Triadic influence as a proxy for compatibility in social relationships.

Networks of social interactions are the substrate upon which civilizations are built. Often, we create new bonds with people that we like or feel that our relationships are damaged through the intervention of third parties. Despite their importance and the huge impact that these processes have in our lives, quantitative scientific understanding of them is still in its infancy, mainly due to the difficulty of collecting large datasets of social networks including individual attributes. In this work, we present a thorough study of real social networks of 13 schools, with more than 3,000 students and 60,000 declared positive and negative relationships, including tests for personal traits of all the students. We introduce a metric-the "triadic influence"-that measures the influence of nearest neighbors in the relationships of their contacts. We use neural networks to predict the sign of the relationships in these social networks, extracting the probability that two students are friends or enemies depending on their personal attributes or the triadic influence. We alternatively use a high-dimensional embedding of the network structure to also predict the relationships. Remarkably, using the triadic influence (a simple one-dimensional metric) achieves the best accuracy, and adding the personal traits of the students does not improve the results, suggesting that the triadic influence acts as a proxy for the social compatibility of students. We postulate that the probabilities extracted from the neural networks-functions of the triadic influence and the personalities of the students-control the evolution of real social networks, opening an avenue for the quantitative study of these systems.

Drought stress and hurricane defoliation influence mountain clouds and moisture recycling in a tropical forest.

Mountain ranges generate clouds, precipitation, and perennial streamflow for water supplies, but the role of forest cover in mountain hydrometeorology and cloud formation is not well understood. In the Luquillo Experimental Forest of Puerto Rico, mountains are immersed in clouds nightly, providing a steady precipitation source to support the tropical forest ecosystems and human uses. A severe drought in 2015 and the removal of forest canopy (defoliation) by Hurricane Maria in 2017 created natural experiments to examine interactions between the living forest and hydroclimatic processes. These unprecedented land-based observations over 4.5 y revealed that the orographic cloud system was highly responsive to local land-surface moisture and energy balances moderated by the forest. Cloud layer thickness and immersion frequency on the mountain slope correlated with antecedent rainfall, linking recycled terrestrial moisture to the formation of mountain clouds; and cloud-base altitude rose during drought stress and posthurricane defoliation. Changes in diurnal cycles of temperature and vapor-pressure deficit and an increase in sensible versus latent heat flux quantified local meteorological response to forest disturbances. Temperature and water vapor anomalies along the mountain slope persisted for at least 12 mo posthurricane, showing that understory recovery did not replace intact forest canopy function. In many similar settings around the world, prolonged drought, increasing temperatures, and deforestation could affect orographic cloud precipitation and the humans and ecosystems that depend on it.

Development of an Effective Immune Response in Adults With Down Syndrome After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination.

BACKGROUND: Immune dysregulation in individuals with Down syndrome (DS) leads to an increased risk for hospitalization and death due to coronavirus disease 2019 (COVID-19) and may impair the generation of protective immunity after vaccine administration. METHODS: The cellular and humoral responses of 55 individuals with DS who received a complete SARS-CoV-2 vaccination regime at 1 to 3 (visit [V 1]) and 6 (V2) months were characterized. RESULTS: SARS-CoV-2-reactive CD4+ and CD8+ T lymphocytes with a predominant Th1 phenotype were observed at V1 and increased at V2. Likewise, an increase in SARS-CoV-2-specific circulating Tfh (cTfh) cells and CD8+ CXCR5+ PD-1hi lymphocytes was already observed at V1 after vaccine administration. Specific immunoglobulin G (IgG) antibodies against SARS-CoV-2 S protein were detected in 96% and 98% of subjects at V1 and V2, respectively, although IgG titers decreased significantly between both time points. CONCLUSIONS: Our findings show that DS individuals develop an effective immune response to usual regimes of SARS-CoV-2 vaccination.

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. RESULTS: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. CONCLUSIONS: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

T regulatory lymphocytes specific for SARS-CoV-2 display increased functional plasticity.

The study of phenotypic and functional characteristics of immune cells involved in host response to SARS-CoV-2 is relevant for understanding COVID-19 pathogenesis and individual differences in disease progression. We have analyzed chemokine receptor expression in SARS-CoV-2-specific CD4+ T lymphocytes from vaccinated donors, and have found an increase of CCR9+ and CCR6+ cells. CCR9+ specific CD4+ cells are enriched in T regulatory (Treg) lymphocytes. These cells specifically show heterogeneous regulatory activity, associated with different profiles of CCR9/CCR6 expression, individual differences in IL-10 and IL-17 production, and variable FoxP3 and Notch4 expression. A higher heterogeneity in FoxP3 is selectively observed in convalescent individuals within vaccinated population. Accordingly, SARS-CoV-2-specific CD4+ lymphocytes from COVID-19 patients are also enriched in CCR9+ and CCR6+ cells. CCR6+ specific Treg lymphocytes are mainly increased in critically ill individuals, indicating a preferential role for these cells in lung injury pathogenesis. We provide experimental evidence for a SARS-CoV-2-specific Treg population with increased plasticity, which may contribute to the differential pathogenic response against SARS-CoV-2 among individuals, and underlie the development of autoimmune conditions following SARS-CoV-2 infection.

Microbiota composition in the lower respiratory tract is associated with severity in patients with acute respiratory distress by influenza.

Several factors are associated with the severity of the respiratory disease caused by the influenza virus. Although viral factors are one of the most studied, in recent years the role of the microbiota and co-infections in severe and fatal outcomes has been recognized. However, most of the work has focused on the microbiota of the upper respiratory tract (URT), hindering potential insights from the lower respiratory tract (LRT) that may help to understand the role of the microbiota in Influenza disease. In this work, we characterized the microbiota of the LRT of patients with Influenza A using 16S rRNA sequencing. We tested if patients with different outcomes (deceased/recovered) and use of antibiotics differ in their microbial community composition. We found important differences in the diversity and composition of the microbiota between deceased and recovered patients. In particular, we detected a high abundance of opportunistic pathogens such as Granulicatella, in patients either deceased or with antibiotic treatment. Also, we found antibiotic treatment correlated with lower diversity of microbial communities and with lower probability of survival in Influenza A patients. Altogether, the loss of microbial diversity could generate a disequilibrium in the community, potentially compromising the immune response increasing viral infectivity, promoting the growth of potentially pathogenic bacteria that, together with altered biochemical parameters, can be leading to severe forms of the disease. Overall, the present study gives one of the first characterizations of the diversity and composition of microbial communities in the LRT of Influenza patients and its relationship with clinical variables and disease severity.

Isolation of Nocuolin A and Synthesis of New Oxadiazine Derivatives. Design, Synthesis, Molecular Docking, Apoptotic Evaluation, and Cathepsin B Inhibition.

Nocuolin A (1), an oxadiazine, was isolated from the cyanobacterium Nostoc sp. Its chemical structure was elucidated using NMR and mass spectroscopic data. From this compound, two new oxadiazines, 3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropyl acetate (2) and 4-{3-[(6R)-5,6-dihydro-4,6-dipentyl-2H-1,2,3-oxadiazin-2-yl]-3-oxopropoxy}-4-oxobutanoic acid (3), were synthesised. The chemical structures of these two compounds were elucidated by a combination of NMR and MS analysis. Compound 3 showed cytotoxicity against the ACHN (0.73 ± 0.10 µM) and Hepa-1c1c7 (0.91 ± 0.08 µM) tumour cell lines. Similarly, compound 3 significantly decreased cathepsin B activity in ACHN and Hepa-1c1c7 tumour cell lines at concentrations of 1.52 ± 0.13 nM and 1.76 ± 0.24 nM, respectively. In addition, compound 3 showed no in vivo toxicity in a murine model treated with a dose of 4 mg/kg body weight.

Ureteral Stenosis and Fistula after Kidney Transplantation.

INTRODUCTION: Ureteral complications after kidney transplantation are frequent and may have a negative impact on morbidity and graft function. Treatment modalities include conservative, endourological, and surgical techniques, with variable outcomes. The purpose of this study was to report the incidence, characteristics, treatment, and outcomes of ureteral complications at our center. METHODS: Retrospective study of kidney transplants performed at our unit between 2015 and 2020, analyzing incidence, characteristics, treatment, and outcomes of ureteral stenoses and fistulas. RESULTS: Of 648 kidney transplants, we present 3.24% stenosis and 2.16% ureteral fistulas, with a mean time from transplantation of 101.4 and 24.4 days, respectively. Primary treatment was open surgical repair in 52.4% stenosis and 100% fistulas, with a success rate of 90.9% and 71.4%, respectively. Anterograde balloon dilatations were performed in 33.3% of stenosis with 40% success. Three patients required surgery as a secondary approach with 100% success. Major complications (Clavien-Dindo III) were observed in 18.5% following surgical repair. After a mean follow-up of 31.1 ± 20.9 months, we observe 88.6% of functioning grafts. We found no significant differences in graft survival between patients with or without ureteral complications (p 0.948). CONCLUSION: Surgical repair of ureteral complications offers satisfactory results with low associated morbidity. Endourological techniques are less effective and should be reserved for selected cases. With adequate management, there is no impact on graft survival.

MindReader: Unsupervised Classification of Electroencephalographic Data.

Electroencephalogram (EEG) interpretation plays a critical role in the clinical assessment of neurological conditions, most notably epilepsy. However, EEG recordings are typically analyzed manually by highly specialized and heavily trained personnel. Moreover, the low rate of capturing abnormal events during the procedure makes interpretation time-consuming, resource-hungry, and overall an expensive process. Automatic detection offers the potential to improve the quality of patient care by shortening the time to diagnosis, managing big data and optimizing the allocation of human resources towards precision medicine. Here, we present MindReader, a novel unsupervised machine-learning method comprised of the interplay between an autoencoder network, a hidden Markov model (HMM), and a generative component: after dividing the signal into overlapping frames and performing a fast Fourier transform, MindReader trains an autoencoder neural network for dimensionality reduction and compact representation of different frequency patterns for each frame. Next, we processed the temporal patterns using a HMM, while a third and generative component hypothesized and characterized the different phases that were then fed back to the HMM. MindReader then automatically generates labels that the physician can interpret as pathological and non-pathological phases, thus effectively reducing the search space for trained personnel. We evaluated MindReader's predictive performance on 686 recordings, encompassing more than 980 h from the publicly available Physionet database. Compared to manual annotations, MindReader identified 197 of 198 epileptic events (99.45%), and is, as such, a highly sensitive method, which is a prerequisite for clinical use.

Prevalence of hepatitis C virus infection in patients with chronic mental disorders: The relevance of dual disorders.

OBJECTIVE: The prevalence of hepatitis C virus (HCV) infection is higher in people with psychiatric disorders compared to the general population. In addition, patients with severe mental illness are frequently affected by substance abuse, which increases the risk of blood-borne viral infections. Epidemiological studies in samples of hospitalised individuals with chronic mental disorders and dual diagnosis (DD) are lacking. The objective of this study was to investigate the prevalence of HCV infection in a sample of in-patients with severe mental illness. PATIENTS AND METHODS: This was a retrospective observational study. All patients meeting selection criteria admitted to the Medium-Term Psychiatric Unit of the University of Salamanca Health Care Complex between 2007 and 2018 were included. The primary endpoint was the prevalence of HCV infection. The secondary endpoint comprised the characteristics influencing the occurrence of HCV infection in these patients. RESULTS: A total of 497 admissions were included and patients' last admission data were considered for analyses (n=345). The overall prevalence of HCV infection was 3.8% and reached 14.3% among DD patients, who showed a higher prevalence than those without this condition (14.3% versus 3.1%, p=0.009). HCV RNA was detected in 6 individuals at diagnosis who received DAA treatment reaching sustained virological response. CONCLUSIONS: The prevalence of HCV infection in our sample was higher than in the general population, especially among DD patients. Despite the multiple barriers to access healthcare by patients with chronic mental illness, efforts to include this population in screening and treatment are mandatory.

Neuropsychological Genotype-Phenotype in Patients with Williams Syndrome with Atypical Deletions: A Systematic Review.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a microdeletion in the q11.23 region of chromosome 7. Recent case series reports and clinical case studies have suggested that the cognitive, behavioral, emotional, and social profile in WS could depend on the genes involved in the deletion. The objective of this systematic review was to analyze and synthesize the variability of the cognitive and behavioral profile of WS with atypical deletion and its probable relationship with the affected genes. The medical subject headings searched were "Williams syndrome," "genotype," "phenotype," "cognitive profile," and "atypical deletion." The studies included were in English or Spanish, with children and adults, and published between January 2000 and October 2022. Twenty-three studies are reported. The characteristics of the participants, the genes involved, the neuropsychological domains and instruments, and the prevalence of the WS cognitive profile criteria were used for the genotype-phenotype analysis. The genes with a major impact on the cognitive profile of WS were (a) LIMK1 and those belonging to the GTF2I family, the former with a greater influence on visuospatial abilities; (b) GTF2IRD1 and GTF2I, which have an impact on intellectual capacity as well as on visuospatial and social skills; (c) FZD9, BAZ1B, STX1A, and CLIP2, which influence the cognitive profile if other genes are also effected; and (d) GTF2IRD2, which is related to the severity of the effect on visuospatial and social skills, producing a behavioral phenotype like that of the autism spectrum. The review revealed four neuropsychological phenotypes, depending on the genes involved, and established the need for more comprehensive study of the neuropsychological profile of these patients. Based on the results found, we propose a model for the investigation of and clinical approach to the WS neuropsychological phenotype.

Allergen immunotherapy and/or biologicals for IgE-mediated food allergy: A systematic review and meta-analysis.

BACKGROUND: There is substantial interest in immunotherapy and biologicals in IgE-mediated food allergy. METHODS: We searched six databases for randomized controlled trials about immunotherapy alone or with biologicals (to April 2021) or biological monotherapy (to September 2021) in food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis. RESULTS: We included 36 trials about immunotherapy with 2126 mainly child participants. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5.-21.4, high certainty); cow's milk (RR 5.7, 1.9-16.7, moderate certainty) and hen's egg allergy (RR 8.9, 4.4-18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300 mg or 1000 mg peanut protein was 2. Oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0-1.2, low certainty) or severe reactions in peanut allergy (RR 1,6, 0.7-3.5, low certainty), but may increase (mild) adverse reactions in cow's milk (RR 3.9, 2.1-7.5, low certainty) and hen's egg allergy (RR 7.0, 2.4-19.8, moderate certainty). Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8-3.8, moderate certainty). Results were unclear for other allergies and administration routes. There were too few trials of biologicals alone (3) or with immunotherapy (1) to draw conclusions. CONCLUSIONS: Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow's milk and hen's egg allergy. More research is needed about quality of life, cost and biologicals.

EAACI guidelines: Anaphylaxis (2021 update).

Anaphylaxis is a clinical emergency which all healthcare professionals need to be able to recognize and manage. The European Academy of Allergy and Clinical Immunology Anaphylaxis multidisciplinary Task Force has updated the 2014 guideline. The guideline was developed using the AGREE II framework and the GRADE approach. The evidence was systematically reviewed and recommendations were created by weighing up benefits and harms. The guideline was peer-reviewed by external experts and reviewed in a public consultation. The use of clinical criteria to identify anaphylaxis is suggested with blood sampling for the later measurement of tryptase. The prompt use of intramuscular adrenaline as first-line management is recommended with the availability of adrenaline autoinjectors to patients in the community. Pharmacokinetic data should be provided for adrenaline autoinjector devices. Structured, comprehensive training for people at risk of anaphylaxis is recommended. Simulation training and visual prompts for healthcare professionals are suggested to improve the management of anaphylaxis. It is suggested that school policies reflect anaphylaxis guidelines. The evidence for the management of anaphylaxis remains mostly at a very low level. There is an urgent need to prioritize clinical trials with the potential to improve the management of patients at risk of anaphylaxis.

INTERGROWTH-21st versus a customized method for the prediction of neonatal nutritional status in hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) generate complications and are one of the principal causes of maternal, foetal, and neonatal mortality worldwide. It has been observed that in pregnancies with HDP, the incidence of foetuses small for their gestational age (SGA) is twice as high as that in noncomplicated pregnancies. In women with HDP, the identification of foetuses (SGA) is substantially important, as management and follow-up are determined by this information. OBJECTIVE: The objective of this study was to evaluate whether the INTERGROWTH-21st method or customized birthweight references better identify newborns with an abnormal nutritional status resulting from HDP. METHOD: A comparative analysis study was designed with two diagnostic methods for the prediction of neonatal nutritional status in pregnancies with HDP. The performance of both methods in identifying neonatal malnutrition (defined by a neonatal body mass index < 10th centile or a ponderal index < 10th centile) was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, diagnostic odds ratio, Youden's index and probability ratios. RESULTS: The study included 226 pregnant women diagnosed with HDP. The customized method identified 45 foetuses as small for gestational age (19.9%), while the INTERGROWTH-21st method identified 27 newborns with SGA (11.9%). The difference between proportions was statistically significant (p < 0.01). Using body mass index (< 10th centile) as a measure of nutritional status, newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR: 4.87 (95% CI: 1.86-12.77) vs. 3.75 (95% CI: 1.49-9.43)) (DOR: 5.56 (95% CI: 1.82-16.98) vs. 4.84 (95% CI: 1.51-15.54)) Even when using Ponderal index (< 10th centile), newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR 2.37 (95% CI: 1.11-5.05) vs. 1.68 (95% CI: 0.70-4.03))(DOR 2.62 (95% CI: 1.00-6.87) vs. 1.90 (95% CI: 0.61-5.92)). CONCLUSION: In pregnant women with HDP, the predictive ability of the customized foetal growth curves to identify neonatal malnutrition appears to surpass that of INTERGROWTH-21st.

A comprehensive approach to complementary and alternative medicine usage among patients from a vascular department.

INTRODUCTION: Use of complementary and alternative medicine (CAM) therapies had been described in patients with disabling, chronic and painful conditions; these characteristics define the majority of vascular surgery (VS) entities. A lack of disclosure about CAM use from patients has been universally cited and may impact effective patient-doctor communication. Our primary objective was to describe CAM use, modalities, perceived benefits, safety, and associated factors among adult patients attending a VS outpatient clinic; we additionally explored patient's attitudes about CAM disclosure with their primary vascular surgeon. METHODS: This cross-sectional study invited 223 consecutive outpatients to an interview where the ICAM-Q (International Complementary and Alternative Medicine Questionnaire) and the PDRQ-9 (Patient-Doctor Relationship Questionnaire-9 items) were applied. In addition, sociodemographics, vascular disease and treatment-related information, comorbidity, and disease severity characteristics were obtained. Appropriated statistics was used; multiple logistic regression analysis identified factors associated to CAM use. All statistical tests were two-sided, and a p value ≤ 0.05 was considered significant. IRB approval was obtained. RESULTS: Patients recruited were primary females (69%) and had a median age of 65 years (54-75). Most frequent vascular diagnoses were chronic venous insufficiency (36.2%) and peripheral artery disease (26%). There were 104 (46.6%) patients who referred CAM use, primarily self-helped practices (96%), and use of herbal, vitamins, or homeopathic medicines (23.7%). Overall, the majority of the patients perceived CAM modalities helpful and 94.6% denied any adverse event. Female sex (OR: 1.768, 95% CI: 0.997-3.135, p = 0.051) and hospitalization during the previous year (OR: 3.173, 95% CI: 1.492-6.748, p = 0.003) were associated to CAM use. The majority of the patients (77%) agreed about CAM disclosure with their primary vascular surgeon; meanwhile, among CAM users, up to 54.9% did not disclose it, and their main reasons were "Doctor didn't ask" (32%) and "I consider it unnecessary" (16%). The patient-doctor relationship was rated by the patients with high scores. CONCLUSIONS: CAM use is frequent and perceived as safe and beneficial among VS outpatients; nonetheless, patients do not disclose CAM use with their primary vascular surgeons, and a wide range of reasons are given by the patients that prevent effective and open communication.

How Do Mexican Patients With Rheumatoid Arthritis Define Sexual and Reproductive Health? A Content Analysis Study.

BACKGROUND: A patient-centered approach is essential for promoting sexual health (SH) and reproductive health (RH) in rheumatoid arthritis patients. The study aimed to describe and interpret Mexican rheumatoid arthritis outpatients' testimonies of their SH and RH definitions. METHODS: Qualitative and quantitative content analysis was conducted on free-text comments from 219 and 223 descriptions of patients' SH and RH definitions, respectively. A comprehensive system of major themes, categories, and subcategories was structured for each definition. The representational foundations of these categories and the context of their production were analyzed. Integration of quantitative and qualitative content analysis was used to comprehend patients' definitions of SH and RH. Internal review board approved the study. RESULTS: Ten major themes emerged for each definition, and their assigned frequencies differed between SH and RH definitions, and between groups of patients integrated according to age, education level, and sex. Both definitions had similar contents, expressed in the shared major themes and categories, and in managing at the same time SH- and RH-related contents within each definition. The "overall prevention-patient oriented care" major theme defined a common core for both definitions' contents. Meanwhile, a diversity of meanings was also evident particularly at the subcategory level. CONCLUSIONS: In our population, SH content was distinguished by related diseases and their consequences, individual actions directed to prevention, and couple mentions. Meanwhile, RH was distinguished by a primarily biological perspective of the reproductive function, which was required at a particular life stage to concrete a family project.

Heregulin-induced cell migration is prevented by trastuzumab and trastuzumab-emtansine in HER2+ breast cancer.

PURPOSE: Heregulin (HRG) signaling has been implicated in the development of an aggressive phenotype in breast cancer (BC) cells, and HER2 overexpression has been associated with a worse prognosis in BC patients. Nevertheless, the molecular mechanisms through which HRG affects the efficiency of anti-HER2 therapies such as trastuzumab (Tz) and trastuzumab-emtansine (T-DM1) are currently unknown. METHODS: In the present study, we evaluate the molecular action of HRG toward fundamental scaffold proteins and several kinases in the signal transduction pathways triggered via HER2/HER3, which integrate precise and sequential steps to promote changes in cell morphology to impulse BC cell migration. In addition, we evaluate the effectiveness of Tz and T-DM1 on the control of key proteins involved in BC cell motility, since the acquisition of a migratory phenotype is essential to promote invasion and metastasis. RESULTS: We show that HRG induces actin cytoskeleton reorganization and focal adhesion complex formation, and promotes actin nucleation in BT-474 BC cells. This signaling is triggered by HER2/HER3 to c-Src, FAK and paxillin. When paxillin is phosphorylated, it recruits PAK1, which then phosphorylates cortactin. In parallel, paxillin signals to N-WASP, and both signalings regulate Arp2/3 complex, leading to the local reorganization of actin fibers. CONCLUSIONS: Our findings reveal an original mechanism by which HRG increases HER2+ BC cell motility, and show that the latter can be abolished by Tz and T-DM1 treatments. These results provide evidence for the molecular mechanisms involved in cell motility and drug resistance. They will be useful to develop new and more specific therapeutic schemes that interfere with the progression and metastasis of HER2+ BC.

Diagnosing, managing and preventing anaphylaxis: Systematic review.

BACKGROUND: This systematic review used the GRADE approach to compile evidence to inform the European Academy of Allergy and Clinical Immunology's (EAACI) anaphylaxis guideline. METHODS: We searched five bibliographic databases from 1946 to 20 April 2020 for studies about the diagnosis, management and prevention of anaphylaxis. We included 50 studies with 18 449 participants: 29 randomized controlled trials, seven controlled clinical trials, seven consecutive case series and seven case-control studies. Findings were summarized narratively because studies were too heterogeneous to conduct meta-analysis. RESULTS: It is unclear whether the NIAID/FAAN criteria or Brighton case definition are valid for immediately diagnosing anaphylaxis due to the very low certainty of evidence. There was also insufficient evidence about the impact of most anaphylaxis management and prevention strategies. Adrenaline is regularly used for first-line emergency management of anaphylaxis but little robust research has assessed its effectiveness. Newer models of adrenaline autoinjectors may slightly increase the proportion of people correctly using the devices and reduce time to administration. Face-to-face training for laypeople may slightly improve anaphylaxis knowledge and competence in using autoinjectors. We searched for but found little or no comparative effectiveness evidence about strategies such as fluid replacement, oxygen, glucocorticosteroids, methylxanthines, bronchodilators, management plans, food labels, drug labels and similar. CONCLUSIONS: Anaphylaxis is a potentially life-threatening condition but, due to practical and ethical challenges, there is a paucity of robust evidence about how to diagnose and manage it.

Identification of TRPV1 Ion Channels Agonists of Tropaeolum tuberosum in Human Skin Keratinocytes.

Tropaeolum tuberosum, commonly known as Mashua, is an herbal remedy used in traditional Andean medicine for the relief of kidney and bladder pain, as well as contusions. This study aimed to evaluate the fractions and isolated compounds from T. tuberosum with analgesic activity mediated by the transient receptor potential vanilloid-1 receptor. A bioguided phytochemical analysis based on NMR/MS was performed to identify the compounds of the n-heptane fractions from samples of purple tubers of T. tuberosum. The transient receptor potential vanilloid-1 agonist and antagonist activity were assessed through the measurement of intracellular Ca2+ in HEK001 cells. The chemical structure determination led to the identification of two alkamides: N-(2-hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (1: ) and N-oleoyldopamine (2: ). Both compounds induced increased intracellular calcium flow with IC50 values of 3.2 nM and 7.9 nM, respectively, thus activating the transient receptor potential vanilloid-1 receptor. Our research is the first report to show that these two compounds isolated from T. tuberosum can act as agonists of the transient receptor potential vanilloid-1 receptor, providing scientific evidence for the traditional use of this species in pain relief.

Cognitive resource allocation determines the organization of personal networks.

The typical human personal social network contains about 150 relationships including kin, friends, and acquaintances, organized into a set of hierarchically inclusive layers of increasing size but decreasing emotional intensity. Data from a number of different sources reveal that these inclusive layers exhibit a constant scaling ratio of [Formula: see text] While the overall size of the networks has been connected to our cognitive capacity, no mechanism explaining why the networks present a layered structure with a consistent scaling has been proposed. Here we show that the existence of a heterogeneous cost to relationships (in terms of time or cognitive investment), together with a limitation in the total capacity an individual has to invest in them, can naturally explain the existence of layers and, when the cost function is linear, explain the scaling between them. We develop a one-parameter Bayesian model that fits the empirical data remarkably well. In addition, the model predicts the existence of a contrasting regime in the case of small communities, such that the layers have an inverted structure (increasing size with increasing emotional intensity). We test the model with five communities and provide clear evidence of the existence of the two predicted regimes. Our model explains, based on first principles, the emergence of structure in the organization of personal networks and allows us to predict a rare phenomenon whose existence we confirm empirically.