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Objectives It is important to assess healthcare providers (HCPs) knowledge, attitudes, perceptions, and preferences towards new pneumococcal vaccines for adults.Methods HCPs who met eligibility criteria completed an online survey between March – May 2024 that included a discrete choice experiment (DCE) to elicit preferences.Results Among 340 participating HCPs, the average age was 44.9 years old, and the majority were male (55.6%), and White (85.3%). Most HCPs reported that they would support (90.3%) and implement (91.5%) a lower age-based recommendation for pneumococcal vaccines (from adults 65+ years to adults 50+ years). A majority of HCPs would offer a supplemental dose of a pneumococcal vaccine to high-risk adults 19–49 years, at-risk or high-risk adults 50–64 years, and adults 65+ years regardless of risk status to increase protection after completing the recommended series. DCE results showed that coverage of pneumococcal pneumonia and invasive pneumococcal disease (IPD) in adults 65+ years were the two most important attributes in evaluating pneumococcal vaccines.Conclusions HCPs preferred a pneumococcal vaccine with increased coverage against pneumococcal pneumonia and IPD, and they supported lowering the age recommendation for pneumococcal vaccination as well as a supplemental vaccine dose to provide additional coverage for adults.

Many bioinformatics tools are available for the quantitative analysis of proteomics experiments. Most of these tools use a dedicated statistical model to derive absolute quantitative protein values from mass spectrometry (MS) data. Here, we present iSanXoT, a standalone application that processes relative abundances between MS signals and then integrates them sequentially to upper levels using the previously published Generic Integration Algorithm (GIA). iSanXoT offers unique capabilities that complement conventional quantitative software applications, including statistical weighting and independent modeling of error distributions in each integration, aggregation of technical or biological replicates, quantification of posttranslational modifications, and analysis of coordinated protein behavior. iSanXoT is a standalone, user-friendly application that accepts output from popular proteomics pipelines and enables unrestricted creation of quantification workflows and fully customizable reports that can be reused across projects or shared among users. Numerous publications attest the successful application of diverse integrative workflows constructed using the GIA for the analysis of high-throughput quantitative proteomics experiments. iSanXoT has been tested with the main operating systems. Download links for the corresponding distributions are available at https://github.com/CNIC-Proteomics/iSanXoT/releases.

Abstract To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most common complications of the preterm newborn. The pathology of the GM-IVH is not completely understood and even regions distant from the lesion area are severely affected. It has been suggested that cerebellar diaschisis may underlie the neurodevelopmental problems that many of these kids show, including cerebral palsy, attention deficit disorders or hyperactivity. Additionally, GM-IVH has no successful treatment. VP3.15 is a dual action phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3β (GSK-3β) inhibitor that limits neuroinflammation and neuronal loss. Therefore, it might also provide a relevant tool to reduce complications associated with GM-IVH. We have used a murine model of GM-IVH to analyze the short and long-term effects of VP3.15 in brain pathology and behavioral complications. In our hands, the induction of unilateral GM-IVH to P7 CD1 mice results in a short-term (P14) compromise of the cerebellar neuronal population and Purkinje cells arborization, an increase of microglia burden in the nuclei and an overall increase of punctuate cerebellar hemorrhages. Whereas brain alterations are no longer observed in the long term (P110), these animals present overt hyperactivity when analyzed in the adulthood, supporting the long-term behavioral impairment. Also, hyperactivity significantly correlates with ipsi and contralateral cerebellar sizes, neuronal densities and myelin basic protein levels. Importantly, treatment with VP3.15 significantly reduces neuronal loss, Purkinje cells simplification, the presence of cerebellar hemorrhages, as well as hyperactivity. Altogether, our data support the neuroprotective effects of VP3.15 in GM-IVH of the PT.

Key Clinical Message Gliosarcoma, a rare cerebral neoplasm, has not been linked to hippocampal changes in cats. We report a case of complex partial seizures with orofacial involvement, revealing gliosarcoma concurrent with bilateral hippocampal sclerosis. Abstract A 16‐year‐old neutered female domestic shorthair cat presented with acute inappetence, ataxia, disorientation, and vacant staring. Brain MRI revealed an ill‐defined, round, intra‐axial mass in the right piriform lobe, showing hyperintensity on T2W, T2‐FLAIR, and T2*W, and hypointensity on T1W images. The lesion exhibited mass effect and contrast enhancement in its center. Bilateral hyperintensity on T2‐FLAIR images and contrast enhancement were observed in the hippocampus. Brain histologic and immunohistochemical analysis revealed cerebral gliosarcoma with concurrent hippocampal sclerosis. Feline LGI1‐antibody testing on the serum and/or CSF was not performed due to insufficient biomaterial. Although retrospective testing on brain tissue was considered, it ultimately proved unfeasible, preventing us from ruling out antibody‐associated limbic encephalitis. In conclusion, cerebral gliosarcoma should be included in feline intracranial tumor differentials, warranting brain MRI and feline LGI1‐antibody testing in cats showing complex partial seizures with orofacial involvement. In our case, the prognosis remained poor due to the presence of a high‐grade glioma.

CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection, and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.

ABSTRACTAs higher-valent pneumococcal conjugate vaccines (PCVs) become available for pediatric populations in the US, it is important to understand healthcare provider (HCP) preferences for and acceptability of PCVs. US HCPs (pediatricians, family medicine physicians and advanced practitioners) completed an online, cross-sectional survey between March and April 2023. HCPs were eligible if they recommended or prescribed vaccines to children age

AbstractCell division cycle 7 kinase (CDC7) has been found overexpressed in many cancer cell lines being also one of the kinases involved in the nuclear protein TDP-43 phosphorylation in vivo. Thus, inhibitors of CDC7 are emerging drug candidates for the treatment of oncological and neurodegenerative unmet diseases. All the known CDC7 inhibitors are ATP-competitives, lacking of selectivity enough for success in clinical trials. As allosteric sites are less conserved among kinase proteins, discovery of allosteric modulators of CDC7 is a great challenge and opportunity in this field.Using different computational approaches, we have here identified new druggable cavities on the human CDC7 structure and subsequently selective CDC7 inhibitors with allosteric modulation mainly targeting the pockets where the interaction between this kinase and its activator DBF4 takes place.

Our aim is to identify new small molecules with antimicrobial potential, especially against colistin-resistant (Col-R) Acinetobacter baumannii and Escherichia coli. After initial hits identification by fingerprint similarity, MIC of 24 heterocyclic derivatives for A. baumannii and E. coli reference strains, and bactericidal activity of selected thiophenes against Col-R strains were determined. We analyzed changes in bacterial membrane permeability and the OMPs profile. Additionally, we determined bacterial adherence to host cells and performed molecular docking studies to assess their binding to bacterial targets. The compounds’ MICs ranged from 4 to >64 mg/L. Thiophene derivatives 4, 5 and 8 exhibited MIC50 values between 16 and 32 mg/L for Col-R A. baumannii and 8 and 32 mg/L for Col-R E. coli. The time-kill curve assay demonstrated that thiophenes 4 and 8 had bactericidal effects against Col-R A. baumannii and E. coli. Furthermore, treatment with them resulted in increased membrane permeabilization and reduced adherence of these isolates to host cells. Finally, the docking studies showed a stronger binding affinity to CarO1 and Omp33 of A. baumannii and OmpW and OmpC of E. coli. These findings indicate that thiophene derivatives possess antibacterial activity against Col-R A. baumannii and E. coli, suggesting that they may enhance the repertoire of drug treatments against bacteria.

Abstract Saffron has many pharmacological properties in addition to being a frequently used food seasoning. Crocin and picrocrocin which accumulate in saffron stigma, are responsible for these pharmacological properties. These natural products have health‐promoting effects for the prevention and treatment of numerous diseases, including age‐related cognitive and memory disfunction. Currently, crocin and picrocrocin are obtained from saffron, considered as the spice with the highest price in the market. To develop an efficient and low‐cost approach to producing these compounds with high bioactivity, biosynthetic genes isolated from saffron can be exploited in the metabolic engineering of heterologous hosts and the production of crocins in productive crop plants. Recently, we engineered tomato fruit producing crocins (Tomafran). In this study, we demonstrated that crocin-rich extract, encapsulated in chitosan or in exosomes may function as a neuroprotective strategy. Crocins contained in the Tomafran extracts and much lower doses in chitosan nanoparticles or exosomes were enough to rescue the neuroblastoma cell line SH-SY5Y after damage caused by okadaic acid. Our results confirm the neuroprotective effect of Tomafran and its exosomes that may be useful for the delay or prevention of neurodegenerative disorders such as Alzheimer’s disease. Graphical Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease without a cure to reverse its progression. Its main hallmark is the nuclear protein TDP-43, which undergoes different post-translational modifications leading to a loss of function in the nucleus and an increase in toxicity in the cytoplasm. Previous reports have indicated that pathogenic TDP-43 exhibits prion-like propagation in various contexts. With the aim of advancing therapeutics focused on preventing the propagation of TDP-43 pathology, we studied the potential role of pathogenic TDP-43 in lymphoblasts from sporadic ALS patients. We used lymphoblastoid cell lines from sporadic ALS patients as a source of pathogenic forms of TDP-43, and healthy human cells (lymphoblasts, myoblasts, neuroblastoma SH-SY5Y, or osteosarcoma U2OS) as recipient cells to investigate the seeding and spread of TDP-43 proteinopathy. Furthermore, we evaluated the potential of targeting TDP-43 phosphorylation with a CK-1 inhibitor to prevent the propagation of the pathology. The results presented herein indicate that pathogenic forms of TDP-43 are secreted into the extracellular medium of sporadic ALS lymphoblasts and could be transported by extracellular vesicles, spreading TDP-43 pathology to healthy cells. Moreover, tunneling nanotubes have also been discovered in pathological cells and may be involved in the transport of TDP-43. Interestingly, targeting TDP-43 phosphorylation with an in-house designed CK-1 inhibitor (IGS2.7) was sufficient to halt TDP-43 pathology transmission, in addition to its known effects on restoring the homeostasis of TDP-43 protein in patients-derived cells.

Background Transthyretin cardiac amyloidosis (ATTR‐CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR‐CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR‐CA using blood biomarkers and assess the association between blood biomarkers and prognosis. Methods and Results This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR‐CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C‐reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR‐CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04–1.37]; P=0.01), high urea (HR, 1.23 [95% CI, 1.04–1.45]; P=0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13–1.57; P=0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01–1.42; P=0.04), hyponatremia (HR, 1.65 [95% CI, 1.28–2.11]; P56 ng/L (HR, 1.72 [95% CI, 1.46–2.03]; P

Objective: To explore the impacts of parental deportation on the health and well-being of U.S. citizen children of Mexican immigrants. Methods: From 2019–2020, this ambi-directional cohort study recruited U.S.-based families with an undocumented Mexican immigrant parent and U.S.-citizen childrens (ages 13–17) recently exposed to parental deportation (N = 61), and similar families without a history of parental deportation (N = 51). Children health, behavioral, economic, and academic outcomes were measured via phone surveys upon enrollment and six months later. A subsample of “exposed” caregivers (N = 14) also completed in-depth semi-structured interviews. Data were analyzed using fixed-effects regression models and thematic analyses. Results: Childrens exposed to parental deportation had significantly worse health status, behavioral problems, material hardship, and academic outcomes than children in the control arm (p

This paper presents a model that analyses the relationship between the coach’s emotional competences and the training climate as predictors of the youngsters’ emotional competences and psychological well-being. In the present study, 309 athletes and 17 coaches participated in the study. A general predictive model was estimated with path analysis and the maximum robust likelihood (MLR) estimation method. The results showed that the coach’s emotional competences are associated with autonomy-supportive climates (β = .15, p < .005). This climate is related to youth’s emotional competences (β = .30, p < .005) and lower emotional (β = -.27, p < .005), behavioural (β = -.51, p < .005), and social (β = -.33, p < .005) symptomatology. These results have important practical implications in designing interventions that promote coaches’ emotional competences given its association with autonomy-supportive climates, which in turn are related to athletes’ emotional competences and psychological well-being.

Summary: Tandem mass tags data-dependent acquisition (TMT-DDA) as well as data-independent acquisition-based label-free quantification (LFQ-DIA) have become the leading workflows to achieve deep proteome and phosphoproteome profiles. We present a modular pipeline for TMT-DDA and LFQ-DIA that integrates steps to perform scalable phosphoproteome profiling, including protein lysate extraction, clean-up, digestion, phosphopeptide enrichment, and TMT-labeling. We also detail peptide and/or phosphopeptide fractionation and pre-mass spectrometry desalting and provide researchers guidance on choosing the best workflow based on sample number and input.For complete details on the use and execution of this protocol, please refer to Koenig et al.1 and Martínez-Val et al.2 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Cellular entry of SARS-CoV-2 has been shown to rely on angiotensin-converting enzyme 2 (ACE2) receptors, whose expression in the testis is among the highest in the body. Additionally, the risk of mortality seems higher among male COVID-19 patients, and though much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and potential consequences for reproductive health. We investigated testicular alterations in non-vaccinated deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the immune, vascular, and molecular fluctuations involved in the pathogenesis. Results We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensors or RT-qPCR using a specific methodology. Through an in vitro experiment exposing VERO cells to testicular macerates, we observed viral content in all samples, and the subgenomic RNA’s presence reinforced the replicative activity of SARS-CoV-2 in testes of the severe COVID-19 patients. The cellular structures and viral particles, observed by transmission electron microscopy, indicated that macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites, where new virions form inside the endoplasmic reticulum Golgi intermediate complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient’s infection. Further, we demonstrated high levels of angiotensin II and activated immune cells in the testes of deceased patients. The infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. Conclusions Our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our findings suggest that patients who become critically ill may exhibit severe alterations and harbor the active virus in the testes.

Abstract The TNF receptor-interacting protein kinases (RIPK)-1 and 3 are regulators of extrinsic cell death response pathways, where RIPK1 makes the cell survival or death decisions by associating with distinct complexes mediating survival signaling, caspase activation or RIPK3-dependent necroptotic cell death in a context-dependent manner. Using a mass spectrometry-based screen to find new components of the ripoptosome/necrosome, we discovered the protein-arginine methyltransferase (PRMT)-5 as a direct interaction partner of RIPK1. Interestingly, RIPK3 but not RIPK1 was then found to be a target of PRMT5-mediated symmetric arginine dimethylation. A conserved arginine residue in RIPK3 (R486 in human, R415 in mouse) was identified as the evolutionarily conserved target for PRMT5-mediated symmetric dimethylation and the mutations R486A and R486K in human RIPK3 almost completely abrogated its methylation. Rescue experiments using these non-methylatable mutants of RIPK3 demonstrated PRMT5-mediated RIPK3 methylation to act as an efficient mechanism of RIPK3-mediated feedback control on RIPK1 activity and function. Therefore, this study reveals PRMT5-mediated RIPK3 methylation as a novel modulator of RIPK1-dependent signaling.

This animated movie presents the mechanism of macroautophagy, hereafter autophagy, by showing the molecular features of the formation of autophagosomes, the hallmark organelle of this intracellular catabolic pathway. It is based on our current knowledge and it also illustrates how autophagosomes can recognize and eliminate selected cargoes.

Chemical libraries have become of utmost importance to boost drug discovery processes. It is widely accepted that the quality of a chemical library depends, among others, on its availability and chemical diversity which help in rising the chances of finding good hits. In this regard, our group has developed a source for useful chemicals named Medicinal and Biological Chemistry (MBC) library. It originates from more than 30 years of experience in drug design and discovery of our research group and has successfully provided effective hits for neurological, neurodegenerative and infectious diseases. Moreover, in the last years, the European research infrastructure for chemical biology EU-OPENSCREEN has generated the European Chemical Biology library (ECBL) to be used as a source of hits for drug discovery. Here we present and discuss the updated version of the MBC library (MBC v.2022), enriched with new scaffolds and containing more than 2,500 compounds together with ECBL that collects about 100,000 small molecules. To properly address the improved potentialities of the new version of our MBC library in drug discovery, up to 44 among physicochemical and pharmaceutical properties have been calculated and compared with those of other well-known publicly available libraries. For comparison, we have used ZINC20, DrugBank, ChEMBL library, ECBL and NuBBE along with an approved drug library. Final results allowed to confirm the competitive chemical space covered by MBC v.2022 and ECBL together with suitable drug-like properties. In all, we can affirm that these two libraries represent an interesting source of new hits for drug discovery.

IntroductionTDP-43 proteinopathy in Alzheimer’s disease (AD) patients is recently emerging as a relevant pathomolecular event that may have been overlooked. Recent results in immortalized lymphocytes from AD patients have shown not only an increase of post-translational modifications in TDP-43, such as hyperphosphorylation and fragmentation, but also its prionic behaviour and cell-to-cell disease transmission. With the main goal to advance therapeutic interventions, we present in this work different kinase inhibitors with potential to restore this pathological mechanism.MethodologyWe have used immortalized lymphocytes from healthy controls and AD severe patients to evaluate the correction of TDP-43 pathology after the treatment with previously synthetized TTBK1 and CK1 inhibitors. Moreover we used the conditioned mediums of these cells to perform different disease propagation experiments.ResultsTDP-43 pathology observed in lymphoblasts from severe AD patients is reduced after the treatment with TTBK1 and CK1 inhibitors (decreasing phosphorylation and increasing nuclear localisation), Furthermore, the significant increase in TDP-43 phosphorylation, cytoplasmic accumulation and aberrant F-actin protrusions (TNT-like structures) observed in control cells growing in CM from AD lymphoblasts were abolished when the CM from AD lymphoblasts treated with previously reported TTBK1 and CK1 inhibitors were used. In addition, the cytosolic transport mediated by molecular motors of the receptor cells was altered with the induced TDP-43 pathology, but it was not produced with the abovementioned pretreated CMs.ConclusionTTBK1 and CK1 inhibitors, specially VNG1.47 and IGS2.7 compounds, restore TDP-43 pathology and avoid cell-to-cell propagation in immortalized lymphocytes from AD patients, being excellent candidates for the future therapy of this prevalent and devastating disease.

Introduction and Objectives: there is insufficient data regarding bacterial infections in patients with cirrhosis to support recommendations for empiric antibiotic treatments, particularly in Latin America. This study aimed to evaluate bacterial infection's clinical impact and microbiological characteristics, intending to serve as a platform to revise current practices. Materials and Methods: multicenter prospective cohort study of patients with cirrhosis and bacterial infections from Argentina and Uruguay. Patient and infection-related information were collected, focusing on microbiology, antibiotic susceptibility patterns, and outcomes. Results: 472 patients were included. Spontaneous bacterial infections and urinary tract infections (UTIs) were registered in 187 (39.6%) and 116 (24.6%) patients, respectively, representing the most common infections. Of the 256 culture-positive infections, 103 (40.2%) were caused by multidrug-resistant organisms (reaching 50% for UTI), and 181 (70.7%) received adequate initial antibiotic treatment. The coverage of cefepime and ceftriaxone was over 70% for the empirical treatment of community-acquired spontaneous infections, but ceftazidime´s coverage was only 40%. For all UTI cases and for healthcare-associated or nosocomial spontaneous bacterial infections, the lower-spectrum antibiotics that covered at least 70% of the isolations were imipenem and meropenem. During hospitalization, a second bacterial infection was diagnosed in 9.8% of patients, 23.9% required at least one organ support, and 19.5% died. Conclusions: short-term mortality of bacterial infections in patients with cirrhosis is very high, and a high percentage were caused by multidrug-resistant organisms, particularly in UTIs. The information provided might serve to adapt recommendations, particularly related to empirical antibiotic treatment in Argentina and Uruguay. The study was registered in Clinical Trials (NCT03919032).

Obesity is one of the main causes of chronic kidney disease; however, the precise molecular mechanisms leading to the onset of kidney injury and dysfunction in obesity-associated nephropathy remain unclear. The present study aimed to unveil the kidney microRNA (miRNA) expression profile in a model of obesity-induced kidney disease in C57BL/6J mice using next-generation sequencing (NGS) analysis. High-fat diet (HFD)-induced obesity led to notable structural alterations in tubular and glomerular regions of the kidney, increased renal expression of proinflammatory and profibrotic genes, as well as an elevated renal expression of genes involved in cellular lipid metabolism. The miRNA sequencing analysis identified a set of nine miRNAs differentially expressed in the kidney upon HFD feeding, with miR-5099, miR-551b-3p, miR-223-3p, miR-146a-3p and miR-21a-3p showing the most significant differential expression between standard diet (STD) and HFD mice. A validation analysis showed that the expression levels of miR-5099, miR-551b-3p and miR-146a-3p were consistent with NGS results, while Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses revealed that these three validated miRNAs modulated target genes involved in metabolic and adipocytokine pathways, fatty acid and lipid metabolism, and inflammatory, senescence and profibrotic pathways. Our results suggest that differentially expressed miRNAs play pivotal roles in the intricate pathophysiology of obesity-associated kidney disease and could potentially create novel treatment strategies to counteract the deleterious effects of obesity on kidney function.

The Photovoltaic Geographical Information System (PVGIS) is a web application that provides free access to solar radiation and temperature data, typical meteorological year (TMY) data, and to photovoltaic performance assessment tools for any place in most parts of the world. The PVGIS was originally developed over 20 years ago, and since then, it has been under continuous development. At present, there are two versions of the PVGIS online—the older version 5.1 and the newest version 5.2. PVGIS 5.2 includes substantial improvements compared to the previous version, e.g., the update of the underlying data sets both in terms of quality, resolution, and geographical coverage and the extension of the time period used. This paper focuses on comparing the TMYs (and more specifically the TMY time series of air temperature), coming from both PVGIS 5.1 and 5.2, with the TMY produced on the basis of ground station meteorological data and with the ground station data itself. The results show that whereas overall the errors and biases for most locations are within the expected range (mean stationRMSE 4.27), these differences increase in places with complicated topography, e.g., in the Alps (maximum stationRMSE 9.50).

Introduction and Objectives: Selecting an empiric antibiotic treatment in patients with cirrhosis and spontaneous bacterial infections is challenging. It is of paramount importance to have local epidemiological data to maximize pathogen coverage while minimizing the unnecessary use of broad-spectrum antibiotics. This study aimed to describe the patterns of antibiotic resistance of spontaneous bacterial infections according to the site of acquisition. Materials and Methods: Analysis of the multicenter prospective cohort study of cirrhotic patients with bacterial infections in Argentina and Uruguay (NCT03919032). Only culture-positive spontaneous infections were included in this study: spontaneous bacterial peritonitis (SBP), spontaneous bacterial empyema (SBE), and spontaneous bacteremia (SB). We estimated the proportion of infections that were sensitive to various antibiotics according to where the infection was acquired: community-acquired (CA), healthcare-associated (HCA), or nosocomial (NOS). Approximately 80% coverage is advisable for empiric treatments in stable patients and 90% for critically-ill patients. Results: The main cohort included 472 patients, of whom 97 presented culture-positive spontaneous infections and were included: with 57 (59%) SBP, 34 (35%) SB, and 4 (6%) SBE. Regarding the site of acquisition, 43% were CA, 36% NOS, and 21% HCA. Gram-positive and negative bacteria were found in 53% and 47% of the infections. The most frequent isolations were Streptococcus spp (26%), E coli (20), K pneumonia (15%), S Aureus (10%), E. faecium (6%) and E. faecalis (4%). Multidrug-resistant organisms (MDROs) were isolated in 35% of the patients. As shown in the table, cefepime and ceftriaxone offer the most rational coverage for CA and HCA infections, and imipenem or meropenem for NOS infections. However, in critically-ill patients, broader-spectrum antibiotics are needed to achieve a coverage closer to 90% (table). Conclusions: We present, for the first time in our region, evidence-based recommendations for the empirical treatment of spontaneous bacterial infections. Prior colonization and/or infections by MDROs might refine even more the antibiotic selection and should be explored.

Not all elements displayed in a YouTube in-stream video ad are attributable to the ad itself. Some of those are automatically introduced by the platform, such as the countdown timer and the time progress bar. In recent years, some authors started exploring the effects associated with the presence of such non-ad items, providing valuable findings. However, objective evaluation of viewers’ visual attention is lacking in this context as well as emotional investigation. In addition, previous research showed how the manipulation of seemingly negligible details can yield dramatically different outcomes in the context of in-stream advertising. To extend knowledge, the authors explored the effects of the non-ad items’ presence by employing eye-tracking and facial coding techniques in combination with self-reports in a between-subjects experimental design focusing on the YouTube 15-s, mid-roll, non-skippable in-stream ad format. Results showed that the ad format currently employed by YouTube performs worse than its equivalent without the non-ad items on all the investigated measures and than its equivalent in which the non-ad items’ presence was experimentally reduced on facial coding disgust, self-reported disgust, ad irritation, and ad attitude. Managerial insights and challenges concerning the future of in-stream advertising and neuromarketing are highlighted.

BackgroundData about long-term prognosis after hospitalisation of elderly multimorbid patients remains scarce.ObjectivesEvaluate medium and long-term prognosis in hospitalised patients older than 75 years of age with multimorbidity. Explore the impact of gender, age, frailty, physical dependence, and chronic diseases on mortality over a seven-year period.MethodsWe included prospectively all patients hospitalised for medical reasons over 75 years of age with two or more chronic illnesses in a specialised ward. Data on chronic diseases were collected using the Charlson comorbidity index and a questionnaire for disorders not included in this index. Demographic characteristics, Clinical Frailty Scale, Barthel index, and complications during hospitalisation were collected.Results514 patients (46% males) with a mean age of 85 (± 5) years were included. The median follow-up was 755 days (interquartile range 25-75%: 76-1,342). Mortality ranged from 44% to 68%, 82% and 91% at one, three, five, and seven years. At inclusion, men were slightly younger and with lower levels of physical impairment. Nevertheless, in the multivariate analysis, men had higher mortality (pConclusionsIn our cohort, individual diseases had a limited predictive prognostic capacity, while the combination of chronic illness, frailty, and physical dependence were independent predictors of survival.

AimsTransthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers.Materials and methods and ResultsWe retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored > 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (p < 0.001) including those diagnosed under age 65 years (p = 0.008) or with early stage cardiomyopathy (p < 0.001).ConclusionCT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.

Protein activity regulated by phosphorylation can result in subcellular relocation. Here, the authors present a high throughput spatial phosphoproteomics approach to profile six subcellular compartments, providing insights into EGFR and stress signalling dynamics.

Abstract Background The application of advanced imaging in pediatric research trials introduces the challenge of how to effectively handle and communicate incidental and reportable findings. This challenge is amplified in underserved populations that experience disparities in access to healthcare as recommendations for follow-up care may be difficult to coordinate. Therefore, the purpose of the present report is to describe the process for identifying and communicating findings from a research MRI to low-income Latino children and families. Methods Latino adolescents (n = 86) aged 12–16 years old with obesity and prediabetes underwent a research MRI (3 Tesla Philips Ingenia®) as part of a randomized controlled diabetes prevention trial. The research MRIs were performed at baseline and 6 months to assess changes in whole-abdominal fat distribution and organ fat in response to the intervention. An institutional pathway was developed for identifying and reporting findings to participants and families. The pathway was developed through a collaborative process with hospital administration, research compliance, radiology, and the research team. All research images were reviewed by a board-certified pediatric radiologist who conveyed findings to the study pediatrician for determination of clinical actionability and reportability to children and families. Pediatric sub-specialists were consulted as necessary and a primary care practitioner (PCP) from a free community health clinic agreed to receive referrals for uninsured participants. Results A total of 139 images (86 pre- and 53 post-intervention) were reviewed with 31 findings identified and 23 deemed clinically actionable and reportable. The only reportable finding was severely elevated liver fat (> 10%, n = 14) with the most common and concerning incidental findings being horseshoe kidney (n = 1) and lung lesion (n = 1). The remainder (n = 7) were less serious. Of youth with a reportable or incidental finding, 18 had a PCP but only 7 scheduled a follow-up appointment. Seven participants without a PCP were referred to a safety-net clinic for follow-up. Conclusions With the increased utilization of high-resolution imaging in pediatric research, additional standardization is needed on what, when, and how to return incidental and reportable findings to participants, particularly among historically underrepresented populations that may be underserved in the community. Trial registration Preventing Diabetes in Latino Youth, NCT02615353

Odontoestomatología es la revista científica oficial de la Facultad de Odontología de la Universidad de la República, Uruguay, órgano difusor de la Sociedad Uruguaya de Investigación Odontológica. A pesar de encontrarse indizada por Lilacs, SciELO, Redalyc, DOAJ y estar presente en los catálogos de Latindex, CiteFactor, Sherpa-Romeo (tipo azul) y sistema Webqualis de Capes (B4) y portal AmeliCA, no existe un reporte oficial del impacto de los manuscritos en la comunidad científica. Objetivos: Analizar marcadores bibliométricos de publicación de la revista Odontoestomatología en el período 2012-2022 como medida de impacto y relevancia de los artículos publicados. Métodos: Se realizará un análisis de los artículos relacionados con odontología publicados en Odontoestomatología entre los años 2012 y 2022 inclusive. Se relevarán las citas de cada artículo, forma de acceso, idioma y país del que se accede, así como país de afiliación de los autores, cantidad de autores, sexo de los autores y temática del manuscrito. Resultados esperados: Se espera encontrar un aumento en el número de citas de los artículos de Odontoestomatología, así como de autores extranjeros, en comparación con los reportados en el informe de bibliometría de 2009-2012.

Summary: We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals.

It has been demonstrated that odors could affect humans at the psychophysiological level. Significant research has been done on odor perception and physiological mechanisms; however, this research was mainly performed in highly controlled conditions in order to highlight the perceptive phenomena and the correlated physiological responses in the time frame of milliseconds. The present study explored how human physiological activity evolves in response to different odor conditions during an ecological olfactory experience on a broader time scale (from 1 to 90 s). Two odors, vanilla and menthol, together with a control condition (blank) were employed as stimuli. Electroencephalographic (EEG) activity in four frequency bands of interest, theta, alpha, low beta, and high beta, and the electrodermal activity (EDA) of the skin conductance level and response (SCL and SCR) were investigated at five time points taken during: (i) the first ten seconds of exposure (short-term analysis) and (ii) throughout the entire exposure to each odor (90 s, long-term analysis). The results revealed significant interactions between the odor conditions and the time periods in the short-term analysis for the overall frontal activity in the theta (p = 0.03), alpha (p = 0.005), and low beta (p = 0.0067) bands, the frontal midline activity in the alpha (p = 0.015) and low beta (p = 0.02) bands, and the SCR component (p = 0.024). For the long-term effects, instead, only one EEG parameter, frontal alpha asymmetry, was significantly sensitive to the considered dimensions (p = 0.037). In conclusion, the present research determined the physiological response to different odor conditions, also demonstrating the sensitivity of the employed parameters in characterizing the dynamic of such response during the time. As an exploratory study, this work points out the relevance of considering the effects of continuous exposure instead of short stimulation when evaluating the human olfactory experience, providing insights for future studies in the field.

Abstract The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Resumen: Introducción: La alergia a las proteínas de la leche de vaca (APLV) es la alergia alimentaria más frecuente en el primer año de vida. No existe un consenso claro respecto a su prevención. Recientemente se ha publicado la recomendación de evitar estas proteínas en la primera semana de vida como medida de prevención en todos los niños, con independencia de su riesgo atópico. El objetivo de este documento es emitir una recomendación sobre el uso de fórmulas extensamente hidrolizadas de PLV en la primera semana de vida para la prevención primaria de la APLV. Métodos: Se constituyó un grupo de expertos propuestos por la Asociación Española de Pediatría (AEP), la Sociedad Española de Inmunología Clínica y Alergología y Asma Pediátrica (SEICAAP), la Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP) y la Sociedad Española de Neonatología (SENEO). Se realizó una revisión crítica de la evidencia publicada en los últimos 10 años sobre el tema. Resultados: Se seleccionaron 72 estudios, de los cuales 66 fueron rechazados por no cumplir los criterios de inclusión. Se incluyeron en la revisión 6 documentos: 3 ensayos clínicos y 3 revisiones sistemáticas, 2 de ellas con metaanálisis. No se observó una reducción estadísticamente significativa en la incidencia de APLV en los grupos de lactantes que recibieron fórmulas hipoalergénicas ni lactancia materna exclusiva. Conclusión: Con base en las evidencias existentes en la actualidad, no se pueden establecer conclusiones claras acerca del efecto de evitar las PLV durante la primera semana de vida en la prevención de la APLV. A pesar de existir datos que pudieran orientar a un cierto efecto beneficioso de su evitación en niños con riesgo atópico, estos resultados no son concluyentes ni generalizables a lactantes sin dicho riesgo. Abstract: Introduction: Cow's milk protein allergy (CMPA) is the most frequent food allergy in the first year of life. There is no clear consensus regarding its prevention. A recommendation to avoid CMP in the first week of life as a preventive measure in all infants, regardless of their atopic risk, has recently been published. The purpose of this document is to issue a recommendation on the use of extensively hydrolyzed CMP formulas in the first week of life for the primary prevention of CMPA. Methods: A group of experts was formed with members proposed by the Spanish Association of Pediatrics (AEP), the Spanish Society of Clinical Immunology and Allergology and Pediatric Asthma (SEICAAP), the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) and the Spanish Society of Neonatology (SENEO). The group conducted a critical review of the evidence on the subject published in the last 10 years. Results: The search yielded 72 studies, of which 66 were rejected for not meeting the inclusion criteria. The final review included 6 documents: 3 clinical trials and 3 systematic reviews, 2 of them with meta-analysis. There was no evidence of a statistically significant reduction in the incidence of CMPA in the infants who received hypoallergenic formulae or exclusive breastfeeding. Conclusion: Based on the current evidence, it is not possible to draw clear conclusions about the effect of avoiding CMP in the first week of life for prevention of CMPA. Although there are data that suggest a certain beneficial effect of avoiding CMPA in atopic risk infants, these results are not conclusive enough to extend the recommendation to the general population.

Introduction: Cow’s milk protein allergy (CMPA) is the most frequent food allergy in the first year of life. There is no clear consensus regarding its prevention. A recommendation to avoid CMP in the first week of life as a preventive measure in all infants, regardless of their atopic risk, has recently been published. The purpose of this document is to issue a recommendation on the use of extensively hydrolyzed CMP formulas in the first week of life for the primary prevention of CMPA. Methods: A group of experts was formed with members proposed by the Spanish Association of Pediatrics (AEP), the Spanish Society of Clinical Immunology and Allergology and Pediatric Asthma (SEICAAP), the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) and the Spanish Society of Neonatology (SENEO). The group conducted a critical review of the evidence on the subject published in the last 10 years. Results: The search yielded 72 studies, of which 66 were rejected for not meeting the inclusion criteria. The final review included 6 documents: 3 clinical trials and 3 systematic reviews, 2 of them with meta-analysis. There was no evidence of a statistically significant reduction in the incidence of CMPA in the infants who received hypoallergenic formulae or exclusive breastfeeding. Conclusion: Based on the current evidence, it is not possible to draw clear conclusions about the effect of avoiding CMP in the first week of life for prevention of CMPA. Although there are data that suggest a certain beneficial effect of avoiding CMPA in atopic risk infants, these results are not conclusive enough to extend the recommendation to the general population. Resumen: Introducción: La alergia a las proteínas de la leche de vaca (APLV) es la alergia alimentaria más frecuente en el primer año de vida. No existe un consenso claro respecto a su prevención. Recientemente se ha publicado la recomendación de evitar estas proteínas en la primera semana de vida como medida de prevención en todos los niños, con independencia de su riesgo atópico. El objetivo de este documento es emitir una recomendación sobre el uso de fórmulas extensamente hidrolizadas de PLV en la primera semana de vida para la prevención primaria de la APLV. Métodos: Se constituyó un grupo de expertos propuestos por la Asociación Española de Pediatría (AEP), la Sociedad Española de Inmunología Clínica y Alergología y Asma Pediátrica (SEICAAP), la Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP) y la Sociedad Española de Neonatología (SENEO). Se realizó una revisión crítica de la evidencia publicada en los últimos 10 años sobre el tema. Resultados: Se seleccionaron 72 estudios, de los cuales 66 fueron rechazados por no cumplir los criterios de inclusión. Se incluyeron en la revisión 6 documentos: 3 ensayos clínicos y 3 revisiones sistemáticas, 2 de ellas con metaanálisis. No se observó una reducción estadísticamente significativa en la incidencia de APLV en los grupos de lactantes que recibieron fórmulas hipoalergénicas ni lactancia materna exclusiva. Conclusión: Con base en las evidencias existentes en la actualidad, no se pueden establecer conclusiones claras acerca del efecto de evitar las PLV durante la primera semana de vida en la prevención de la APLV. A pesar de existir datos que pudieran orientar a un cierto efecto beneficioso de su evitación en niños con riesgo atópico, estos resultados no son concluyentes ni generalizables a lactantes sin dicho riesgo.

NOTCH1 is a driver of T-cell acute lymphoblastic leukemia that can be inhibited by γ-secretase inhibitors (GSIs), but their clinical efficacy is limited. Here, the authors compare the phosphoproteomes of GSI resistant and sensitive models, and identify potential kinase targets to overcome GSI resistance.

Naïve pluripotency can be stabilized through different pharmacological approaches. Here, the authors profile temporal changes of protein phosphorylation, proteome and metabolome as mESCs transition to the naïve state in response to two pharmacological treatments, revealing general and treatment-specific processes.

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

Abstract Aims Cardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course. Methods and results We performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P

Display and native ads represent two of the most widely used digital advertising formats employed by advertisers that aim to grab the attention of online users. In recent years, the native format has become very popular because it relies on deceptive features that make harder the recognition of its advertising nature, reducing avoiding behaviors such as the banner blindness phenomena, traditionally associated to display advertising, and so increasing its advertising effectiveness. The present study, based on a forefront research protocol specifically designed for the advertising research on smartphone devices, aims to investigate through neurophysiological and self-reported measures, the perception of display and native ads placed within article webpages, and to assess the efficacy of an integrated approach. Eye-tracking results showed higher visual attention and longer viewing time associated with native advertisements in comparison to traditional display advertisements, confirming and extending evidence provided by previous research. Despite a significantly higher rate of self-reported advertising intent was detected for articles containing display ads when compared to articles containing native ads, no differences have been found while performing the same comparison for the neurophysiological measures of emotional involvement and approaching motivation of for the self-reported measures of pleasantness and annoyance. Such findings along with the employment of an innovative research protocol, contribute to providing further cues to the current debate related to the effectiveness of two of the most widely used digital advertising formats.

Renal fibrosis is a deleterious process and a final manifestation of chronic kidney disease. Here, the authors demonstrate a role of alpha-synuclein in the maintenance of the epithelial phenotype of renal proximal tubular epithelial cells and in protecting kidney parenchyma against injury.

Abstract Background Phosphate is an essential plant macronutrient required to achieve maximum crop yield. Roots are able to uptake soil phosphate from the immediate root area, thus creating a nutrient depletion zone. Many plants are able to exploit phosphate from beyond this root nutrient depletion zone through symbiotic association with Arbuscular Mycorrhizal Fungi (AMF). Here we characterise the relationship between root architecture, AMF association and low phosphate tolerance in strawberries. The contrasting root architecture in the parental strawberry cultivars ‘Redgauntlet’ and ‘Hapil’ was studied through a mapping population of 168 progeny. Low phosphate tolerance and AMF association was quantified for each genotype to allow assessment of the phenotypic and genotypic relationships between traits. Results A “phosphate scavenging” root phenotype where individuals exhibit a high proportion of surface lateral roots was associated with a reduction in root system size across genotypes. A genetic correlation between “root system size” traits was observed with a network of pleiotropic QTL found to represent five “root system size” traits. By contrast, average root diameter and the distribution of roots appeared to be under two discrete methods of genetic control. A total of 18 QTL were associated with plant traits, 4 of which were associated with solidity that explained 46% of the observed variation. Investigations into the relationship between AMF association and root architecture found that a higher root density was associated with greater AMF colonisation across genotypes. However, no phenotypic correlation or genotypic association was found between low phosphate tolerance and the propensity for AMF association, nor root architectural traits when plants are grown under optimal nutrient conditions. Conclusions Understanding the genetic relationships underpinning phosphate capture can inform the breeding of strawberry varieties with better nutrient use efficiency. Solid root systems were associated with greater AMF colonisation. However, low P-tolerance was not phenotypically or genotypically associated with root architecture traits in strawberry plants. Furthermore, a trade-off was observed between root system size and root architecture type, highlighting the energetic costs associated with a “phosphate scavenging” root architecture.

Localizing phosphorylation sites by data-independent acquisition (DIA)-based proteomics is still challenging. Here, the authors develop algorithms for phosphosite localization and stoichiometry determination, and incorporate them into single-shot DIA-phosphoproteomics workflows.

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.

Latino men who have sex with men (MSM) continue to be disproportionately impacted by HIV/AIDS. Latino MSM experienced a 13% increase in HIV diagnoses in the U.S., more than any other racial/ethnic group of MSM. Identifying the role of multiple syndemic factors associated with sexual risk behaviors is imperative for developing effective prevention and treatment strategies. Data for this study are derived from three cycles of the Philadelphia portion of the National HIV Behavioral Surveillance System and explored the impact of syndemic factors – heavy drinking, exchange sex, and homophobic discrimination – on sexual HIV risk behaviors, operationalized as number of male partners, and condomless anal intercourse (CAI) with main and casual partners among Latino MSM (n=464). Analyses took two forms: a syndemic approach, using the cumulative number of conditions as an independent variable; and a non-syndemic approach, incorporating each condition as a unique predictor. In multivariable syndemic analyses, participants with two or more factors reported more male partners and more CAI casual male partners than those with none. In non-syndemic models, homophobic discrimination and exchange sex were significantly positively associated with total number of male partners and heavy drinking was associated with more casual CAI partners. Quantitative results indicate that syndemic and non-syndemic approaches vary in their relative capacity to account for sexual risk among Latino MSM.