IL-37 possesses both anti-inflammatory and antiviral effects against Middle East respiratory syndrome coronavirus infection.

BACKGROUND: The aim was to elucidate the function of IL-37 in middle east respiratory syndrome coronavirus (MERS-CoV) infection, thereby providing a novel therapeutic strategy for managing the clinical treatment of inflammatory response caused by respiratory virus infection. METHODS: We investigated the development of MERS by infecting hDPP4 mice with hCoV-EMC (107 TCID50 [50% tissue culture infectious dose]) intranasally. We infected A549 cells with MERS-CoV, which concurrently interfered with IL-37, detecting the viral titer, viral load, and cytokine expression at certain points postinfection. Meanwhile, we administered IL-37 (12.5 µg/kg) intravenously to hDPP4 mice 2 h after MERS-CoV-2 infection and collected the serum and lungs 5 days after infection to investigate the efficacy of IL-37 in MERS-CoV infection. RESULTS: The viral titer of MERS-CoV-infected A549 cells interfering with IL-37 was significantly reduced by 4.7-fold, and the viral load of MERS-CoV-infected hDPP4 mice was decreased by 59-fold in lung tissue. Furthermore, the administration of IL-37 suppressed inflammatory cytokine and chemokine (monocyte chemoattractant protein 1, interferon-γ, and IL-17A) expression and ameliorated the infiltration of inflammatory cells in hDPP4 mice. CONCLUSION: IL-37 exhibits protective properties in severe pneumonia induced by MERS-CoV infection. This effect is achieved through attenuation of lung viral load, suppression of inflammatory cytokine secretion, reduction in inflammatory cell infiltration, and mitigation of pulmonary injury.

Target organ damage in untreated hypertensive patients with primary aldosteronism.

An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong-Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima-media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

Glycated Hemoglobin Variability Is Associated With Adverse Outcomes in Patients With Heart Failure Irrespective of Diabetic Status.

BACKGROUND: The effect of glycated hemoglobin (HbA1c) variability on adverse outcomes in patients with heart failure (HF) is unclear. We aim to investigate the predictive value of HbA1c variability on the risks of all-cause death and HF rehospitalization in patients with HF irrespective of their diabetic status. METHODS AND RESULTS: Using a previously validated territory-wide clinical data registry, HbA1c variability was assessed by average successive variability (ASV) or SD of all HbA1c measurements after HF diagnosis. Multivariable Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and its corresponding 95% CI. A total of 65 950 patients with HF were included in the study. Over a median follow-up of 6.7 (interquartile range, 4.0-10.6) years, 34 508 patients died and 52 446 required HF rehospitalization. Every unit increment of variability in HbA1c was significantly associated with higher HF rehospitalization (HR ASV, 1.20 [95% CI, 1.18-1.23]) and all-cause death (HR ASV, 1.50 [95% CI, 1.47-1.53]). Diabetes significantly modified the association between HbA1c variability and outcomes (Pinteraction<0.001). HbA1c variability in patients with HF without diabetes conferred a higher risk of rehospitalization (HR ASV, 1.92 [95% CI, 1.70-2.17] versus HR ASV, 1.19 [95% CI, 1.17-1.21]), and all-cause death (HR ASV, 3.90 [95% CI, 3.31-4.61] versus HR ASV, 1.47 [95% CI, 1.43-1.50] compared with patients with diabetes). CONCLUSIONS: HbA1c variability is significantly associated with greater risk of rehospitalization and all-cause death in patients with HF, irrespective of their diabetic status. These observations were more pronounced in patients with HF without diabetes.

Elevated ITGA1 levels in type 2 diabetes: implications for cardiac function impairment.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is known to contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, identifying HFpEF in individuals with type 2 diabetes early on is often challenging due to a limited array of biomarkers. This study aims to investigate specific biomarkers associated with the progression of HFpEF in individuals with type 2 diabetes, for the purpose of enabling early detection and more effective management strategies. METHODS: Blood samples were collected from individuals with type 2 diabetes, both with and without HFpEF, for proteomic analysis. Plasma integrin α1 (ITGA1) levels were measured and compared between the two groups. Participants were further categorised based on ITGA1 levels and underwent detailed transthoracic echocardiography at baseline and during a median follow-up period of 30 months. Multivariable linear and Cox regression analyses were conducted separately to assess the associations between plasma ITGA1 levels and changes in echocardiography indicators and re-hospitalisation risk. Additionally, proteomic data for the individuals' left ventricles, from ProteomeXchange database, were analysed to uncover mechanisms underlying the change in ITGA1 levels in HFpEF. RESULTS: Individuals with type 2 diabetes and HFpEF showed significantly higher plasma ITGA1 levels than the individuals with type 2 diabetes without HFpEF. These elevated ITGA1 levels were associated with left ventricular remodelling and impaired diastolic function. Furthermore, during a median follow-up of 30 months, multivariable analysis revealed that elevated ITGA1 levels independently correlated with deterioration of both diastolic and systolic cardiac functions. Additionally, higher baseline plasma ITGA1 levels independently predicted re-hospitalisation risk (HR 2.331 [95% CI 1.387, 3.917], p=0.001). Proteomic analysis of left ventricular myocardial tissue provided insights into the impact of increased ITGA1 levels on cardiac fibrosis-related pathways and the contribution made by these changes to the development and progression of HFpEF. CONCLUSIONS/INTERPRETATION: ITGA1 serves as a biomarker for monitoring cardiac structural and functional damage, can be used to accurately diagnose the presence of HFpEF, and can be used to predict potential deterioration in cardiac structure and function as well as re-hospitalisation for individuals with type 2 diabetes. Its measurement holds promise for facilitating risk stratification and early intervention to mitigate the adverse cardiovascular effects associated with diabetes. DATA AVAILABILITY: The proteomic data of left ventricular myocardial tissue from individuals with type 2 diabetes, encompassing both those with and without HFpEF, is available from the ProteomeXchange database at http://proteomecentral.proteomexchange.org .

Conditionals in context: Brain signatures of prediction in discourse processing.

Comprehenders are known to generate expectations about upcoming linguistic input at the sentence and discourse level. However, most previous studies on prediction focused mainly on word-induced brain activity rather than examining neural activity preceding a critical stimulus in discourse processing, where prediction actually takes place. In this EEG study, participants were presented with multiple sentences resembling a discourse including conditional sentences with either only if or if, which are characterized by different semantics, triggering stronger or weaker predictions about the possible continuation of the presented discourses, respectively. Results revealed that discourses including only if, as compared to discourses with bare if, triggered an increased predictive neural activity before the expected critical word, resembling the readiness potential. Moreover, word-induced P300 brain responses were found to be enhanced by unpredictable discourse continuations and reduced in predictable discourse continuations. Intriguingly, brain responses preceding and following the critical word were found to be correlated, which yields evidence for predictive activity modulating word-induced processing on the discourse level. These findings shed light on the predictive nature of neural processes at the discourse level, critically advancing our understanding of the functional interconnection between discourse understanding and prediction processes in brain and mind.

Statin Therapy Is Associated With a Lower Risk of Heart Failure in Patients With Atrial Fibrillation: A Population-Based Study.

BACKGROUND: Whether statin use can reduce the risk of heart failure (HF) remains controversial. The present study evaluates the association between statin use and HF in patients with atrial fibrillation. METHODS AND RESULTS: Patients with newly diagnosed atrial fibrillation from 2010 to 2018 were included. An inverse probability of treatment weighting was used to balance baseline covariates between statin users (n=23 239) and statin nonusers (n=29 251). The primary outcome was incident HF. Cox proportional hazard models with competing risk regression were used to evaluate the risk of HF between statin users and nonusers. The median age of the cohort was 74.7 years, and 47.3% were women. Over a median follow-up of 5.1 years, incident HF occurred in 3673 (15.8%) statin users and 5595 (19.1%) statin nonusers. Statin use was associated with a 19% lower risk of HF (adjusted subdistribution hazard ratio, 0.81 [95% CI, 0.78-0.85]). Restricted to the statin users, duration of statin use was measured during follow-up; compared with short-term use (3 months to <2 years), there was a stepwise reduction in the risk of incident HF among those with 2 to <4 years of statin use (subdistribution hazard ratio, 0.86 [95% CI, 0.84-0.88]), 4 to <6 years of statin use (subdistribution hazard ratio, 0.74 [95% CI, 0.72-0.76]), and ≥6 years of statin use (subdistribution hazard ratio, 0.71 [95% CI, 0.69-0.74]). Subgroup analysis showed consistent reductions in the risk of HF with statin use. CONCLUSIONS: Statin use was associated with a decreased risk of incident HF in a duration-dependent manner among patients with atrial fibrillation.

Habitual physical activity improves outcomes among patients with myocardial infarction.

Purpose: This study evaluates the association between habitual physical activity (HPA) and the outcomes of patients with myocardial infarction (MI). Methods: Patients newly diagnosed with MI were divided into two groups based on whether they engaged in HPA, defined as an aerobic activity with a duration of no less than 150 min/week, before the index admission. The primary outcomes included major adverse cardiovascular events (MACEs), cardiovascular (CV) mortality, and cardiac readmission rate 1 year following the index date of admission. A binary logistic regression model was applied to analyze whether HPA was independently associated with 1-year MACEs, 1-year CV mortality, and 1-year cardiac readmission rate. Results: Among the 1,266 patients (mean age 63.4 years, 72% male), 571 (45%) engaged in HPA, and 695 (55%) did not engage in HPA before MI. Patients who participated in HPA were independently associated with a lower Killip class upon admission (OR = 0.48: 95% CI, 0.32-0.71, p < 0.001) and a lower prevalence of 1-year MACEs (OR = 0.74: 95% CI, 0.56-0.98, p = 0.038) and 1-year CV mortality (OR = 0.50: 95% CI, 0.28-0.88, p = 0.017) than those who did not participate in HPA. HPA was not associated with cardiac-related readmission (OR = 0.87: 95% CI, 0.64-1.17, p = 0.35). Conclusions: HPA before MI was independently associated with a lower Killip class upon admission, 1-year MACEs, and 1-year CV mortality rate.

Language and face in interactions: emotion perception, social meanings, and communicative intentions.

Introduction: Human emotions can be complex to interpret as they have multiple sources and are often times ambiguous, for example, when the signals sent by different channels of communication are inconsistent. Our study investigates the interaction of linguistic and facial expressions of emotions. Methods: In two experiments, participants read short scenarios in German containing a direct utterance with positive or negative emotive markers, in combination with different facial expressions as still images of the speaker (i.e., the protagonist in the story). They answered questions about their perception regarding the intensity of the emotions (e.g., happiness, sadness), the properties of the expresser (e.g., honesty, warmth, likeability) and their relation to the addressee (e.g., closeness), as well as the expresser intention (e.g., irony, joke). Results: The findings suggest that facial expressions have a more dominant role in the emotion perception in comparison to emotive markers. Furthermore, consistent and inconsistent combinations of emotive markers and facial expressions convey distinct social meanings and communicative intentions. Conclusion: This research points to the importance to consider emotive markers in the emotional context that they occur in.

Comparison of the replication and neutralization of different SARS-CoV-2 Omicron subvariants in vitro.

BACKGROUND: New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5. Their pathogenicity has changed from that of wild-type (WH-09) and Omicron variants have over time become globally dominant. The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants, which is likely to cause immune escape and the reduction of the protective effect of the vaccine. Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies. METHODS: We collected cellular supernatant and cell lysates and measured the viral titers, viral RNA loads, and E subgenomic RNA (E sgRNA) loads in different Omicron subvariants grown in Vero E6 cells, using WH-09 and Delta variants as a reference. Additionally, we evaluated the in vitro neutralizing activity of different Omicron subvariants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity. RESULTS: As the SARS-CoV-2 evolved into Omicron BA.1, the replication ability in vitro began to decrease. Then with the emergence of new subvariants, the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants. In WH-09-inactivated vaccine sera, geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09. In Delta-inactivated vaccine sera, geometric mean titers of neutralization antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta. CONCLUSION: According to the findings of this research, the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants, and was lower in BA.1 than in other Omicron subvariants. After two doses of inactivated (WH-09 or Delta) vaccine, cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.

Prediabetes Is Associated With Increased Risk of Heart Failure Among Patients With Atrial Fibrillation.

OBJECTIVE: To evaluate the association between prediabetes and heart failure (HF) and the association of HF with changes in glycemic status. RESEARCH DESIGN AND METHODS: Patients newly diagnosed with atrial fibrillation (AF) between 2015 and 2018 were divided into three groups (normoglycemia, prediabetes, and type 2 diabetes) according to their baseline glycemic status. The primary outcome was incident HF. The Fine and Gray competing risks model was applied, with death defined as the competing event. RESULTS: Among 17,943 patients with AF (mean age 75.5 years, 47% female), 3,711 (20.7%) had prediabetes, and 10,127 (56.4%) had diabetes at baseline. Over a median follow-up of 4.7 years, HF developed in 518 (14%) patients with normoglycemia, 646 (15.7%) with prediabetes, and 1,795 (17.7%) with diabetes. Prediabetes was associated with an increased risk of HF compared with normoglycemia (subdistribution hazard ratio [SHR] 1.12, 95% CI 1.03-1.22). In patients with prediabetes at baseline, 403 (11.1%) progressed to diabetes, and 311 (8.6%) reversed to normoglycemia at 2 years. Compared with remaining prediabetic, progression to diabetes was associated with an increased risk of HF (SHR 1.50, 95% CI 1.13-1.97), whereas reversion to normoglycemia was associated with a decreased risk (SHR 0.61, 95% CI 0.42-0.94). CONCLUSIONS: Prediabetes was associated with an increased risk of HF in patients with AF. Compared with patients who remained prediabetic, those who progressed to diabetes at 2 years experienced an increased risk of HF, whereas those who reversed to normoglycemia incurred a lower risk of HF.

Cardioprotective Effect of Paeonol on Chronic Heart Failure Induced by Doxorubicin via Regulating the miR-21-5p/S-Phase Kinase-Associated Protein 2 Axis.

Background: This study primarily explored the role of paeonol in doxorubicin (DOX)-induced chronic heart failure (CHF), considering the cardioprotective effect of paeonol on an epirubicin-induced cardiac injury. Methods: DOX-induced CHF-modeled rats were treated with paeonol. Cardiac function and myocardial damage in rats were evaluated by using the multifunction instrument, and the histopathology, apoptosis, and the expression of miR-21-5p and S-phase kinase-associated protein 2 (SKP2) in myocardium were detected. The target gene of miR-21-5p was confirmed by a dual-luciferase reporter assay. After the required transfection or paeonol treatment, the viability, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) of the DOX-induced cardiomyocytes were determined. Reverse-transcription quantitative-PCR (RT-qPCR) and Western blot were performed to quantify the expressions of miR-21-5p, SKP2, and apoptosis-related factors. Results: Paeonol improved cardiac function and also ameliorated the cardiac damage of CHF-modeled rats, where the downregulation of abnormally elevated myocardial damage markers, including brain natriuretic peptide, lactate dehydrogenase, renin, angiotensin II, aldosterone, and endothelin 1, was observed. Paeonol alleviated the histopathological injury and suppressed the apoptosis in CHF-modeled rats, inhibited miR-21-5p expression, and upregulated SKP2 expression in vitro and in vivo. miR-21-5p targeted SKP2. Paeonol and SKP2 increased the viability and MMP, but reduced apoptosis and ROS in the DOX-induced cardiomyocytes. miR-21-5p exerted effects opposite to PAE and SKP2, and it downregulated the expression of Bcl-2 and mitochondrion-Cytochrome c (Cyt c) and upregulated the expression of Bax, C-caspase-3, and cytoplasm-Cyt c. miR-21-5p reversed the effects of paeonol, and its effects were further reversed by SKP2. Conclusion: Paeonol shows a cardioprotective effect on DOX-induced CHF via regulating the miR-21-5p/SKP2 axis.

Processing Attenuating NPIs in Indicative and Counterfactual Conditionals.

Both indicative and counterfactual conditionals are known to be licensing contexts for negative polarity items (NPIs). However, a recent theoretical account suggests that the licensing of attenuating NPIs like English all that in the conditional antecedent is sensitive to pragmatic differences between various types of conditionals. We conducted three behavioral experiments in order to test key predictions made by that proposal. In Experiment 1, we tested hypothetical indicative and counterfactual conditionals with the English NPI all that, finding that the NPI is degraded in the former compared to the latter. In Experiment 2, we compared hypothetical indicative conditionals and premise conditionals with the same NPI, again finding a degradation only for the former. Both results align with theoretically derived predictions purporting that hypothetical indicative conditionals are degraded due to their susceptibility to conditional perfection. Finally, Experiment 3 provides empirical evidence that comprehenders readily strengthen counterfactual conditionals to biconditionals, in line with theoretical analyses that assume that conditional perfection and counterfactual inferences are compatible. Their ability to still host attenuating NPIs in the conditional antecedent, by contrast, falls into place via the antiveridical inference to the falsity of the antecedent. Altogether, our study sheds light on the interplay between NPI licensing and the semantic and pragmatic properties of various types of conditionals. Moreover, it provides a novel perspective on the processing of different kinds of conditionals in context, in particular, with regard to their (non)veridicality properties.

Role of Cardiomyocyte-Derived Exosomal MicroRNA-146a-5p in Macrophage Polarization and Activation.

Myocardial infarction arises from an excessive or prolonged inflammatory response, leading to ventricular remodeling or impaired cardiac function. Macrophages exhibit different polarization types associated with inflammation both at steady state and after myocardial infarction. Exosomal miR-146a-5p has been identified as an important molecule in the cardiovascular field in recent years. However, the effect of cardiomyocyte-derived exosomal miR-146a-5p on macrophages has not yet been elucidated. Initially, we found that exosomes with low expression of miR-146a-5p derived from myocardial infarction tissues modulated macrophage polarization. To determine whether cardiomyocyte-derived exosomal miR-146a-5p mediated macrophage polarization, we treated macrophages with exosomes rich in miR-146a-5p collected from neonatal mouse cardiomyocytes. The effects of exosomal miR-146a-5p on macrophage polarization were measured using RT-qPCR, transwell assays, and western blotting. The results showed that the increased expression of miR-146a-5p promoted M1 macrophage polarization, inhibited M2 macrophage polarization, and increased the expression of VEGFA. However, the decreased expression of exosomalmiR-146a-5p showed the opposite trends. Interestingly, in contrast to treatment with the solitary miR-146a-5p mimic, exosomal miR-146a-5p derived from neonatal mouse cardiomyocytes reduced TNFα and iNOS expression. In addition, when macrophages were activated by the miR-146a-5p mimic or exosomal miR-146a-5p, the expression of TNF receptor-associated factor 6 (TRAF6), a target gene of miR-146a-5p, was reduced significantly. Taken together, these findings indicate that exosomal miR-146a-5p derived from cardiomyocytes could stimulate M1 macrophage polarization to induce an inflammatory reaction, while targeting TRAF6, exerting an anti-inflammatory effect. Exosomal miR-146a-5p plays important roles in macrophages, illuminating a novel potential therapeutic target in myocardial infarction.

Sequential immunizations confer cross-protection against variants of SARS-CoV-2, including Omicron in Rhesus macaques.

Variants of concern (VOCs) like Delta and Omicron, harbor a high number of mutations, which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies (NAbs). In this study, Rhesus macaques immunized with 2-dose inactivated vaccines (Coronavac) were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine, or a bivalent inactivated vaccine (Beta and Delta) to determine the effectiveness of sequential immunization. The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type, Beta, Delta, and Omicron. Animals administered with an indicated booster dose and subsequently challenged with Delta or Omicron variants showed markedly reduced viral loads and improved histopathological profiles compared to control animals, indicating that sequential immunization could protect primates against Omicron. These results suggest that sequential immunization of inactivated vaccines or polyvalent vaccines could be a potentially effective countermeasure against newly emerging variants.

Sequentially immune-induced antibodies could cross-neutralize SARS-CoV-2 variants.

BACKGROUND: The Omicron (B.1.1.529) SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein. Since the vaccine-induced neutralizing antibody targets are the spike protein, this may lead to the possibility of vaccine-induced humoral immunity escape. METHODS: We measured the neutralizing activity in vitro for Omicron and compared this with wild type (WH-09) and Delta variants in human and monkey sera from different types of immunity. The monkey sera samples were collected at 1 and 3 months post three-dose inactivated (PiCoVacc) and recombinant protein (ZF2001) vaccination. Human sera were collected from 1 month post three-dose inactivated vaccination. RESULTS: In inactivated vaccine sera, at 1/3 months post three-dose, geometric mean titers (GMTs) of neutralization antibody (NAb) against the Omicron variant were 4.9/5.2-fold lower than those of the wild type. In recombinant protein vaccine sera, GMTs of NAb against Omicron were 15.7/8.9-fold lower than those of the wild type. In human sera, at 1 month post three-dose inactivated vaccination, GMTs of NAb against Omicron were 3.1-fold lower than those of the wild type. CONCLUSION: This study demonstrated that despite a reduction in neutralization titers, cross-neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.

Integrated histopathological, lipidomic, and metabolomic profiles reveal mink is a useful animal model to mimic the pathogenicity of severe COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.

Antilocality effect without head-final dependencies.

Antilocality effects provide strong evidence for expectation-based sentence parsing models. Previous discussion of the antilocality effect, however, largely focused on the argument-verb dependencies in verb-final constructions, for which a memory retrieval-based account has been argued to be equally adequate. To test whether the principles of expectation/memory-based accounts hold for a wider range of dependencies, we report on two self-paced reading experiments that compared two different determiners in German: the morphologically complex determiner derjenige 'the-jenig,' which obligatorily requires a relative clause, and the bare determiner der 'the,' which does not trigger such expectations. The first experiment did not show the expected antilocality effect, but the reliability of our results was restricted by the experiment's low statistical power. In a large-scale second experiment we addressed confounds in the design of Experiment 1 and found evidence for an antilocality effect with the complex determiner. As the antilocality effect found in our study does not involve argument-verb dependencies, the memory-based account cannot be extended to the current case. Thus, our findings provide novel empirical support for the expectation-based antilocality effect. At the same time, the experiment attests to a processing cost in later sentence regions, hinting that memory- and expectation-based effects can co-occur within the same structure. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods.

In the present review paper by members of the collaborative research center "Register: Language Users' Knowledge of Situational-Functional Variation" (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define "register" as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of "register", by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.

Body volume is the major determinant of worsening renal function in acutely decompensated heart failure with reduced left ventricular ejection fraction.

AIMS: Little is known about the relative importance of body volume and haemodynamic parameters in the development of worsening of renal function in acutely decompensated heart failure (ADHF). To study the relationship between haemodynamic parameters, body water content and worsening of renal function in patients with heart failure with reduced ejection fraction (HFrEF) hospitalised for ADHF. METHODS AND RESULTS: This prospective observational study involved 51 consecutive patients with HFrEF (age: 73±14 years, male: 60%, left ventricular ejection fraction: 33.3%±9.9%) hospitalised for ADHF. Echocardiographic-determined haemodynamic parameters and body volume determined using a bioelectric impedance analyser were serially obtained. All patients received intravenous furosemide 160 mg/day for 3 days. There was a mean weight loss of 3.95±2.82 kg (p<0.01), and brain natriuretic peptide (BNP) reduced from 1380±901 pg/mL to 797±738 pg/mL (p<0.01). Nonetheless serum creatinine (SCr) increased from 134±46 µmol/L to 151±53 µmol/L (p<0.01), and 35% of patients developed worsening of renal function. The change in SCr was positively correlated with age (r=0.34, p=0.017); and negatively with the ratio of extracellular water to total body water, a parameter of body volume status (r=-0.58, p<0.001); E:E' ratio (r=-0.36, p=0.01); right ventricular systolic pressure (r=-0.40, p=0.009); and BNP (r=-0.40, p=0.004). Counterintuitively, no correlation was observed between SCr and cardiac output, or total peripheral vascular resistance. Regression analysis revealed that normal body volume and lower BNP independently predicted worsening of renal function. CONCLUSIONS: Normal body volume and lower serum BNP on admission were associated with worsening of renal function in patients with HFrEF hospitalised for ADHF.