Are there conserved biosynthetic genes in lichens? Genome-wide assessment of terpene biosynthetic genes suggests ubiquitous distribution of the squalene synthase cluster.

Lichen-forming fungi (LFF) are prolific producers of functionally and structurally diverse secondary metabolites, most of which are taxonomically exclusive and play lineage-specific roles. To date, widely distributed, evolutionarily conserved biosynthetic pathways in LFF are not known. However, this idea stems from polyketide derivatives, since most biochemical research on lichens has concentrated on polyketide synthases (PKSs). Here, we present the first systematic identification and comparison of terpene biosynthetic genes of LFF using all the available Lecanoromycete reference genomes and 22 de novo sequenced ones (111 in total, representing 60 genera and 23 families). We implemented genome mining and gene networking approaches to identify and group the biosynthetic gene clusters (BGCs) into networks of similar BGCs. Our large-scale analysis led to the identification of 724 terpene BGCs with varying degrees of pairwise similarity. Most BGCs in the dataset were unique with no similarity to a previously known fungal or bacterial BGC or among each other. Remarkably, we found two BGCs that were widely distributed in LFF. Interestingly, both conserved BGCs contain the same core gene, i.e., putatively a squalene/phytoene synthase (SQS), involved in sterol biosynthesis. This indicates that early gene duplications, followed by gene losses/gains and gene rearrangement are the major evolutionary factors shaping the composition of these widely distributed SQS BGCs across LFF. We provide an in-depth overview of these BGCs, including the transmembrane, conserved, variable and LFF-specific regions. Our study revealed that lichenized fungi do have a highly conserved BGC, providing the first evidence that a biosynthetic gene may constitute essential genes in lichens.

The Prognostic Significance of Tumor-Infiltrating Lymphocytes, PD-L1, BRCA Mutation Status and Tumor Mutational Burden in Early-Stage High-Grade Serous Ovarian Carcinoma-A Study by the Spanish Group for Ovarian Cancer Research (GEICO).

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.

Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.

Differentiating between different forms of moral obligations.

We argue that Tomasello's account overlooks important psychological distinctions between how humans judge different types of moral obligations, such as prescriptive obligations (i.e., what one should do) and proscriptive obligations (i.e., what one should not do). Specifically, evaluating these different types of obligations rests on different psychological inputs and has distinct downstream consequences for judgments of moral character.

Parasite stress and pathogen avoidance relate to distinct dimensions of political ideology across 30 nations.

People who are more avoidant of pathogens are more politically conservative, as are nations with greater parasite stress. In the current research, we test two prominent hypotheses that have been proposed as explanations for these relationships. The first, which is an intragroup account, holds that these relationships between pathogens and politics are based on motivations to adhere to local norms, which are sometimes shaped by cultural evolution to have pathogen-neutralizing properties. The second, which is an intergroup account, holds that these same relationships are based on motivations to avoid contact with outgroups, who might pose greater infectious disease threats than ingroup members. Results from a study surveying 11,501 participants across 30 nations are more consistent with the intragroup account than with the intergroup account. National parasite stress relates to traditionalism (an aspect of conservatism especially related to adherence to group norms) but not to social dominance orientation (SDO; an aspect of conservatism especially related to endorsements of intergroup barriers and negativity toward ethnic and racial outgroups). Further, individual differences in pathogen-avoidance motives (i.e., disgust sensitivity) relate more strongly to traditionalism than to SDO within the 30 nations.

Mesoscopic study of the ternary phase diagram of the PS-PB-PtBMA triblock copolymer: modification of the phase structure by the composition effect.

We explored in detail the ordered nanostructures and the ternary phase diagram of the polystyrene-polybutadiene-poly(tert-butyl methacrylate) (PS-PB-PtBMA) triblock copolymer via dissipative particle dynamics (DPD) simulations and coarse-grained models. The mesoscopic simulations show that the PS-PB-PtBMA copolymer in the bulk state can generate eight equilibrium phase regions with well-defined morphologies such as core-shell variations of spheres, cylinders, perforated layers, lamellar, gyroid, as well as cylinder-in-lamella, spheres-in-lamella, and cylinders in hexagonal lattice. The ordered phases exhibit high dependence on the chemical nature and volume fraction, thus portraying specific composition regions with high thermodynamic stability over a ternary phase diagram. The ternary phase diagram, including all equilibrium and metastable nanostructures detected, is described, and analysed in this work in detail. Finally, our dynamic simulation outcomes agree with experimental results. Our aim is to contribute to the understanding of the relationship between block volume fractions and bulk morphologies in ternary polymer systems.

The challenge of accounting for individual differences in folk-economic beliefs.

We argue that existing data on folk-economic beliefs (FEBs) present challenges to Boyer & Petersen's model. Specifically, the widespread individual variation in endorsement of FEBs casts doubt on the claim that humans are evolutionarily predisposed towards particular economic beliefs. Additionally, the authors' model cannot account for the systematic covariance between certain FEBs, such as those observed in distinct political ideologies.

Disgust, politics, and responses to threat.

We address two questions regarding the relationship between political ideology and responses to threatening or aversive stimuli. The first concerns the reason for the connection between disgust and specific political and moral attitudes; the second concerns the observation that some responses to threat (i.e., neuroticism/anxiety) are associated with a more left-wing political orientation.

On the Highway to Hell: Slippery Slope Perceptions in Judgments of Moral Character.

Across four studies, we test the hypothesis that people exhibit "slippery slope" thinking in their judgments of moral character-that is, do observers judge that a person who behaves immorally will become increasingly immoral over time? In Study 1, we find that a person who commits an immoral act is judged as more likely to behave immorally and as having a worse character in the future than in the past. In Study 2, we find that it is the commission of an immoral act specifically-rather than merely attempting an immoral act-that drives this slippery slope effect. In Study 3, we demonstrate that observers judge the moral agent as more likely to commit acts of greater severity further in time after the initial immoral act. In Study 4, we find that this effect is driven by an anticipated corrupting of moral character, related to perceptions of the agent's guilt.

Praise Is for Actions That Are Neither Expected nor Required.

In six studies, we examined two foundational questions about moral praise. First, what makes an action praiseworthy? In Study 1, participants reported that actions that exceed duties (compared with dutiful actions) deserve greater praise and are perceived as less likely to happen. Second, what do observers infer from praise? Praise may communicate information about local norms. In Study 2, we found that-in general-participants expect praise to increase the likelihood of a behavior. However, in Studies 3-6, participants inferred that moral behavior that receives praise is less common and is less required and expected of people. These inferences led individuals to judge that someone would be less likely to perform a behavior that was praised. These studies provide insight into the lay beliefs and communicative function of moral praise.

Exploring the Effects of Tasks with Different Decision-Making Levels on Ball Control, Passing Performance, and External Load in Youth Football.

This study aimed to understand how the design of decision-making tasks affects youth football players' ball control, passing performance, and external load. A total of 16 male youth football players (age: 12.94 ± 0.25 years) competed in various tasks based on the following levels of decision-making: (i) low decision-making (Low DM), which consisted of a predefined ball control and passing sequence; (ii) moderate decision-making (Mod DM), which consisted of maintaining possession in a square with four players and two balls while maintaining the same position; and (iii) high decision-making (High DM), which consisted of a 3 vs. 3 + 2 neutral players ball possession game. The study design consisted of a pre-post design (a 6 min pre-test game, a 6 min intervention, and a 6 min post-test game). The players' ball control and passing performance were measured using the game performance evaluation tool and notational analysis, while GPS data were used to determine their physical performance. The pre-post test analysis revealed decrements in players' ability to identify more offensive players after the Mod DM task (W = 9.50, p = 0.016), while there was an increase in their ability to receive the ball towards the space following the High DM task (t = -2.40, p = 0.016). Analysis between groups showed lower values in most ball control variables for the Low DM task compared to the Mod DM task (ball control execution, p = 0.030; appropriateness, p = 0.031; motor space, p = 0.025), while there were also lower values in the distance covered while sprinting (p = 0.042). Overall, prescriptive tasks (Low DM) that are repetitive in nature may affect players' perceptual attunement, whereas static tasks (e.g., Mod DM) may limit their ability to locate players in more offensive positions. Moreover, game-based situations (High DM) seem to acutely enhance players' performance, possibly due to contextual dependency. Overall, coaches should carefully consider the type of practice structure when designing tasks that aim to improve players' technical skills in youth football.

Detecting the trustworthiness of novel partners in economic exchange.

Because trusting strangers can entail high risk, an ability to infer a potential partner's trustworthiness would be highly advantageous. To date, however, little evidence indicates that humans are able to accurately assess the cooperative intentions of novel partners by using nonverbal signals. In two studies involving human-human and human-robot interactions, we found that accuracy in judging the trustworthiness of novel partners is heightened through exposure to nonverbal cues and identified a specific set of cues that are predictive of economic behavior. Employing the precision offered by robotics technology to model and control humanlike movements, we demonstrated not only that experimental manipulation of the identified cues directly affects perceptions of trustworthiness and subsequent exchange behavior, but also that the human mind will utilize such cues to ascribe social intentions to technological entities.

The Clonal Relationship Between the Ductal and Lobular Components of Mixed Ductal-Lobular Carcinomas Suggested a Ductal Origin in Most Tumors.

The relationship between the ductal and lobular components of invasive ductolobular carcinomas (IDLC) has not been fully elucidated. In this study, the molecular alterations of both components were analyzed in a series of 20 IDLC that were selected, not only by morphologic criteria, but also by the loss of E-cadherin expression in the lobular component. We found that 80% of tumors shared alterations of driver genes in both components, being PIK3CA the most common alteration. In addition, 45% of IDLC carried CDH1 mutations in their lobular component that were absent in the ductal component. Fluorescent in situ hybridization analysis of the CDH1 gene excluded homozygous CDH1 loss as a frequent cause of E-cadherin loss in tumors without CDH1 mutations. In addition, no pathogenic mutations of catenin genes were detected in this series of tumors. In 25% of tumors, actionable mutations in PIK3CA , AKT1 , and ERBB2 were found in only 1 component. Altogether, our results confirm that most IDLC derive from invasive carcinoma of no special type, in which a population of cells lose E-cadherin and acquire a lobular phenotype. The frequency of CDH1 mutations in IDLC appears to be lower than in conventional invasive lobular carcinomas, suggesting the implication of alternative mechanisms of E-cadherin loss. Moreover, molecular heterogeneity between ductal and lobular areas suggests the need for molecular characterization of both components to guide targeted therapies.

Differences in the Molecular Profile between Primary Breast Carcinomas and Their Cutaneous Metastases.

BACKGROUND: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished. METHODS: To investigate the molecular alterations of BC and their CM, a total of 66 samples (33 BC and 33 CM) from 33 patients were analyzed by immunohistochemical and massive parallel sequencing analyses. In addition, the clinicopathological characteristics of patients and tumors were analyzed. RESULTS: Triple negative (TN) BCs were overrepresented (36.4%) among tumors that developed CM. A change of tumor surrogate molecular type in metastases was found in 15% of patients and 48.5% of the CM presented some additional molecular alteration with respect to the primary tumor, the most frequent were amplification of MYC and MDM4, and mutations in TP53 and PIK3CA. Survival was related to histological grade, tumor surrogate molecular type and TP53 mutations in the univariate analysis but only the tumor surrogate molecular type remained as a prognostic factor in the multivariate analysis. CONCLUSIONS: The TN molecular type has a greater risk of developing skin metastases. There are phenotypic changes and additional molecular alterations in skin metastases compared to the corresponding primary breast tumors in nearly half of the patients. Although these changes do not follow a specific pattern and varied from patient to patient, they could impact on the treatment. More studies with larger patient and sample cohorts are needed.

Progression to lung fibrosis in severe COVID-19 patients: A morphological and transcriptomic study in postmortem samples.

The development of lung fibrosis is a major concern in patients recovered from severe COVID-19 pneumonia. This study aimed to document the evolution of diffuse alveolar damage (DAD) to the fibrosing pattern and define the transcriptional programs involved. Morphological, immunohistochemical and transcriptional analysis were performed in lung samples obtained from autopsy of 33 severe COVID-19 patients (median illness duration: 36 days). Normal lung and idiopathic pulmonary fibrosis (IPF) were used for comparison. Twenty-seven patients with DAD and disease evolution of more than 2 weeks had fibrosis. Pathways and genes related with collagen biosynthesis and extracellular matrix (ECM) biosynthesis and degradation, myofibroblastic differentiation and epithelial to mesenchymal transition (EMT) were overexpressed in COVID-19. This pattern had similarities with that observed in IPF. By immunohistochemistry, pathological fibroblasts (pFBs), with CTHRC1 and SPARC expression, increased in areas of proliferative DAD and decreased in areas of mature fibrosis. Immunohistochemical analysis demonstrated constitutive expression of cadherin-11 in normal epithelial cells and a similar pattern of cadherin and catenin expression in epithelial cells from both normal and COVID-19 samples. Transcriptomic analysis revealed downregulation of the Hippo pathway, concordant with the observation of YAP overexpression in hyperplastic alveolar epithelial cells. Progression to fibrosis in severe COVID-19 is associated with overexpression of fibrogenic pathways and increased in CTHRC1- and SPARC-positive pFBs. Whereas the Hippo pathway seemed to be implicated in the response to epithelial cell damage, EMT was not a major process implicated in COVID-19 mediated lung fibrosis.

Neuropathological findings in fatal COVID-19 and their associated neurological clinical manifestations.

Severe cases of Coronavirus Disease 2019 (COVID-19) can present with multiple neurological symptoms. The available neuropathological studies have described different lesions; the most frequent was the presence of neuroinflammation and vascular-related lesions. The objective of this study was to report the neuropathological studies performed in a medical institution, with abundant long intensive care unit stays, and their associated clinical manifestations. This is a retrospective monocentric case series study based on the neuropathological reports of 13 autopsies with a wide range of illness duration (13-108 days). A neuroinflammatory score was calculated based on the quantification of CD8- and CD68-positive cells in representative areas of the central nervous system. This score was correlated afterwards with illness duration and parameters related to systemic inflammation. Widespread microglial and cytotoxic T-cell activation was found in all patients. There was no correlation between the neuroinflammatory score and the duration of the illness; nor with parameters of systemic inflammation such as the peak of IL-6 or the HScore (a parameter of systemic macrophage activation syndrome). Two patients had global hypoxic ischaemic damage and five patients had subacute infarcts. One patient had many more brain vascular microthrombi compared to the others and multiple subacute pituitary infarcts. SARS-CoV-2 RNA was not detected with qRT-PCR. The proportion of brain lesions in severe COVID-19 patients could be related to illness duration. In our series, with abundant long hospitalisation stays, neuroinflammation was present in all patients and was more prominent between day 34 and day 45 after onset of symptoms. Clinical correlation showed that two patients with the highest neuroinflammatory scores had severe encephalopathies that were not attributable to any other cause. The second most frequent lesions were related to vascular pathology.

RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies.

The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9-108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of <2 weeks, but in none of the 23 adult patients with an illness duration of >2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease.

Dirty liberals! Reminders of physical cleanliness influence moral and political attitudes.

Many moral codes place a special emphasis on bodily purity, and manipulations that directly target bodily purity have been shown to influence a variety of moral judgments. Across two studies, we demonstrated that reminders of physical purity influence specific moral judgments regarding behaviors in the sexual domain as well as broad political attitudes. In Study 1, individuals in a public setting who were given a reminder of physical cleansing reported being more politically conservative than did individuals who were not given such a reminder. In Study 2, individuals reminded of physical cleansing in the laboratory demonstrated harsher moral judgments toward violations of sexual purity and were more likely to report being politically conservative than control participants. Together, these experiments provide further evidence of a deep link between physical purity and moral judgment, and they offer preliminary evidence that manipulations of physical purity can influence general (and putatively stable) political attitudes.

How Informational Constraints for Decision-Making on Passing, Dribbling and Shooting Change With the Manipulation of Small-Sided Games Changes in Futsal.

In this study, we explored how manipulating floaters' positions in small-sided futsal games (SSGs) promote changes in the informational constraints that support decision-making (DM) for passing, dribbling and shooting tactics. We made changes in four experimental 3 vs 3 small-sided game conditions with 30 male futsal players (U19 age category): (a) Floaters Off (FO), (b) Final Line Floaters (FLF), (c) Lateral Floaters own field sideline (LFofsl) and (d) Lateral Floaters full field sideline (LFffsl). We assessed players' activity with WIMU PRO™ software during the SSGs, using the Game Performance Evaluation Tool (GPET) to analyze a total of 1,635 decisions. DM for dribbling was generally based on the interpersonal distance between the ball carrier and direct opponent, considering the defensive team length and the offensive team area. Shooting decisions were constrained, by certain attacking-defending teams' spatial-temporal relations with regard to playing space and team balance as affected by manipulating floaters' positions. The coaches' decisions to change the floaters' positions during SSGs may change informational variables sustaining the dribbling decision, but no changes in SSG variables affected passing DM.

How the Number of Players and Floaters' Positioning Changes the Offensive Performance during Futsal Small-Sided and Conditioned Games.

This study aims to analyse the effects of floater positioning within futsal Gk + 3vs3 + Gk and Gk + 2vs2 + Gk small-sided and conditioned games (SSCG) on youth offensive performance on an action per minute per player basis. Three experimental conditions were carried out through the manipulation of floater positioning: floaters off (FO), final line floaters (FLF) and lateral floaters (LF). Thirty male futsal players (U19 age category) participated in the study and played once within each situation in a random order on different days. Offensive performance based on "action per minute per player" was analysed through indirect and external systematic observation. Results showed significant differences between both SSCGs (2vs2 and 3vs3). Specifically, according to the game principles analysed, 3vs3 is associated with higher values of passing and dribbling action to progress towards the goal without beating a defensive line (moderate to large effect size), while 2vs2 is associated with higher values of passing and dribbling actions that beating a defensive line (moderate to very large effect size). In addition, 2vs2 is associated with dribbling and shooting actions to shoot at goal with the lowest level of opposition (moderate effect size). Indeed, whilst the 2vs2 game format seems to promote more 1vs1 situations, the 3vs3 game format encourages more ball possession and collective tactical behaviours. Thus, training tasks intended to improve dribbling and shooting actions should use a smaller number of players whereas tasks intended to improve passing actions for ball possession should include a higher number of players with or without floaters. It seems that the number of players can influence the tactical behaviour of the team. These findings should be considered for the design of futsal training tasks, according to the main objective of the training session. For example, if the coach aims to promote the number of dribbles and shots within a SSCG, 2vs2 SSCG situations should be prioritised.