies (Domes et al., 2007; Radke & de Bruijn, 2015), individuals performed worse in the OT condition compared to the placebo condition (p = 0.023, Cohen's d = 0.55, 95% confidence interval [CI] [0.08, 1.02], BF10 = 6.93). OT effects did not depend on item characteristics (difficulty, valence, intensity, sex) of the RMET. Furthermore, OT serum levels did not change after intranasal OT administration. Given that similar study designs lead to heterogeneous outcomes, our results highlight the complexity of OT effects and support evidence that OT might even interfere with social cognitive abilities. However, the Bayesian analysis approach shows that there is only moderate evidence that OT influences mind-reading, highlighting the need for larger-scale studies considering the discussed aspects that might have led to divergent study results.

Observation of Polarization Singularities and Topological Textures in Sound Waves.

Polarization singularities and topological polarization structures are generic features of inhomogeneous vector wave fields of any nature. However, their experimental studies mostly remain restricted to optical waves. Here, we report the observation of polarization singularities, topological Möbius-strip structures, and skyrmionic textures in 3D polarization fields of inhomogeneous sound waves. Our experiments are made in the ultrasonic domain using nonparaxial propagating fields generated by space-variant 2D acoustic sources. We also retrieve distributions of the 3D spin density in these fields. Our results open the avenue to investigations and applications of topological features and nontrivial 3D vector properties of structured sound waves.

Impact of Penicillin Allergy Label on Length of Stay and Mortality in Hospitalized Patients through a Clinical Administrative National Dataset.

BACKGROUND: Penicillin allergy is a common problem in the management of infectious diseases. The aim of this study was to determine the impact of penicillin allergy on length of hospital stay (LOHS) among hospitalized adult patients and on in-hospital mortality at a national level. METHODS: A retrospective cohort study of adult patients discharged from the Spanish Hospital System between 2006 and 2015 was conducted using the Minimum Basic Data Set (MBDS). We compared LOHS and in-hospital mortality of adult patients whose records contained penicillin allergy code V14.0 (International Classification of Diseases, Ninth Revision, Clinical Modification) as a secondary diagnosis, with a random sample without such a code. RESULTS: We identified 981,291 admissions with code V14.0, which corresponded to 2.63% of all hospitalizations. Adults patients with a penicillin allergy label were significantly older than patients without such a label, with a median of 70 years (interquartile range [IQR]: 51-80) versus 63 years (IQR: 40-77). The proportion of women and the prevalence of infectious diseases were higher in the group with a penicillin allergy label (61.40% vs. 53.84%; 34.04% vs. 30.01%; respectively). We found a higher median Elixhauser-Van Walraven score in hospitalized patients with an allergy label. The median LOHS for hospitalizations with a penicillin allergy label (5 [IQR: 2-9]) was significantly longer than that in those without such a label (4 [IQR: 2-9]). Multivariate analysis showed an increase in LOHS due to the penicillin allergy label (odds ratio [OR] [95% confidence interval [CI]: 1.061 [1.057-1.065]) and a decrease in mortality in penicillin allergy records (OR [95% CI]: 0.834 [0.825-0.844]). CONCLUSION: In our study, the prevalence of a penicillin allergy label in hospitalized patients, using the MBDS, is low. Hospitalizations with an allergy label was associated with a longer LOHS. However, penicillin-allergic patients did not show higher mortality rates. Inaccurate reporting of penicillin allergies may have an impact on healthcare resources.

Multi-dimensional and spatiotemporal correlative imaging at the plasma membrane of live cells to determine the continuum nano-to-micro scale lipid adaptation and collective motion.

The primary cilium is a specialized plasma membrane protrusion with important receptors for signalling pathways. In polarized epithelial cells, the primary cilium assembles after the midbody remnant (MBR) encounters the centrosome at the apical surface. The membrane surrounding the MBR, namely remnant-associated membrane patch (RAMP), once situated next to the centrosome, releases some of its lipid components to form a centrosome-associated membrane patch (CAMP) from which the ciliary membrane stems. The RAMP undergoes a spatiotemporal membrane refinement during the formation of the CAMP, which becomes highly enriched in condensed membranes with low lateral mobility. To better understand this process, we have developed a correlative imaging approach that yields quantitative information about the lipid lateral packing, its mobility and collective assembly at the plasma membrane at different spatial scales over time. Our work paves the way towards a quantitative understanding of the spatiotemporal lipid collective assembly at the plasma membrane as a functional determinant in cell biology and its direct correlation with the membrane physicochemical state. These findings allowed us to gain a deeper insight into the mechanisms behind the biogenesis of the ciliary membrane of polarized epithelial cells.

100 years of Emil Wolf: introduction.

The groundbreaking research and ideas introduced by Emil Wolf continue to inspire researchers and motivate ongoing research in the wave properties of light. This special issue commemorates the legacy of Emil Wolf with research in physical optics, with specific focus on those areas where Wolf was active, such as optical coherence theory, inverse problems, singular optics, imaging, and polarization, and the intersection of these fields of study. Here we discuss the life of Emil Wolf and his influence on optical science and the optics community.

Using fluorescent beads to emulate single fluorophores.

We study the conditions under which fluorescent beads can be used to emulate single fluorescent molecules in the calibration of optical microscopes. Although beads are widely used due to their brightness and easy manipulation, there can be notable differences between the point spread functions (PSFs) they produce and those for single-molecule fluorophores, caused by their different emission patterns and sizes. We study theoretically these differences for various scenarios, e.g., with or without polarization channel splitting, to determine the conditions under which the use of beads as a model for single molecules is valid. We also propose methods to model the blurring due to the size difference and compensate for it to produce PSFs that are more similar to those for single molecules.

Epitheliosis is a histopathological finding associated with malignancy and poor prognosis in dogs with mammary tumors.

Canine mammary epitheliosis (ME) is a poorly studied dysplasia that may have premalignant potential. In this study, the clinicopathological relevance of ME was prospectively studied in 90 female dogs with mammary tumors (MTs) that underwent radical mastectomy. ME distribution, extent, and coexistence with benign and malignant MTs were evaluated for each case (505 mammary glands). ME was macroscopically undetectable and was present in 47/90 (52%) cases, frequently bilateral. In dogs with malignant MTs and ME, diffuse ME throughout the mammary chain was present in 10/39 (26%) cases. A histological ME-carcinoma transition was evident in certain histotypes. By immunohistochemistry (AE1/AE3, cytokeratin 14 [CK-14], CK-8/18, vimentin, calponin, p63, Ki-67, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2), ME was a slow-growing, triple-negative process with a strong predominance of basal-like nonmyoepithelial cells. ME was associated with older dogs (P = .016), malignant tumors (P = .044), worse clinical stages (P = .013), lymph node metastasis (LNM, P = .021), higher histological grade tumors (P = .035), and shorter overall survival (OS) in univariate analysis (P = .012). Interestingly, ME was distantly located to the malignant tumor in most cases (P = .007). In multivariate analyses, LNM (P = .005), histological grade (P = .006), and tumor size (P = .006) were independent predictors of OS. For the pathologist, the observation of ME should be clearly stated in the MT biopsy report to alert the surgeon/oncologist. Given the differences between canine ME and its human histopathological counterpart (atypical ductal hyperplasia), "epitheliosis" should remain the preferred term for the dog.