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Abstract 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.

PurposeThis study evaluates the association between habitual physical activity (HPA) and the outcomes of patients with myocardial infarction (MI).MethodsPatients 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.ResultsAmong 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

IntroductionHuman 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.MethodsIn 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).ResultsThe 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.ConclusionThis research points to the importance to consider emotive markers in the emotional context that they occur in.

Abstract 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.

Abstract 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.

Abstract 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.

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.

Abstract Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.

BackgroundThis 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.MethodsDOX-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.ResultsPaeonol 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.ConclusionPaeonol shows a cardioprotective effect on DOX-induced CHF via regulating the miR-21-5p/SKP2 axis.

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.

SARS-CoV-2 mainly transmits via respiratory droplets. Here Deng et al. show that SARS-CoV-2 can infect rhesus macaques via ocular conjunctival inoculation.

Abstract Background Since December 2019, an outbreak of the Corona Virus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) in Wuhan, China, has become a public health emergency of international concern. The high fatality of aged cases caused by SARS‐CoV‐2 was a need to explore the possible age‐related phenomena with non‐human primate models. Methods Three 3‐5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS‐CoV‐2, and then analyzed by clinical signs, viral replication, chest X‐ray, histopathological changes and immune response. Results Viral replication of nasopharyngeal swabs, anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS‐CoV‐2 challenge. Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema, notably, old monkeys exhibited diffuse severe interstitial pneumonia. Viral antigens were detected mainly in alveolar epithelial cells and macrophages. Conclusion SARS‐CoV‐2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys. Rhesus macaque models infected with SARS‐CoV‐2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS‐CoV‐2 infection.

Logical connectives in natural language pose challenges to truth-conditional semantics due to pragmatics and gradience in their meaning. This paper reports on a case study of the conditional connectives (CCs) wenn/falls ‘if/when, if/in case’ in German. Using distributional evidence, I argue that wenn and falls differ in lexical pragmatics: They express different degrees of speaker commitment (i.e., credence) toward the modified antecedent proposition at the non-at-issue dimension. This contrast can be modeled using the speaker commitment scale (Giannakidou and Mari, 2016), i.e., More committedLess committed. Four experiments are reported which tested the wenn/falls contrast, as well as the summary of an additional one from Liu (2019). Experiment 1 tested the naturalness of sentences containing the CCs (wenn or falls) and conditional antecedents with varying degrees of likelihood (very likely/likely/unlikely). The starting prediction was that falls might be degraded in combination with very likely and likely events in comparison to the other conditions, which was not borne out. Experiment 2 used the forced lexical choice paradigm, testing the choice between wenn and falls in the doxastic agent’s conditional thought, depending on their belief or disbelief in the antecedent. The finding was that subjects chose falls significantly more often than wenn in the disbelief-context, and vice versa in the belief-context. Experiment 3 tested the naturalness of sentences with CCs and an additional relative clause conveying the speaker’s belief or disbelief in the antecedent. An interaction was found: While in the belief-context, wenn was rated more natural than falls, the reverse pattern was found in the disbelief-context. While the results are mixed, the combination of the findings in Experiment 2, Experiment 3 and that of Experiment 4a from Liu (2019) that falls led to lower speaker commitment ratings than wenn, provide evidence for the CC scale. Experiment 4b tested the interaction between two speaker commitment scales, namely, one of connectives (including weil ‘because’ and wenn/falls) and the other of adverbs (factive vs. non-factive, Liu, 2012). While factive and non-factive adverbs were rated equally natural for the factive causal connective, non-factive adverbs were preferred over factive ones by both CCs, with no difference between wenn and falls. This is discussed together with the result in Liu (2019), where the wenn/falls difference occurred in the absence of negative polarity items (NPIs), but disappeared in the presence of NPIs. This raises further questions on how different speaker commitment scales interact and why.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread across the world and impacted global healthcare systems. For clinical patients, COVID-19 not only induces pulmonary lesions but also affects extrapulmonary organs. An ideal animal model that mimics COVID-19 in humans in terms of the induced systematic lesions is urgently needed. Here, we report that Syrian hamster is highly permissive to SARS-CoV-2 and exhibit diffuse alveolar damage and induced extrapulmonary multi-organs damage, including spleen, lymph nodes, different segments of alimentary tract, kidney, adrenal gland, ovary, vesicular gland and prostate damage, at 3–7 days post inoculation (dpi), based on qRT-PCR, in situ hybridization and immunohistochemistry detection. Notably, the adrenal gland is a novel target organ, with abundant viral RNA and antigen expression detected, accompanied by focal to diffuse inflammation. Additionally, viral RNA was also detected in the corpus luteum of the ovary, vesicular gland and prostate. Focal lesions in liver, gallbladder, myocardium, and lymph nodes were still present at 18 dpi, suggesting potential damage after disease. Our findings illustrate systemic histological observations and the viral RNA and antigen distribution in infected hamsters during disease and convalescence to recapitulate those observed in humans with COVID-19, providing helpful data to the pathophysiologic characterization of SARS-CoV-2-induced systemic disease and the development of effective treatment strategies.

Viral pneumonitis caused by influenza A (H1N1) virus leads to high levels of morbidity and mortality. Given the limited treatment options for severe influenza pneumonia, it is necessary to explore effective amelioration approaches. Interleukin-37 (IL-37) has been reported to inhibit excessive immune responses and protect against a variety of inflammatory diseases. In this study, by using BALB/c mice intranasally infected with A/California/07/2009 (H1N1), we found that IL-37 treatment increases the survival rate and body weight, and reduces the pulmonary index, impaired the lung injury and decreased production of pro-inflammatory cytokines in the BALF and lung tissue. Moreover, IL-37 administration enhanced not only the percentage of macrophages, but also the percentage of IL-18Rα+ macrophages, suggesting that enhancing the macrophages function may improve outcomes in a murine model of H1N1 infection. Indeed, macrophages depletion reduced the protective effect of IL-37 during H1N1 infection. Furthermore, IL-37 administration inhibited MAPK signaling in RAW264.7 cells infected with H1N1. This study demonstrates that IL-37 treatment can ameliorate influenza pneumonia by attenuating cytokine production, especially by macrophages. Thus, IL-37 might serve as a promising new target for the treatment of influenza A-induced pneumonia.

One unresolved question about polarity sensitivity in theoretical linguistics concerns whether and to what extent negative and positive polarity items are parallel. Using event-related brain potentials (ERPs), previous studies found N400 and/or P600 components for negative and positive polarity violations with inconsistent results. We report on an ERP study of German polarity items. Both negative and positive polarity violations elicited biphasic N400/P600 effects relative to correct polarity conditions. Furthermore, negative polarity violations elicited a P600-only effect relative to positive polarity violations. The lack of a graded N400 effect indicates that both kinds of violations involve similar semantic processing costs. We attribute the increase in P600 amplitude of negative polarity violations relative to positive polarity violations to their different nature: the former are syntactic anomalies triggering structural reanalysis, whereas the latter are pragmatic oddities inducing discourse reanalysis. We conclude that negative and positive polarity violations involve at least partly distinct mechanisms.

Disordered calcium homeostasis can lead to endoplasmic reticulum (ER) stress. Our previous data showed that time course activation of ER stress contributes to time-related increase in ischemia-reperfusion (I/R) injury. However, it has not been tested whether PI3K/Akt and JAK2/STAT3 pathways play differential roles in reducing ER stress to protect the heart. In the present study, using fasudil which is a specific inhibitor of ROCK, we aimed to investigate whether improved SERCA expression and activity accounts for reduced ER stress by ROCK inhibition, specifically whether PI3K/Akt and JAK2/STAT3 pathways are differentially involved in modulating SERCA activity to reduce ER stress and hence I/R injury. The results showed that during the reperfusion period following 45 min of coronary ligation the infarct size (IS) increased from 3 h of reperfusion (45.4±5.57%) to 24 h reperfusion (64.21±5.43, P

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 andmodeling 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 ofmultiple complementarymethods andmeasures 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]