Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Two Novel Candidate Genetic Variants Associated With the Responsiveness to Influenza Vaccination

Background Annual vaccination is the most effective prevention of influenza infection. Up to now, a series of studies have demonstrated the role of genetic variants in regulating the antibody response to influenza vaccine. However, among the Chinese population, the relationship between genetic factors and the responsiveness to influenza vaccination has not been clarified through genome-wide association study (GWAS). Method A total of 1,968 healthy volunteers of Chinese descent were recruited and 1,582 of them were available for the subsequent two-stage analysis. In the discovery stage, according to our inclusion criteria, 123 of 1,582 subjects were selected as group 1 and received whole-genome sequencing to identify potential variants and genes. In the verification stage, 29 candidate variants identified by GWAS were selected for further validation in 481 subjects in group 2. Besides, we also analyzed nine variants from previously published reports in our study. Results Multivariate logistic regression analysis showed that compared with the TT genotype of ZBTB46 rs2281929, the TC + CC genotype was associated with a lower risk of low responsiveness to influenza vaccination adjusted for gender and age (Group 2: P = 7.75E-05, OR = 0.466, 95%CI = 0.319–0.680; Combined group: P = 1.18E-06, OR = 0.423, 95%CI = 0.299–0.599). In the combined group, IQGAP2 rs2455230 GC + CC genotype was correlated with a lower risk of low responsiveness to influenza vaccination compared with the GG genotype (P = 8.90E-04, OR = 0.535, 95%CI = 0.370–0.774), but the difference was not statistically significant in group 2 (P = 0.008). The antibody fold rises of subjects with ZBTB46 rs2281929 TT genotype against H1N1, H3N2,and B were all significantly lower than that of subjects with TC + CC genotype (P < 0.001). Compared with IQGAP2 rs2455230 GC + CC carriers, GG carriers had lower antibody fold rises to H1N1 (P = 0.001) and B (P = 0.032). The GG genotype of rs2455230 tended to be correlated with lower antibody fold rises (P = 0.096) against H3N2, but the difference was not statistically significant. No correlation was found between nine SNPs from previously published reports and the serological response to influenza vaccine in our study. Conclusion Our study identified two novel candidate missense variants, ZBTB46 rs2281929 and IQGAP2 rs2455230, were associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide more evidence for future research and improve the individualized influenza vaccination program.
CircSNHG5 Sponges Mir-495-3p and Modulates CITED2 to Protect Cartilage Endplate From Degradation

Background Intervertebral disc degeneration (IDD) is a highly prevalent degenerating disease that produces tremendous amount of low back and neck pain. The cartilage endplate (CEP) is vitally important to intervertebral discs in both physiological and pathological conditions. In addition, circular RNAs (circRNAs) have been shown to be involved in the regulation of various diseases, including IDD. However, the particular role of circRNAs in cervical vertebral CEP degeneration remains unclear. Here, we examined the unique role of circRNAs in CEP of patients with cervical fracture and degenerative cervical myelopathy (DCM). Methods Human competitive endogenous RNA (ceRNA) microarray was performed by previous research. Western blot (WB), immunofluorescence (IF), quantitative RT-PCR (qRT-PCR), luciferase assay, and fluorescence in situ hybridization (FISH) were employed to analyze the function of circSNHG5 and its downstream effectors, miR-495-3p, and CITED2. Results We demonstrated that circSNHG5 expression was substantially low in degenerative CEP tissues. Knockdown of circSNHG5 in chondrocytes resulted in a loss of cell proliferation and followed by degradation of extracellular matrix (ECM). In addition, circSNHG5 was shown to sponge miR-495-3p and modulate the expression of the downstream gene CITED2. This mechanism of action was further validated via overexpression and knockdown of CITED2. Conclusion Our findings identified a novel circSNHG5-miR-495-3p axis responsible for IDD progression. Future investigations into IDD therapy may benefit from targeting this axis.
Glial and Neuronal Neuroglian, Semaphorin-1a and Plexin A Regulate Morphological and Functional Differentiation of Drosophila Insulin-Producing Cells

The insulin-producing cells (IPCs), a group of 14 neurons in the Drosophila brain, regulate numerous processes, including energy homeostasis, lifespan, stress response, fecundity, and various behaviors, such as foraging and sleep. Despite their importance, little is known about the development and the factors that regulate morphological and functional differentiation of IPCs. In this study, we describe the use of a new transgenic reporter to characterize the role of the Drosophila L1-CAM homolog Neuroglian (Nrg), and the transmembrane Semaphorin-1a (Sema-1a) and its receptor Plexin A (PlexA) in the differentiation of the insulin-producing neurons. Loss of Nrg results in defasciculation and abnormal neurite branching, including ectopic neurites in the IPC neurons. Cell-type specific RNAi knockdown experiments reveal that Nrg, Sema-1a and PlexA are required in IPCs and glia to control normal morphological differentiation of IPCs albeit with a stronger contribution of Nrg and Sema-1a in glia and of PlexA in the IPCs. These observations provide new insights into the development of the IPC neurons and identify a novel role for Sema-1a in glia. In addition, we show that Nrg, Sema-1a and PlexA in glia and IPCs not only regulate morphological but also functional differentiation of the IPCs and that the functional deficits are likely independent of the morphological phenotypes. The requirements of nrg, Sema-1a, and PlexA in IPC development and the expression of their vertebrate counterparts in the hypothalamic-pituitary axis, suggest that these functions may be evolutionarily conserved in the establishment of vertebrate endocrine systems.
Risks Elaborated vs. Risks Downplayed: The Effect of Risk Comparisons in Mainstream Media During Covid-19 on Risk Perceptions and Anxiety Levels

This study examines the effects of risk comparisons in mainstream media during the Covid-19 outbreak that either expressed the severity of the outbreak or downplayed it by comparing the mortality rates of the disease to those of other risks. In an online experiment of undergraduate students at a large university in the U.S. Mountain West (n = 78) in early May 2020, we found that trust in government agencies played an important role in how people interpret risk messages in media. When the risks are amplified, those who hold low levels of trust in government agencies are more likely to report higher levels of anxiety. When risks are downplayed, people who hold high levels of trust in government agencies are more likely to report greater risk perceptions than those who hold low levels of trust in government agencies. The implications are discussed.
Systematic Prediction of Antifungal Drug Synergy by Chemogenomic Screening in Saccharomyces cerevisiae

Since the earliest days of using natural remedies, combining therapies for disease treatment has been standard practice. Combination treatments exhibit synergistic effects, broadly defined as a greater-than-additive effect of two or more therapeutic agents. Clinicians often use their experience and expertise to tailor such combinations to maximize the therapeutic effect. Although understanding and predicting biophysical underpinnings of synergy have benefitted from high-throughput screening and computational studies, one challenge is how to best design and analyze the results of synergy studies, especially because the number of possible combinations to test quickly becomes unmanageable. Nevertheless, the benefits of such studies are clear—by combining multiple drugs in the treatment of infectious disease and cancer, for instance, one can lessen host toxicity and simultaneously reduce the likelihood of resistance to treatment. This study introduces a new approach to characterize drug synergy, in which we extend the widely validated chemogenomic HIP–HOP assay to drug combinations; this assay involves parallel screening of comprehensive collections of barcoded deletion mutants. We identify a class of “combination-specific sensitive strains” that introduces mechanisms for the synergies we observe and further suggest focused follow-up studies.
Neuro4PD: An Initial Neurorobotics Model of Parkinson's Disease

In this work, we present the first steps toward the creation of a new neurorobotics model of Parkinson's Disease (PD) that embeds, for the first time in a real robot, a well-established computational model of PD. PD mostly affects the modulation of movement in humans. The number of people suffering from this neurodegenerative disease is set to double in the next 15 years and there is still no cure. With the new model we were capable to further explore the dynamics of the disease using a humanoid robot. Results show that the embedded model under both conditions, healthy and parkinsonian, was capable of performing a simple behavioural task with different levels of motor disturbance. We believe that this neurorobotics model is a stepping stone to the development of more sophisticated models that could eventually test and inform new PD therapies and help to reduce and replace animals in research.
Peptide Based Inhibitors of Protein Binding to the Mitogen-Activated Protein Kinase Docking Groove

Mitogen-activated protein kinases (MAPK) are important regulatory units in cells and they take part in the regulation of many cellular functions such as cell division, differentiation or apoptosis. All MAPKs have a shallow docking groove that interacts with linear binding motifs of their substrate proteins and their regulatory proteins such as kinases, phosphatases, scaffolds. Inhibition of these protein–protein interactions may reduce or abolish the activity of the targeted kinase. Based on the wide range of their biological activity, this kind of inhibition can be useful in the treatment of many disorders like tumors, inflammation or undesired cell apoptosis. In this study a linear binding motif from the RHDF1 protein—a 15 amino acids long peptide—was selected for optimization to increase its cellular uptake but retaining its low micromolar binding affinity. First, we synthesized an octaarginine conjugate that showed efficient cellular uptake. Next, we set out to reduce the size of this construct. We were able to decrease the length of the original peptide, and to increase its cellular uptake with specific chemical modifications. These new constructs bound better to ERK2 and p38 kinases than the original peptide and they showed markedly increased cellular uptake. The new octaarginine conjugate and one of the minimized bicyclic derivatives could inhibit the phosphorylation of intracellular ERK or p38. However, the modulation of MAPK phosphorylation levels by these cell-penetrating peptides were complex, despite that in biochemical assays they all inhibited MAPK-substrate binding as well as phosphorylation. The optimized peptides depending on the applied concentration caused an expected decrease, but also some unexpected increase in MAPK phosphorylation patterns in the cell. This possibly reflects the complexity of MAPK docking groove mediated protein–protein interactions including bone fide MAPK clients such activator kinases, deactivating phosphatases or regulatory scaffolds. Thus, our findings with optimized cell-penetrating “inhibitory” peptides highlight the opportunities but also the pitfalls of docking peptide based MAPK activity regulation and call for a better quantitative understanding of MAPK mediated protein–protein interactions in cells.
IVIM Parameters on MRI Could Predict ISUP Risk Groups of Prostate Cancers on Radical Prostatectomy

Purpose To elucidate the usefulness of intravoxel incoherent motion (IVIM)/apparent diffusion coefficient (ADC) parameters in preoperative risk stratification using International Society of Urological Pathology (ISUP) grades. Materials and Methods Forty-five prostate cancer (PCa) patients undergoing radical prostatectomy (RP) after prostate multiparametric magnetic resonance imaging (mpMRI) were included. The ISUP grades were categorized into low-risk (I-II) and high-risk (III-V) groups, and the concordance between the preoperative and postoperative grades was analyzed. The largest region of interest (ROI) of the dominant tumor on each IVIM/ADC image was delineated to obtain its histogram values (i.e., minimum, mean, and kurtosis) of diffusivity (D), pseudodiffusivity (D*), perfusion fraction (PF), and ADC. Multivariable logistic regression analysis of the IVIM/ADC parameters without and with preoperative ISUP grades were performed to identify predictors for the postoperative high-risk group. Results Thirty-two (71.1%) of 45 patients had concordant preoperative and postoperative ISUP grades. Dmean, D*kurtosis, PFkurtosis, ADCmin, and ADCmean were significantly associated with the postoperative ISUP risk group (all p < 0.05). Dmean and D*kurtosis (model I, both p < 0.05) could predict the postoperative ISUP high-risk group with an area under the curve (AUC) of 0.842 and a 95% confidence interval (CI) of 0.726–0.958. The addition of D*kurtosis to the preoperative ISUP grade (model II) may enhance prediction performance, with an AUC of 0.907 (95% CI 0.822–0.992). Conclusions The postoperative ISUP risk group could be predicted by Dmean and D*kurtosis from mpMRI, especially D*kurtosis. Obtaining the biexponential IVIM parameters is important for better risk stratification for PCa.
Connectivity Measures Differentiate Cortical and Subcortical Sub-Acute Ischemic Stroke Patients

Brain lesions caused by cerebral ischemia lead to network disturbances in both hemispheres, causing a subsequent reorganization of functional connectivity both locally and remotely with respect to the injury. Quantitative electroencephalography (qEEG) methods have long been used for exploring brain electrical activity and functional connectivity modifications after stroke. However, results obtained so far are not univocal. Here, we used basic and advanced EEG methods to characterize how brain activity and functional connectivity change after stroke. Thirty-three unilateral post stroke patients in the sub-acute phase and ten neurologically intact age-matched right-handed subjects were enrolled. Patients were subdivided into two groups based on lesion location: cortico-subcortical (CS, n = 18) and subcortical (S, n = 15), respectively. Stroke patients were evaluated in the period ranging from 45 days since the acute event (T0) up to 3 months after stroke (T1) with both neurophysiological (resting state EEG) and clinical assessment (Barthel Index, BI) measures, while healthy subjects were evaluated once. Brain power at T0 was similar between the two groups of patients in all frequency bands considered (δ, θ, α, and β). However, evolution of θ-band power over time was different, with a normalization only in the CS group. Instead, average connectivity and specific network measures (Integration, Segregation, and Small-worldness) in the β-band at T0 were significantly different between the two groups. The connectivity and network measures at T0 also appear to have a predictive role in functional recovery (BI T1-T0), again group-dependent. The results obtained in this study showed that connectivity measures and correlations between EEG features and recovery depend on lesion location. These data, if confirmed in further studies, on the one hand could explain the heterogeneity of results so far observed in previous studies, on the other hand they could be used by researchers as biomarkers predicting spontaneous recovery, to select homogenous groups of patients for the inclusion in clinical trials.
Identification of a Genetically Linked but Functionally Independent Two-Component System Important for Cell Division of the Rice Pathogen Burkholderia glumae

Bacterial two-component regulatory systems control the expression of sets of genes to coordinate physiological functions in response to environmental cues. Here, we report a genetically linked but functionally unpaired two-component system (TCS) comprising the sensor kinase GluS (BGLU_1G13350) and the response regulator GluR (BGLU_1G13360), which is critical for cell division in the rice pathogen Burkholderia glumae BGR1. The gluR null mutant, unlike the gluS mutant, formed filamentous cells in Lysogeny Broth medium and was sensitive to exposure to 42°C. Expression of genes responsible for cell division and cell-wall (dcw) biosynthesis in the gluR mutant was elevated at transcription levels compared with the wild type. GluR-His bound to the putative promoter regions of ftsA and ftsZ is involved in septum formation, indicating that repression of genes in the dcw cluster by GluR is critical for cell division in B. glumae. The gluR mutant did not form filamentous cells in M9 minimal medium, whereas exogenous addition of glutamine or glutamate to the medium induced filamentous cell formation. These results indicate that glutamine and glutamate influence GluR-mediated cell division in B. glumae, suggesting that GluR controls cell division of B. glumae in a nutrition-dependent manner. These findings provide insight into how the recognition of external signals by TCS affects the sophisticated molecular mechanisms involved in controlling bacterial cell division.
Intermittent Hypoxia Training Prevents Deficient Learning-Memory Behavior in Mice Modeling Alzheimer's Disease: A Pilot Study

In mouse models of Alzheimer's disease (AD), normobaric intermittent hypoxia training (IHT) can preserve neurobehavioral function when applied before deficits develop, but IHT's effectiveness after onset of amyloid-β (Aβ) accumulation is unclear. This study tested the hypothesis that IHT improves learning-memory behavior, diminishes Aβ accumulation in cerebral cortex and hippocampus, and enhances cerebrocortical contents of the neuroprotective trophic factors erythropoietin and brain-derived neurotrophic factor (BDNF) in mice manifesting AD traits. Twelve-month-old female 3xTg-AD mice were assigned to untreated 3xTg-AD (n = 6), AD+IHT (n = 6), and AD+sham-IHT (n = 6) groups; 8 untreated wild-type (WT) mice also were studied. AD+IHT mice alternately breathed 10% O2 for 6 min and room air for 4 min, 10 cycles/day for 21 days; AD+sham-IHT mice breathed room air. Spatial learning-memory was assessed by Morris water maze. Cerebrocortical and hippocampal Aβ40 and Aβ42 contents were determined by ELISA, and cerebrocortical erythropoietin and BDNF were analyzed by immunoblotting and ELISA. The significance of time (12 vs. 12 months + 21 days) and treatment (IHT vs. sham-IHT) was evaluated by two-factor ANOVA. The change in swimming distance to find the water maze platform after 21 d IHT (−1.6 ± 1.8 m) differed from that after sham-IHT (+5.8 ± 2.6 m). Cerebrocortical and hippocampal Aβ42 contents were greater in 3xTg-AD than WT mice, but neither time nor treatment significantly affected Aβ40 or Aβ42 contents in the 3xTg-AD mice. Cerebrocortical erythropoietin and BDNF contents increased appreciably after IHT as compared to untreated 3xTg-AD and AD+sham-IHT mice. In conclusion, moderate, normobaric IHT prevented spatial learning-memory decline and restored cerebrocortical erythropoietin and BDNF contents despite ongoing Aβ accumulation in 3xTg-AD mice.
Development and Validation of a Prognostic Nomogram for Colorectal Cancer Patients With Synchronous Peritoneal Metastasis

Purpose Synchronous peritoneal metastasis (S-PM) is considered a poor prognostic factor for colorectal cancer (CRC) and there is no nomogram to predict the survival of these patients. In this study, we aimed to use a multicenter data to identify the factors associated with S-PM of CRC to construct a nomogram for predicting the overall survival (OS) of these patients. Methods CRC patients with S-PM from two medical centers were enrolled between September 2007 and June 2017. Multivariate analysis was used to identify independent factors associated with OS for the nomogram to predict the 1-, 2-, and 3-year OS rates in the development group. The concordance index (C-index), calibration plot, relative operating characteristic (ROC) curve with area under the curve (AUC) were calculated to evaluate the performance of the nomogram in both the development and an external validation group. Results 277 CRC patients with S-PM in the development group and 68 patients in the validation group were eligible for this study. In multivariate analysis of development group, age, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and chemotherapy were independent variables for OS, based on which the nomogram was built. The C-index of the nomogram in the development and validation group was 0.701 (95% Cl, 0.666–0.736) and 0.716 (95% Cl, 0.622–0.810); demonstrating good discriminative ability. The calibration plots showed satisfactory consistency between actual observation and nomogram-predicted OS probabilities in the development and external validation group. The nomogram showed good predictive accuracy for 1-, 2-, and 3-year OS rates in both groups with AUC >0.70. An online dynamic webserver was also developed for increasing the ease of the nomogram. Conclusions We developed and validated a predictive nomogram with good discriminative and high accuracy to predict the OS in CRC patients with S-PM.
Insights Into the Older Adults' World: Concepts of Aging, Care, and Using Assistive Technology in Late Adulthood

The ongoing demographic change forces different stakeholders to cope with increasing needs in nursing care and the economic costs. Consequences arising from the population aging can be supported by assistive technologies to maintain older individuals' autonomy. However, older adults' opinions on the assistance of health-related technologies and their attitudes toward aging and care largely remain underexplored. This paper provides a geriatric and socio-technical perspective, investigating individual perceptions of (a) aging, (b) nursing care, and (c) the adoption of assistive technologies in a cross-national subject group. For this purpose, N = 384 individuals (60+ years) participated in an online survey. Findings indicate that most older adults are open to assistive technologies and that individual care preferences contribute to a successful adoption of these technologies. Among individual factors, health status, and gender affect respondents' opinions the most. Our findings help to understand older adults' acceptance of assistive technologies and contribute to the research on the nursing care in private and professional environments.