Miracle-dz/UniFAR-FTUs huggingface dataset:
A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

Aim Heart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods 31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing young and old animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. Results Echocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in young and old animals: in young animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In old animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In old animals, SAR247799 reduced cardiac hypertrophy (mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In young animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In old animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization. Conclusions These experimental findings suggest that S1P1 activation with SAR247799 could improve LVH, cardiac diastolic and renal function in HFpEF patients.
Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Following CNS injury astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here we used mice in which TG2 was specifically deleted in astrocytes (Gfap-Cre+/-TG2fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO_mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days postinjury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis reveals a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron-astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.
Sound localization of world and head-centered space in ferrets

The location of sounds can be described in multiple coordinate systems that are defined relative to ourselves, or the world around us. Evidence from neural recordings in animals point toward the existence of both head-centered and world-centered representations of sound location in the brain; however, it is unclear whether such neural representations have perceptual correlates in the sound localization abilities of nonhuman listeners. Here, we establish novel behavioral tests to determine the coordinate systems in which ferrets can localize sounds. We found that ferrets could learn to discriminate between sound locations that were fixed in either world-centered or head-centered space, across wide variations in sound location in the alternative coordinate system. Using probe sounds to assess broader generalization of spatial hearing, we demonstrated that in both head and world-centered tasks, animals used continuous maps of auditory space to guide behavior. Single trial responses of individual animals were sufficiently informative that we could then model sound localization using speaker position in specific coordinate systems and accurately predict ferrets' actions in held-out data. Our results demonstrate that ferrets, an animal model in which neurons are known to be tuned to sound location in egocentric and allocentric reference frames, can also localize sounds in multiple head and world-centered spaces. SIGNIFICANCE STATEMENT Humans can describe the location of sounds either relative to themselves, or in the world, independent of their momentary position. These different spaces are also represented in the activity of neurons in animals, but it is not clear whether nonhuman listeners also perceive both head and world-centered sound location. Here, we designed behavioral tasks in which ferrets discriminated between sounds using their position in the world, or relative to the head. Subjects learnt to solve both problems and generalized sound location in each space when presented with infrequent probe sounds. These findings reveal a perceptual correlate of neural sensitivity previously observed in the ferret brain and establish that, like humans, ferrets can access an auditory map of their local environment.
Programmable mammalian translational modulators by CRISPR-associated proteins

Translational modulation based on RNA-binding proteins can be used to construct artificial gene circuits, but RNA-binding proteins capable of regulating translation efficiently and orthogonally remain scarce. Here we report CARTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Gene control) to repurpose Cas proteins as translational modulators in mammalian cells. We demonstrate that a set of Cas proteins efficiently and orthogonally repress or activate the translation of designed mRNAs that contain a Cas-binding RNA motif in the 5’-UTR. By linking multiple Cas-mediated translational modulators, we designed and built artificial circuits like logic gates, cascades, and half-subtractor circuits. Moreover, we show that various CRISPR-related technologies like anti-CRISPR and split-Cas9 platforms could be similarly repurposed to control translation. Coupling Cas-mediated translational and transcriptional regulation enhanced the complexity of synthetic circuits built by only introducing a few additional elements. Collectively, CARTRIDGE has enormous potential as a versatile molecular toolkit for mammalian synthetic biology. The scarcity of qualified RNA-binding proteins hinders the development of artificial translational regulators and synthetic gene circuits. Here, the authors repurposed CRISPR-Cas proteins as translational regulators to build synthetic circuits.
The nuts and bolts of SARS-CoV-2 Spike Receptor Binding Domain heterologous expression

COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight current and future outbreaks. The receptor-binding domain (RBD) of the SARS-CoV-2 surface Spike protein is the main target for vaccines and represents a helpful “tool” to produce neutralizing antibodies or diagnostic kits. In this work, we provide a detailed characterization of the native RBD produced in three major model systems: Escherichia coli, insect and HEK-293 cells. Circular dichroism, gel filtration chromatography and thermal denaturation experiments indicated that recombinant SARS-CoV-2 RBD proteins are stable and correctly folded. In addition, their functionality and receptor-binding ability were further evaluated through ELISA, flow cytometry assays and bio-layer interferometry.
Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice

Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.
A Review of Using Mathematical Modeling to Improve Our Understanding of Bacteriophage, Bacteria, and Eukaryotic Interactions

Phage therapy, the therapeutic usage of viruses to treat bacterial infections, has many theoretical benefits in the ‘post antibiotic era. ’ Nevertheless, there are currently no approved mainstream phage therapies. One reason for this is a lack of understanding of the complex interactions between bacteriophage, bacteria and eukaryotic hosts. These three-component interactions are complex, with non-linear or synergistic relationships, anatomical barriers and genetic or phenotypic heterogeneity all leading to disparity between performance and efficacy in in vivo versus in vitro environments. Realistic computer or mathematical models of these complex environments are a potential route to improve the predictive power of in vitro studies for the in vivo environment, and to streamline lab work. Here, we introduce and review the current status of mathematical modeling and highlight that data on genetic heterogeneity and mutational stochasticity, time delays and population densities could be critical in the development of realistic phage therapy models in the future. With this in mind, we aim to inform and encourage the collaboration and sharing of knowledge and expertise between microbiologists and theoretical modelers, synergising skills and smoothing the road to regulatory approval and widespread use of phage therapy.
Data Driven Explanation of Temporal and Spatial Variability of Maize Yield in the United States

Maize yield has demonstrated significant variability both temporally and spatially. Numerous models have been presented to explain such variability in crop yield using data from multiple sources with varying temporal and spatial resolutions. Some of these models are data driven, which focus on approximating the complex relationship between explanatory variables and crop yield from massive data sets. Others are knowledge driven, which focus on integrating scientific understanding of crop growth mechanism in the modeling structure. We propose a new model that leverages the computational efficiency and prediction accuracy of data driven models and incorporates agronomic insights from knowledge driven models. Referred to as the GEM model, this model estimates three independent components of (G)enetics, (E)nvironment, and (M)anagement, the product of which is used as the predicted crop yield. The aim of this study is to produce not only accurate crop yield predictions but also insightful explanations of temporal and spatial variability with respect to weather, soil, and management variables. Computational experiments were conducted on a data set that includes maize yield, weather, soil, and management data covering 2,649 counties in the U.S. from 1980 to 2019. Results suggested that the GEM model is able to achieve a comparable prediction performance with state-of-the-art machine learning models and produce meaningful insights such as the estimated growth potential, effectiveness of management practices, and genetic progress.
Adaptation of Staphylococcus aureus to the Human Skin Environment Identified Using an ex vivo Tissue Model

The healthy human epidermis provides physical protection and is impenetrable for pathogenic microbes. Nevertheless, commensal and pathogen bacteria such as Staphylococcus aureus are able to colonize the skin surface, which may subsequently lead to infection. To identify and characterize regulatory elements facilitating adaptation of S. aureus to the human skin environment we used ex vivo tissue explants and quantified S. aureus gene transcription during co-culture. This analysis provided evidence for a significant downregulation of the global virulence regulator agr upon initial contact with skin, regardless of the growth phase of S. aureus prior to co-culture. In contrast, the alternative sigma factor B (sigB) and the antimicrobial peptide-sensing system (graRS) were expressed during early colonization. Consistently, sigB target genes such as the clumping factor A (clfA) and fibrinogen and fibronectin binding protein A (fnbA) were strongly upregulated upon skin contact. At later timepoints of the adhesion process, wall teichoic acid (WTA) synthesis was induced. Besides the expression of adhesive molecules, transcription of molecules involved in immune evasion were increased during late colonization (staphylococcal complement inhibitor and staphylokinase). Similar to nasal colonization, enzymes involved in cell wall metabolism (sceD and atlA) were highly transcribed. Finally, we detected a strong expression of proteases from all three catalytic classes during the entire colonization process. Taken together, we here present an ex vivo skin colonization model that allows the detailed characterization of the bacterial adaptation to the skin environment.
Organisational Climate and Pro-environmental Behaviours at Work: The Mediating Role of Personal Norms

Organisations are currently strongly encouraged to adopt more responsible production patterns aligned with sustainable development goals (SDGs). Pro-environmental behaviours (PEBs) in the workplace can strengthen the expected positive impacts of organisations’ environmental performance and engender more sustainable transitions to low-carbon production. Research on PEBs at work is relatively recent, so this field still lacks studies of the role of organisational policies and practices in workers’ adoption of these behaviours and of psychosocial processes that contribute to more sustainable workplaces. The present research examined how perceptions of organisations’ environmental policies and practices (i.e., organisational climate or injunctive norms) and of coworkers’ PEBs (i.e., descriptive norms) affect employees’ self-reported voluntary PEBs. Thogersen’s norm taxonomy model was also applied to address the role of personal norms. Self-commitment to sustainable goals at work can play a fundamental role in workers’ behavioural choices, so this research further investigated whether personal norms mediate the relationship between perceived pro-environmental organisational climate and reported workplace PEBs. To test the proposed model, data were collected on 210 workers from different business sectors, who completed an online questionnaire. The analyses showed that, after controlling for the effects of tenure, education level, and a management position, a pro-environmental organisational climate predicts stronger personal norms and a greater tendency to adopt PEBs at work (adjusted R squared=0.36), providing evidence of complete mediation. Coworkers’ perceived descriptive norms also contribute directly to self-reported PEBs. The discussion of the results focuses on the importance of organisational level initiatives as a way to promote change in individuals’ behaviours, which can have positive consequences for workplaces’ transition to sustainability.
The Effect of Emotional Labor on Presenteeism of Chinese Nurses in Tertiary-Level Hospitals: The Mediating Role of Job Burnout

Background: Employees who are physically present but work insufficiently because of illness are deemed as having presenteeism. In the health care setting, the issue has taken on greater importance because of the impairment of the physical and mental health of nurses and the nursing safety of the patients. According to the Job Demand-Resource Model, burnout may link emotional labor with presenteeism. Thus, this study analyzed the role of burnout as a mediating factor between the three types of emotional labor strategies and presenteeism among nurses in tertiary-level hospitals. Methods: A cross-sectional study of 1,038 nurses from six Chinese hospitals was conducted. The questionnaires, including the 14-item emotional labor strategies scale, 22-item Maslach Burnout Inventory scale, 6-item Stanford Presenteeism Scale, and items about demographic characteristics and work-related factors, were used to collect data. A multivariable linear regression was used to predict work-related factors and investigate the correlation of emotional labor, burnout, and presenteeism. The structural equation model was implemented to test the mediating effects of job burnout. Results: The results of the study showed that the average presenteeism score of the participants was 14.18 (4.33), which is higher than in Spanish, Portuguese, and Brazilian nurses. Presenteeism was explained by 22.8% of the variance in the final model in multivariable linear regression (P < 0.01). Presenteeism was found to be positively correlated with surface acting, emotionally expressed demands, deep acting, emotional exhaustion, depersonalization, and low personal accomplishment (P < 0.01). Notably, presenteeism was negatively correlated with deep acting (P < 0.01). In addition, burnout partially mediated the correlation between emotionally expressed demands, deep acting, and presenteeism with a mediatory effect of 24 and 63.31% of the total effect. Burnout completely mediated the association between surface acting and presenteeism, a mediating effect of 86.44% of the total effect. Conclusions: The results of this study suggested that different emotional labor strategies affect presenteeism, either directly or indirectly. Nursing managers should intervene to reduce presenteeism by improving the ability of the nurses to manage emotions, thereby alleviating burnout.
Obesity and Mental Health: A Longitudinal, Cross-Cultural Examination in Germany and China

The present study examines the relationship between obesity and mental health using longitudinal data. Participants with data at baseline and one-year follow-up were included from two countries: Germany (364) and China (9007). A series of structural equation models with three mediators and one moderator were conducted separately for female and male students in Germany and China. Zero-order correlations indicated that overweight/obesity was significantly related to later depression and anxiety in Chinese males. Additional effects of obesity on later mental health flowed through effects on attractiveness (Chinese and German females, and Chinese males), physical health (Chinese males), and life satisfaction (German females). Though overweight/obesity is related to mental health across many other studies, results in this study yield total effects between overweight/obesity and follow-up mental health only in Chinese males. The relationship between overweight/obesity and follow-up mental health was significantly mediated by follow-up attractiveness, or health state, or life satisfaction in German females, Chinese females, and Chinese male students, with no significant indirect effects found in German male students. This highlights the possible importance of culture in examining these effects.
Comparison of Perioperative, Renal Functional, and Oncological Outcomes Between Off-Clamp and On-Clamp Robot-Assisted Partial Nephrectomy for Renal Tumors: An Updated Evidence-Based Analysis

Objectives We aimed to report the latest and largest pooled analysis and evidence update to compare the perioperative, renal functional, and oncological outcomes between off-clamp and on-clamp robot-assisted partial nephrectomy (RAPN) for renal tumors. Patients and methods We performed a systematic literature search using PubMed, Embase, and Web of Science up to August 2021 for studies that compared the efficacy and/or safety between off-clamp and on-clamp RAPN for renal tumors. Outcomes measured were operating time, estimated blood loss (EBL), conversion rate, length of stay (LOS), complication rate, transfusion rate, long-term % decrease in estimated glomerular filtration rate (eGFR), positive surgical margin rate, and recurrence rate. Results A total of 21 eligible articles involving 4,493 patients (1,274 off-clamp versus 3,219 on-clamp) were included for the evidence synthesis. Baseline characteristics of the two groups were similar in all outcomes except that lower R.E. N.A. L. score and smaller tumor size were observed in the off-clamp group. Pooled analysis showed shorter operative time, higher EBL, and lower complication rate in the off-clamp group. No significant difference was observed in the conversion rate, LOS, and transfusion rate. The recurrence rates were similar in the two groups, while a lower positive surgical margin rate was observed in the off-clamp group. Finally, the off-clamp group had a superior postoperative renal functional outcome. Conclusions Given the presence of heterogeneity and potential bias, urologists should select the clamp strategy based on their experience and patient-specific factors.