Miracle-dz/UniFAR-FTUs huggingface dataset:
Study of Hepatitis E Virus-4 Infection in Human Liver-Chimeric, Immunodeficient, and Immunocompetent Mice

The hepatitis E virus (HEV) is responsible for 20 million infections worldwide per year. Although, HEV infection is mostly self-limiting, immunocompromised individuals may evolve toward chronicity. The lack of an efficient small animal model has hampered the study of HEV and the discovery of anti-HEV therapies. Furthermore, new HEV strains, infectious to humans, are being discovered. Human liver-chimeric mice have greatly aided in the understanding of HEV, but only two genotypes (HEV-1 and HEV-3) have been studied in this model. Moreover, the immunodeficient nature of this mouse model does not allow full investigation of the virus and all aspects of its interaction with the host. Recent studies have shown the susceptibility of regular and nude Balb/c mice to a HEV-4 strain (KM01). This model should allow the investigation of the interplay between HEV and the adaptive immune system of its host, and potential immune-mediated complications. Here, we assess the susceptibility of human liver-chimeric and non-humanised mice to a different HEV-4 strain (BeSW67HEV4-2008). We report that humanised mice could be readily infected with this isolate, resulting in an infection pattern comparable to HEV-3 infection. Despite these results and in contrast to KM01, non-humanised mice were not susceptible to infection with this viral strain. Further investigation, using other HEV-4 isolates, is needed to conclusively determine HEV-4 tropism and mouse susceptibility.
Non-Canonical Amino Acid-Based Engineering of (R)-Amine Transaminase

Non-canonical amino acids (ncAAs) have been utilized as an invaluable tool for modulating the active site of the enzymes, probing the complex enzyme mechanisms, improving catalytic activity, and designing new to nature enzymes. Here, we report site-specific incorporation of p-benzoyl phenylalanine (pBpA) to engineer (R)-amine transaminase previously created from d-amino acid aminotransferase scaffold. Replacement of the single Phe88 residue at the active site with pBpA exhibits a significant 15-fold and 8-fold enhancement in activity for 1-phenylpropan-1-amine and benzaldehyde, respectively. Reshaping of the enzyme’s active site afforded an another variant F86A/F88pBpA, with 30% higher thermostability at 55°C without affecting parent enzyme activity. Moreover, various racemic amines were successfully resolved by transaminase variants into (S)-amines with excellent conversions (∼50%) and enantiomeric excess (>99%) using pyruvate as an amino acceptor. Additionally, kinetic resolution of the 1-phenylpropan-1-amine was performed using benzaldehyde as an amino acceptor, which is cheaper than pyruvate. Our results highlight the utility of ncAAs for designing enzymes with enhanced functionality beyond the limit of 20 canonical amino acids.
Vaccine Type-, Age- and Past Infection-Dependence of the Humoral Response to SARS-CoV-2 Spike S Protein

The emergence of COVID-19 has led to a worldwide challenge for the rapid development of vaccines. Several types of safe and effective vaccines have been available in a time frame never seen before. Now that several hundred million people have been vaccinated there is an opportunity to compare vaccines in terms of protection and immune response. Here, we have applied a highly sensitive multiplexed flow cytometry method to measure simultaneously IgM, IgG1 and IgA anti-spike protein antibodies generated in response to three vaccines: ChAdOx1 (Oxford-AstraZeneca), mRNA-1273 (Moderna), and BNT162b2 (Pfizer-BioNTech). We have found that mRNA vaccines (mRNA-1273 and BNT162b2) induce a stronger humoral response, both after the first and the second dose, than the adenovirus-based ChAdOx1 vaccine. We also found that, in the elderly, antibody titers negatively correlate with the age of the donor but, also, that antibody titers remain stable for at least 6 months after complete vaccination. Finally, we found that one dose of BNT162b2 is sufficient to induce the highest antibody titers in seropositive pre-vaccination donors. We hope these data will help to guide future decisions on vaccination strategies.
Study Protocol for a Randomized Controlled Trial Assessing the Effectiveness of Personalized Computerized Cognitive Training for Individuals With Insomnia

Insomnia is a frequent and heightened pathology in the general population of developed countries, and its condition generally leads to health discomfort and performance drop in daily and work-related tasks. As current pharmacological treatments for insomnia do not always seem sufficient to mitigate impairment, contemporary cognitive approaches might shed light on developing complementary therapies for this population. We propose a cognitive stimulation intervention program based on the importance of cognitive abilities as precipitating and maintenance variables of sleep disturbances. A full phase I-II-III clinical trial is proposed in which the first two studies will serve to assess the safety of the intervention and to identify the maximum tolerated time of the computerized cognitive training (phase I) and the minimum effective number of training sessions (phase II) in the absence of adverse events or side effects. Next, a phase-III double-blind randomized controlled trial design will be set. Sixty individuals with insomnia aged 25 to 55 years will enroll in a home-based personalized computerized cognitive stimulation program for a total time of 8 weeks, training 5 days per week. Sixty insomnia patients matched in a variety of factors will constitute the active control group, where the orthogonal activities will not be cognitively demanding. Sleep, cognitive, emotional, and quality of life variables will be measured before and immediately after training. A linear mixed model and hierarchical regression analysis will be used to investigate intervention effects. The results derived from this study will be precious for future research and treatment in cognitive performance and clinical pathologies. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT05050292].
Bullous Pemphigoid Associated With COVID-19 Vaccines: An Italian Multicentre Study

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by circulating autoantibodies toward the hemidesmosomal antigens BP180 and BP230. Cases of BP have been described following vaccinations against tetanus, poliomyelitis, diphtheria, influenza, pneumococcus, meningococcus, hepatitis B and rabies. The putative mechanism by which COVID-19-vaccines may induce BP has not been clarified. An Italian multicentre study was conducted to collect clinical, histopathological and immunopathological data of patients with BP associated with COVID-19-vaccines. Twenty-one cases were collected, including 9 females and 12 males (M/F = 1.3) with a median age at diagnosis of 82 years. Seventeen patients received the COMIRNATY Pfizer-BioNTech vaccine, two the Moderna mRNA-1273 vaccine, one the ChAdOx1/nCoV-19-AstraZeneca/ Vaxzevria vaccine and one received the first dose with the ChAdOx1/nCoV-19-AstraZeneca/Vaxzevria vaccine and the second dose with the COMIRNATY Pfizer-BioNTech vaccine. Median latency time between the first dose of anti-SARS-CoV-2 vaccine and the onset of cutaneous manifestations was 27 days. Median BPDAI at onset was 42. Eleven out of seventeen patients (65%) had positive titres for anti-BP180 antibodies with a median value of 106.3 U/mL on ELISA; in contrast, only five out of seventeen (29%) were positive for anti-BP230 antibodies, with a median of 35.3 U/mL. In conclusion, in terms of mean age, disease severity at diagnosis and clinical phenotype vaccine-associated BP patients seem to be similar to idiopathic BP with an overall benign course with appropriate treatment. On the other hand, the slight male predominance and the reduced humoral response to BP230 represent peculiar features of this subset of patients.
Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

A ubiquitously expressed cytokine, transforming growth factor-beta (TGF-β) plays a significant role in various ongoing cellular mechanisms. The gain or loss-of-function of TGF-β and its downstream mediators could lead to a plethora of diseases includes tumorigenesis. Specifically, at the early onset of malignancy TGF-β act as tumour suppressor and plays a key role in clearing malignant cells by reducing the cellular proliferation and differentiation thus triggers the process of apoptosis. Subsequently, TGF-β at an advanced stage of malignancy promotes tumorigenesis by augmenting cellular transformation, epithelial-mesenchymal-transition invasion, and metastasis. Besides playing the dual roles, depending upon the stage of malignancy, TGF-β also regulates cell fate through immune and stroma components. This oscillatory role of TGF-β to fight against cancer or act as a traitor to collaborate and crosstalk with other tumorigenic signaling pathways and its betrayal within the cell depends upon the cellular context. Therefore, the current review highlights and understands the dual role of TGF-β under different cellular conditions and its crosstalk with other signaling pathways in modulating cell fate.
Swipes and Saves: A Taxonomy of Factors Influencing Aesthetic Assessments and Perceived Beauty of Mobile Phone Photographs

Digital images taken by mobile phones are the most frequent class of images created today. Due to their omnipresence and the many ways they are encountered, they require a specific focus in research. However, to date, there is no systematic compilation of the various factors that may determine our evaluations of such images, and thus no explanation of how users select and identify relatively “better” or “worse” photos. Here, we propose a theoretical taxonomy of factors influencing the aesthetic appeal of mobile phone photographs. Beyond addressing relatively basic/universal image characteristics, perhaps more related to fast (bottom-up) perceptual processing of an image, we also consider factors involved in the slower (top-down) re-appraisal or deepened aesthetic appreciation of an image. We span this taxonomy across specific types of picture genres commonly taken—portraits of other people, selfies, scenes and food. We also discuss the variety of goals, uses, and contextual aspects of users of mobile phone photography. As a working hypothesis, we propose that two main decisions are often made with mobile phone photographs: (1) Users assess images at a first glance—by swiping through a stack of images—focusing on visual aspects that might be decisive to classify them from “low quality” (too dark, out of focus) to “acceptable” to, in rare cases, “an exceptionally beautiful picture. ” (2) Users make more deliberate decisions regarding one’s “favorite” picture or the desire to preserve or share a picture with others, which are presumably tied to aspects such as content, framing, but also culture or personality, which have largely been overlooked in empirical research on perception of photographs. In sum, the present review provides an overview of current focal areas and gaps in research and offers a working foundation for upcoming research on the perception of mobile phone photographs as well as future developments in the fields of image recording and sharing technology.
Sleep Quality, Sleep Duration, and the Risk of Adverse Clinical Outcomes in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries

Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with varying underlying etiologies and occurs in ~5–10% of patients with acute myocardial infarction. Sleep disorders and short sleep duration are common phenomena experienced by patients with coronary heart disease and are associated with poor clinical outcomes. However, the association between sleep quality, sleep duration, and the MINOCA prognosis is less clear. Methods We performed a prospective observational study of 607 patients with MINOCA between February 2016 and June 2018. The mean follow-up period was 3.9 years. Sleep quality and sleep duration were measured by the Chinese version of the Pittsburgh Sleep Quality Index. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and heart failure hospitalization. Results During the follow-up period, all-cause death occurred in 69 participants and 105 participants developed MACE. The Kaplan–Meier survival analysis demonstrated a significant association between poor sleep quality and all-cause mortality (log-rank P = 0.005) and MACE (log-rank P = 0.004). Multivariable Cox regression model indicated that poor sleep quality was an independent predictor of all-cause mortality as well as MACE [adjusted hazard ratio (HR) = 1.649; 95% confidence interval (CI), 1.124–2.790; P < 0.001; and adjusted HR = 1.432; 95% CI, 1.043–2.004; P = 0.003, respectively]. For sleep duration, short sleep duration (<6 h/d) was significantly associated with an increased risk of all-cause mortality and MACE (adjusted HR = 1.326; 95% CI, 1.103–1.812; P = 0.004; and adjusted HR = 1.443; 95% CI, 1.145–1.877; P < 0.001, respectively), whereas long sleep duration was not (>8 h/d). A poorer sleep profile (including poor sleep quality and short sleep duration) was associated with a 149.4% increased risk of death (HR = 2.494; 95% CI, 1.754–4.562; P < 0.001) and a 96.7% increased risk of MACE (HR = 1.967; 95% CI, 1.442–3.639; P < 0.001) than those with neither. Conclusion Sleep disorders were common among Chinese patients with MINOCA. Poor sleep quality and short sleep duration were independently associated with an increased risk of all-cause mortality and MACE in the MINOCA population. Meanwhile, a poor sleep profile has an additive effect with regard to cardiovascular risks; in these populations, efforts should be made to improve both sleep quality and sleep duration for secondary cardiovascular prevention. Clinical Trial Registration http://www.chictr. org.cn, identifier: ChiCTR2000040701.
The Affective Neuroscience of Sexuality: Development of a LUST Scale

Background In recent years, there have been many studies using the Affective Neuroscience Personality Scales (ANPS) to investigate individual differences in primary emotion traits. However, in contrast to other primary emotion traits proposed by Jaak Panksepp and colleagues, there is a considerable lack of research on the LUST (L) dimension – defined as an individual’s capacity to attain sexual desire and satisfaction – a circumstance mainly caused by its exclusion from the ANPS. Therefore, this study aims to take a first step toward the development of a standardized self-rate measurement for the L-disposition. For this purpose, two versions of the L-scales (L-12 and L-5) were developed and evaluated regarding reliability and aspects of validity. Materials and Methods After a pilot study (N = 204; female: 81%) with an initial 20-item pool item reductions were conducted. This led to the construction of a 12-item (L-12) version and a 5-item version (L-5), which were assessed in a second sample consisting of 371 German-speaking healthy adults (58.50% female) aged 18–69 years (M = 28; SD = 9.75). Aspects of external validity were assessed by investigation of correlations with the ANPS, psychiatric symptoms (Brief Symptom Inventory-18), attachment security (Adult Attachment Scales) and personality functioning (Operationalized Psychodynamic Diagnostics Structure Questionnaire). To evaluate structural validity, both L-scales were investigated via confirmatory factor analysis (CFA). Results Cronbach’s α indicated excellent internal consistency regarding L-12 (α = 0.90), while L-5 showed acceptable reliability (α = 0.82). CFA of a bifactor model of the L-12 indicated excellent model fit. Moreover, an excellent model fit was observed regarding a single factor model of L-5. For both scales small to moderate positive correlations were observed with SEEKING, PLAY, and secure attachment, while they exhibited small to moderate negative correlations with SADNESS, insecure attachment, lower personality functioning, and increased psychiatric symptom load. Conclusion Both newly developed scales exhibit satisfying psychometric properties, indicating high reliability, good structural validity and plausible correlations with external criteria. Hence, this study poses an important step toward the operationalization of the LUST concept. However, more research is needed in particular with respect to the scale’s external validity and its applicability in clinical populations.
Differential Role of Sex and Age in the Synaptic Transmission of Degus (Octodon degus)

Octodon degus are a diurnal long-lived social animal widely used to perform longitudinal studies and complex cognitive tasks to test for physiological conditions with similitude in human behavior. They show a complex social organization feasible to be studied under different conditions and ages. Several aspects in degus physiology demonstrated that these animals are susceptible to environmental conditions, such as stress, fear, feeding quality, and isolation. However, the relevance of these factors in life of this animal depends on sex and age. Despite its significance, there are few studies with the intent to characterize neurological parameters that include these two parameters. To determine the basal neurophysiological status, we analyzed basic electrophysiological parameters generated during basal activity or synaptic plasticity in the brain slices of young and aged female and male degus. We studied the hippocampal circuit of animals kept in social ambient in captivity under controlled conditions. The study of basal synaptic activity in young animals (12–24 months old) was similar between sexes, but female degus showed more efficient synaptic transmission than male degus. We found the opposite in aged animals (60–84 months old), where male degus had a more efficient basal transmission and facilitation index than female degus. Furthermore, female and male degus develop significant but not different long-term synaptic plasticity (LTP). However, aged female degus need to recruit twice as many axons to evoke the same postsynaptic activity as male degus and four times more when compared to young female degus. These data suggest that, unlike male degus, the neural status of aged female degus change, showing less number or functional axons available at advanced ages. Our data represent the first approach to incorporate the effect of sex along with age progression in basal neural status.
Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters

Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.
A Novel Bacterial Protease Inhibitor Adjuvant in RBD-Based COVID-19 Vaccine Formulations Containing Alum Increases Neutralizing Antibodies, Specific Germinal Center B Cells and Confers Protection Against SARS-CoV-2 Infection in Mice

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8+ T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice.