Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.

Fundamentals of osteoarthritis: Inflammatory mediators in osteoarthritis.

OBJECTIVES: As more has become known of the pathophysiology of osteoarthritis (OA), evidence that inflammation plays a critical role in its development and progression has accumulated. Here, we aim to review current knowledge of the complex inflammatory network in the OA joint. DESIGN: This narrative review is presented in three main sections: local inflammation, systemic inflammation, and therapeutic implications. We focused on inflammatory mediators and their link to OA structural changes in the joint. RESULTS: OA is characterized by chronic and low-grade inflammation mediated mostly by the innate immune system, which results in cartilage degradation, bone remodeling and synovial changes. Synovitis is regarded as an OA characteristic and associated with increased severity of symptoms and joint dysfunction. However, the articular cartilage and the subchondral bone also produce several pro-inflammatory mediators thus establishing a complex interplay between the different tissues of the joint. In addition, systemic low-grade inflammation induced by aging, obesity and metabolic syndrome can contribute to OA development and progression. The main inflammatory mediators associated with OA include cytokines, chemokines, growth factors, adipokines, and neuropeptides. CONCLUSIONS: Future research is needed to deeper understand the molecular pathways mediating the inflammation in OA to provide new therapeutics that target these pathways, or to repurpose existing drugs.

Musical dynamics in early triadic interactions: a case study.

Research of the last 30 years showed the importance of music for psychological development. Communicative musicality studies described musical organisations in dyadic interactions (adult-baby). However, other perspectives proposed that, from the beginning of life, there are early triadic interactions (adult-object-baby) that should also be analysed. Following previous research, we hypothesised that early triadic interactions have a structured musical organisation. We recorded a 2-month-old child interacting with his mother and an object in their home and performed a microgenetic quantitative-qualitative analysis. Given the child's age, we focused on musical characteristics of the mother's actions. To our knowledge, this is the first study to combine data processing provided by ELAN, Finale, and Matlab-MIRtoolbox. Our analysis shows that the child participates in triadic interactions in which the mother communicates about and through the maraca using musical resources in increasingly complex ways. Musical structuring happens at the intersegment, intrasequence, and intersequence levels, and involves different musical parameters. We suggest musical organisation in early triadic interactions follows a holographic structure in which each piece carries information about dynamic processes of different timescales. Results highlight the importance of considering objects and their uses to better understand early communicative musicality.

Getting away from the point: the emergence of ostensive gestures and their functions.

Within developmental psychology, pointing gestures have received a great deal of attention, while ostensive gestures have been overlooked in terms of their emergence and intentionality. In a longitudinal and micro-genetic study with six children at 9, 11, and 13 months of age, we codified gesture production of children within second-by-second data frames. We identified 480 instances of gestures and categorised whether they were of ostensive, ostensive-indexical, or indexical nature. We specified the communicative function of each gesture by analysing the object involved and their circumstances of production. Data analysis include frequencies, binomial tests, proportion comparisons, and repeated measures ANOVA. We identified a phatic function in other-directed gestures, as well as exploratory and private functions in self-directed gestures. This has important implications for child development since ostensive gestures are easier to produce and to understand than pointing. The consideration of objects would be essential for defining the communicative function of gestures.

MSH2 Gene Point Mutations Are Not Antifungal Resistance Markers in Candida glabrata.

The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n = 81), subsequent candidemia episodes (n = 9), endocarditis (n = 2), and in vitro-generated echinocandin-resistant isolates (n = 32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro, and patient prognosis. The MSH2 gene was sequenced, and isolates were genotyped using six microsatellite markers and multilocus sequence typing (MLST) based on six housekeeping genes. According to EUCAST, isolates causing candidemia (n = 90) were echinocandin susceptible, and four of them were fluconazole resistant (MIC ≥64 mg/liter). One isolate obtained from a heart valve was resistant to micafungin and anidulafungin (MICs, 2 mg/liter and 1 mg/liter, respectively). MSH2 gene mutations were present in 44.4% of the incident isolates, the most common being V239L. The presence of MSH2 mutations was not correlated with in vitro or in vivo antifungal resistance. Microsatellite and MLST revealed 27 genotypes and 17 sequence types, respectively. Fluconazole-resistant isolates were unrelated. Most MSH2 mutations were found in cluster isolates; conversely, some mutations were found in more than one genotype. No clinical differences, including previous antifungal use, were found between patients infected by wild-type MSH2 gene isolates and isolates with any point mutation. The presence of MSH2 gene mutations in C. glabrata isolates causing candidemia is not correlated with specific genotypes, the promotion of antifungal resistance, or the clinical outcome.

Reduced platelet aggregation in women after intercourse: a possible role for the cyclooxygenase pathway.

We hypothesise that molecules in the cyclooxygenase pathway affect platelet activity when seminal fluid (SF) is present. We considered the influence of SF on platelet aggregation in women, and believe that the prostanoids in SF signalling are significant. Thirty-one female subjects were studied, 20 of whom were sexually active. Male partners were given either aspirin or indomethacin to inhibit cyclooxygenase. The 6-keto prostaglandin F1α (6-keto PGF1α) and prostaglandin E metabolite (PGE-M) in SF were measured by competitive assay. Platelets and prostanoids were evaluated in women, periodically, before and after intercourse. The platelets were tested with adenosine diphosphate (ADP) and arachidonic acid (AA). To block the interaction between the uterus and SF, some couples used condoms. We found that the 6-keto prostaglandin F1α in urine at 2 hours post-intercourse (1418.75 pg/mL, Std 688.39) was greater than pre-intercourse (772.68 pg/mL, Std 116.54). Post-intercourse, a transient decrease in platelet aggregation was observed in women whose partners did not use condoms. Averages for platelet aggregation were 20.16% with ADP, and more significantly, 37.79% with AA after 2 hours. In contrast, couples using condoms showed no changes, averaging 64.02% with ADP and 72.06% with AA. Women whose partners were taking aspirin or indomethacin also showed no changes. SF from men taking aspirin or indomethacin led to no reduction in platelet aggregometry in their partners. These results indicate that in cases of exposure to SF, the transient change in women's platelet activity could be related to the cyclooxygenase pathway.

Comparative Pathogenicity of Lomentospora prolificans (Scedosporium prolificans) Isolates from Mexican Patients.

We identified 11 Lomentospora prolificans isolates recovered from Mexican patients using phenotypic and molecular characteristics. The identification of isolates was assessed by internal transcribed spacer (ITS rDNA) sequencing. In vitro susceptibility to amphotericin B, fluconazole, voriconazole, posaconazole, caspofungin, anidulafungin and micafungin was determined according to Clinical and Laboratory Standards Institute (CLSI) procedures. Three isolates (07-2239, 11-2242 and 04-2673) were used to induce systemic infection in immunocompetent ICR mice. Survival and tissue burden studies were used as markers of pathogenicity. All of the strains were resistant to every antifungal tested with MIC's for AmB (8->8 µg/ml), VRC (16->16 µg/ml), PSC (16->16 µg/ml), FLC (64->64 µg/ml) and echinocandins with MICs ≥8 µg/ml. One hundred, ninety and sixty percent of the infected mice with the strains 07-2239, 11-2242 and 04-2673 died during the study, respectively. Regarding tissue burden, the highest fungal load of the infected mice was detected in brain followed by spleen and kidney, regardless of the strain.

Tuning the host-guest interactions in a phosphine coordination polymer through different types of post-synthetic modification.

The porous Phosphine Coordination Material, PCM-10 contains abundant free P(III) donor sites that can be subjected to a variety of post-synthetic modifications. The diverse P(III)/P(V) organic reactivity and coordination chemistry available to aryl phosphines have been exploited to decorate the pores of PCM-10, allowing for an extensive structure-function study. Polar P═O moieties, charged P(+)-CH3 phosphonium species with exchangeable coanions (I(-), F(-), BF4(-), and PF6(-)) and P-AuCl groups have been successfully post-synthetically incorporated. These modifications directly affect the strength of the resulting host-guest interactions, as demonstrated by comparative sorption studies of CO2, H2, and other gases in the solid-state. Broad tunability of the enthalpy of CO2 adsorption is observed: incorporation of BF4(-) ions inside the pores of PCM-10 results in 24% enhancement of the isosteric adsorption enthalpy of CO2 compared to the parent material, while F(-) anions induce a 36% reduction. Meanwhile, AuCl-decorated PCM-10 shows a high H2 sorption capacity of 4.72 wt % at 77 K and 1.0 bar, versus only 0.63 wt % in the unmodified material.

A snapshot of patients' perceptions of oncology providers' cultural competence.

In this paper, we describe an anonymous cross-sectional survey with a sample of 100 racially diverse adult oncology patients using a newly developed patient-reported measure of providers' cultural competence, the Physicians' Cultural Competence for Patient Satisfaction Scale (PCCPS) [1, 2], which was developed using a US midwestern sample of primary care patients. Our primary aims were to examine the reliability of the PCCPS in a more racially diverse urban oncology clinical setting and to identify salient domains of oncology provider cultural competence based on patient-reported satisfaction with direct clinical encounters. Results suggest that patient-reported satisfaction was significantly associated with one of the four domains measured by the PCCPS, physician's patient-centered cultural competence (r = 0.40, p = 0.01), and female patients were more satisfied (t (91) = 5.23, p = 0.02). The PCCPS demonstrated good reliability in an urban diverse cancer patient population. Results help to inform the development of clinical tools that can improve oncology providers' cultural competency.

Gestures, Objects, and Spaces: Exploring Teachers' Multimodal Communication in Nursery Schools.

This study builds on the increasing evidence that the multimodal nature of adult-child interactions and the use of objects play an important role in early linguistic development. Most of these studies analyzed dyadic interactions at home, whereas few research has been conducted in early childhood education and care settings. In this paper, we characterized the multimodal nature of teachers' communicative bids during classroom-based group interactions in nursery schools. Observational data of circle-time activities was collected from 16 Spanish nursery school classrooms, comprising 16 teachers and 161 children between two and three years of age. We analyzed teachers' communicative bids (i.e., verbal utterances and verbal-gestural bids) considering the frequency of use of different types of gestures, to whom are they addressed (i.e., the whole group or a single child), the extent to which they involve the use of objects, the classroom layout, and the relationship between the communicative bids and the number of children that participated in each classroom. Teachers' communication with toddlers is highly multimodal and rely on different types of gestures, although the use of objects in our sample was scarce. Descriptive analysis suggest that certain classroom layouts may favor teachers' use of some types of gestures over others. In this article, we discuss the implications of both the use of objects and space for understanding how adults shape the linguistic contexts of young children, and the potential opportunities and limitations they pose for classroom interactions.

The haplolethal gene wupA of Drosophila exhibits potential as a target for an X-poisoning gene drive.

A synthetic gene drive that targets haplolethal genes on the X chromosome can skew the sex ratio toward males. Like an "X-shredder," it does not involve "homing," and that has advantages including the reduction of gene drive resistance allele formation. We examine this "X-poisoning" strategy by targeting 4 of the 11 known X-linked haplolethal/haplosterile genes of Drosophila melanogaster with CRISPR/Cas9. We find that targeting the wupA gene during spermatogenesis skews the sex ratio so fewer than 14% of progeny are daughters. That is unless we cross the mutagenic males to X^XY female flies that bear attached-X chromosomes, which reverses the inheritance of the poisoned X chromosome so that sons inherit it from their father, in which case only 2% of the progeny are sons. These sex ratio biases suggest that most of the CRISPR/Cas9 mutants we induced in the wupA gene are haplolethal but some are recessive lethal. The males generating wupA mutants do not suffer from reduced fertility; rather, the haplolethal mutants arrest development in the late stages of embryogenesis well after fertilized eggs have been laid. This provides a distinct advantage over genetic manipulation strategies involving sterility which can be countered by the remating of females. We also find that wupA mutants that destroy the nuclear localization signal of shorter isoforms are not haplolethal as long as the open reading frame remains intact. Like D. melanogaster, wupA orthologs of Drosophila suzukii and Anopheles mosquitos are found on X chromosomes making wupA a viable X-poisoning target in multiple species.

Flexible metallic core-shell nanostructured electrodes for neural interfacing.

Electrodes with nanostructured surface have emerged as promising low-impedance neural interfaces that can avoid the charge-injection restrictions typically associated to microelectrodes. In this work, we propose a novel approximation, based on a two-step template assisted electrodeposition technique, to obtain flexible nanostructured electrodes coated with core-shell Ni-Au vertical nanowires. These nanowires benefit from biocompatibility of the Au shell exposed to the environment and the mechanical properties of Ni that allow for nanowires longer and more homogeneous in length than their only-Au counterparts. The nanostructured electrodes show impedance values, measured by electrochemical impedance spectroscopy (EIS), at least 9 times lower than those of flat reference electrodes. This ratio is in good accordance with the increased effective surface area determined both from SEM images and cyclic voltammetry measurements, evidencing that only Au is exposed to the medium. The observed EIS profile evolution of Ni-Au electrodes over 7 days were very close to those of Au electrodes and differently from Ni ones. Finally, the morphology, viability and neuronal differentiation of rat embryonic cortical cells cultured on Ni-Au NW electrodes were found to be similar to those on control (glass) substrates and Au NW electrodes, accompanied by a lower glial cell differentiation. This positive in-vitro neural cell behavior encourages further investigation to explore the tissue responses that the implantation of these nanostructured electrodes might elicit in healthy (damaged) neural tissues in vivo, with special emphasis on eventual tissue encapsulation.

Multilevel and spatial-time trend analyses of the prevalence of hypertension in a large urban city in the USA.

We aimed to test two hypotheses that (1) there were significant variations in the prevalence of hypertension (HBP) across neighborhoods in the city of Philadelphia and (2) these variations were significantly explained by the variations in the neighborhood physical and socioeconomic environment (PSE). We used data from the Southeastern Pennsylvania Household Health Surveys in 2002-2004 (study period 1, n = 8,567), and in 2008-2010 (period 2, n = 8,747). An index of neighborhood PSE was constructed using multiple specific measures. The associations of HBP with PSE at the neighborhood level and other risk factors at the individual level were examined using multilevel regression analysis. The results show that age-adjusted prevalence of HBP increased from 30.33 to 33.04 % from study periods 1 to 2 (p < 0.001). An estimate of 44 and 53 % of the variations in the prevalence of HBP could be explained by the variations in neighborhood PSE in study periods 1 and 2, respectively. In conclusion, prevalence of HBP significantly increased from 2002-2004 to 2008-2010. Individuals living in neighborhoods with disadvantaged PSE have significantly higher risk of the prevalence of HBP.

Early triadic interactions in the first year of life: a systematic review on object-mediated shared encounters.

Infants' early interactions with adults and everyday objects are key to socio-communicative development, but their emergence and development are still under debate. Aiming at describing the diversity of theoretical and methodological approaches on triadicity during the first year of life, we conducted a systematic and qualitative review of recent literature. Following PRISMA 2020 guidelines, we explored the scientific production of recent decades on triadic interactions up to 12 months of age. We initially screened 1943 items from which we obtained a final sample of 51 publications. Studies are usually conducted in laboratory settings, while ecological research is becoming increasingly common, especially in home settings. According to a thematic analysis of the data, we discussed the different perspectives on the origin and conceptualization of triadic interactions, and how they contribute to structuring and facilitating other developmental phenomena, such as the children's communicative gestures and uses of objects. Prior to the origin of intentional communication, adults facilitate early forms of triadicity based on fostering opportunities for infants' communication and engagement with both adults and materiality. However, there is a need for further research that explore the potential of early triadic interactions for parenting and early childhood education practises.

Pelvic + Anatomy: A new interactive pelvic anatomy model. Prospective randomized control trial with first-year midwife residents.

Detailed knowledge of female pelvic floor anatomy is essential for midwifery and other professionals in obstetrics. Physical models have shown great potential for teaching anatomy and enhancing surgical skills. In this article, we introduce an innovative physical anatomy model called "Pelvic+" to teach anatomical relationships in the female pelvis. The Pelvic+ model's value was compared to a traditional lecture in 61 first-year midwifery students randomly allocated to either the Pelvic+ (n = 30) or a control group (n = 32). The primary outcome measure was a quiz comprised of 15 multiple choice questions on pelvic anatomy. Participants were assessed at baseline (Pre-Test), upon completion of the intervention (Post-Test1) and 4 months afterward (Post-Test2). Satisfaction with the approach was assessed at Post-Test1. Increase in knowledge was greater and the approach more accepted among resident midwives when Pelvic+ was used instead of standard lectures. Four months after the intervention, the improvement in knowledge was preserved in the Pelvic+ group. This randomized study demonstrates that the Pelvic+ simulator is more effective than classical learning for pelvic anatomy education, and offers a higher level of satisfaction among students during the educational process. Medical students training in obstetrics and gynecology, or any professional who specializes in the female pelvic floor might also benefit from incorporation of the Pelvic+ model into their training program.

Bio-potential noise of dry printed electrodes: physiology versus the skin-electrode impedance.

Objective. To explore noise characteristics and the effect physiological activity has on the link between impedance and noise.Approach. Dry-printed electrodes are emerging as a new and exciting technology for skin electro-physiology. Such electrode arrays offer many advantages including user convenience, quick placement, and high resolution. Here we analyze extensive electro-physiological data recorded from the arm and the face to study and quantify the noise of dry electrodes, and to characterize the link between noise and impedance. In particular, we studied the effect of the physiological state of the subject (e.g. rapid eye movement sleep) on noise.Main results. We show that baseline noise values extracted from dry electrodes in the arm are in agreement with the Nyquist equation. In the face, on the other hand, the measured noise values were higher than the values predicted by the Nyquist equation. In addition, we studied how different electrode properties affect performances, including electrode size, shape, and material properties.Significance. Altogether, the results presented here provide a basis for understanding dry electrode performances and substantiate their great potential in electro-physiological investigations.

Points to Consider When Using KPIs/Metrics.

Pharmaceutical quality systems according to ICH Q10 require the identification of processes that need to be measured. Designing and maintaining a metrics system in a way that serves its purpose well requires careful consideration of various aspects in order to meet expectations. The purpose of using key performance indicators/metrics can be defined by main aspects that include: 1) supporting the achievement of objectives by making them measurable, 2) reaching comparability and/or standardization of performance for organizational units, and 3) achieving objectiveness in assessing performance. The first two aspects are closely linked to management responsibilities. Therefore, management needs to be strongly involved with the activities of setting up and maintaining a metrics system. This article provides an overview of the points to be considered when setting up and managing a quality-related metrics system.

Electrodeposited Magnetic Nanowires with Radial Modulation of Composition.

In the last few years, magnetic nanowires have gained attention due to their potential implementation as building blocks in spintronics applications and, in particular, in domain-wall- based devices. In these devices, the control of the magnetic properties is a must. Cylindrical magnetic nanowires can be synthesized rather easily by electrodeposition and the control of their magnetic properties can be achieved by modulating the composition of the nanowire along the axial direction. In this work, we report the possibility of introducing changes in the composition along the radial direction, increasing the degrees of freedom to harness the magnetization. In particular, we report the synthesis, using template-assisted deposition, of FeNi (or Co) magnetic nanowires, coated with a Au/Co (Au/FeNi) bilayer. The diameter of the nanowire as well as the thickness of both layers can be tuned at will. In addition to a detailed structural characterization, we report a preliminary study on the magnetic properties, establishing the role of each layer in the global collective behavior of the system.

Zika vector competence data reveals risks of outbreaks: the contribution of the European ZIKAlliance project.

First identified in 1947, Zika virus took roughly 70 years to cause a pandemic unusually associated with virus-induced brain damage in newborns. Zika virus is transmitted by mosquitoes, mainly Aedes aegypti, and secondarily, Aedes albopictus, both colonizing a large strip encompassing tropical and temperate regions. As part of the international project ZIKAlliance initiated in 2016, 50 mosquito populations from six species collected in 12 countries were experimentally infected with different Zika viruses. Here, we show that Ae. aegypti is mainly responsible for Zika virus transmission having the highest susceptibility to viral infections. Other species play a secondary role in transmission while Culex mosquitoes are largely non-susceptible. Zika strain is expected to significantly modulate transmission efficiency with African strains being more likely to cause an outbreak. As the distribution of Ae. aegypti will doubtless expand with climate change and without new marketed vaccines, all the ingredients are in place to relive a new pandemic of Zika.