Miracle-dz/UniFAR-FTUs huggingface dataset:
Listeria monocytogenes exploits host exocytosis to promote cell-to-cell spread

Significance Whether protrusion formation during cell-to-cell spread of the bacterium Listeria monocytogenes involves exploitation of host physiological processes apart from actin polymerization is not understood. In this work, we demonstrate that Listeria stimulates the host process of exocytosis in order to efficiently generate protrusions. This stimulation of exocytosis is mediated by the Listeria protein InlC and the host exocyst complex. InlC and the exocyst complex control the length of Listeria protrusions, suggesting that they regulate protrusion elongation. Our results identify exocytosis as a host process controlling bacterial cell-to-cell spread. The facultative intracellular pathogen Listeria monocytogenes uses an actin-based motility process to spread within human tissues. Filamentous actin from the human cell forms a tail behind bacteria, propelling microbes through the cytoplasm. Motile bacteria remodel the host plasma membrane into protrusions that are internalized by neighboring cells. A critical unresolved question is whether generation of protrusions by Listeria involves stimulation of host processes apart from actin polymerization. Here we demonstrate that efficient protrusion formation in polarized epithelial cells involves bacterial subversion of host exocytosis. Confocal microscopy imaging indicated that exocytosis is up-regulated in protrusions of Listeria in a manner that depends on the host exocyst complex. Depletion of components of the exocyst complex by RNA interference inhibited the formation of Listeria protrusions and subsequent cell-to-cell spread of bacteria. Additional genetic studies indicated important roles for the exocyst regulators Rab8 and Rab11 in bacterial protrusion formation and spread. The secreted Listeria virulence factor InlC associated with the exocyst component Exo70 and mediated the recruitment of Exo70 to bacterial protrusions. Depletion of exocyst proteins reduced the length of Listeria protrusions, suggesting that the exocyst complex promotes protrusion elongation. Collectively, these results demonstrate that Listeria exploits host exocytosis to stimulate intercellular spread of bacteria.
MEWS++: Enhancing the Prediction of Clinical Deterioration in Admitted Patients through a Machine Learning Model

Early detection of patients at risk for clinical deterioration is crucial for timely intervention. Traditional detection systems rely on a limited set of variables and are unable to predict the time of decline. We describe a machine learning model called MEWS++ that enables the identification of patients at risk of escalation of care or death six hours prior to the event. A retrospective single-center cohort study was conducted from July 2011 to July 2017 of adult (age > 18) inpatients excluding psychiatric, parturient, and hospice patients. Three machine learning models were trained and tested: random forest (RF), linear support vector machine, and logistic regression. We compared the models’ performance to the traditional Modified Early Warning Score (MEWS) using sensitivity, specificity, and Area Under the Curve for Receiver Operating Characteristic (AUC-ROC) and Precision-Recall curves (AUC-PR). The primary outcome was escalation of care from a floor bed to an intensive care or step-down unit, or death, within 6 h. A total of 96,645 patients with 157,984 hospital encounters and 244,343 bed movements were included. Overall rate of escalation or death was 3.4%. The RF model had the best performance with sensitivity 81.6%, specificity 75.5%, AUC-ROC of 0.85, and AUC-PR of 0.37. Compared to traditional MEWS, sensitivity increased 37%, specificity increased 11%, and AUC-ROC increased 14%. This study found that using machine learning and readily available clinical data, clinical deterioration or death can be predicted 6 h prior to the event. The model we developed can warn of patient deterioration hours before the event, thus helping make timely clinical decisions.
Patterns of Bullying Victimization and Associations with Mental Health Problems in Chinese Adolescents: A Latent Class Analysis

Bullying victimization in school students is a serious public health concern and has been linked to a wide range of mental health problems. The current study aims to examine patterns of involvement in different types of bullying victimization among Chinese adolescents and evaluate the associations between bullying victimization and mental health problems. Cross-sectional data from 20,722 middle school students from Guangdong Province were sampled using a multistage, stratified cluster-randomized sampling method. Latent class analysis (LCA) was performed on seven items representing bullying victimization. Levels of mental health outcomes were compared across each latent class. Four latent classes were identified for boys: the high victimization class (0.6%), the moderate victimization class (2.8%), the verbal victimization class (12.4%), and the low victimization class (84.2%). For girls, three latent classes were identified: the high victimization class (0.7%), the moderate victimization class (5.6%), and the low victimization class (93.7%). Characteristics of the item probabilities were different between boys and girls. For both genders, a graded relationship was found between bullying victimization class membership and mental health outcomes. These findings underline the complexity of bullying victimization patterns among Chinese adolescents. Students with higher involvement in bullying victimization have more severe mental health problems.
Proteome-wide structural probing of low-abundant protein interactions by crosslinking

Proteome-wide crosslinking studies have spurred great interest as they facilitate structural probing of protein interactions in living cells and organisms. However, current studies have a bias for high-abundant proteins. In a paradigm shift, we demonstrate both experimentally and by a kinetic model that this bias is caused by the propensity of crosslinks to preferentially form on high abundant proteins and not by the inability to detect crosslinks due to limitations in current technology. We further show, by using both an in-vitro mimic of a crowded cellular environment and eukaryotic cell lysates, that parameters optimized towards a pseudo 1st order kinetics model result in a significant 3 to 10-fold overall increase in the detection of lower-abundant proteins on a proteome-wide scale. Our study therefore explains the cause of a major limitation in current proteome-wide crosslinking studies and demonstrates how to address a larger part of the proteome by crosslinking.
Beneficial Effect of Foot Plantar Stimulation in Gait Parameters in Individuals with Parkinson’s Disease

New treatments based on peripheral stimulation of the sensory-motor system have shown to be promising in rehabilitation strategies for patients with neurological disorders, including Parkinson’s disease (PD), especially in regards to reducing gait impairment, and hence, the incidence of falls. The aim of this study was to evaluate the change in several gait parameters measured by sensor inertial measurement in PD patients after acute plantar stimulation, under the distal phalanx of the big toe, and underneath the head of the first metatarsal joint of both feet, using a 3D printing insole. In order to assess whether the effects are selective for PD patients, we compared the effect of the treatment in a control group (age-matched) consisting of patients with other neurological disorders which also displayed gait and balance impairment, and a similar cognitive function, depressive symptoms, body mass index, and comorbidity burden observed in the PD group. Plantar foot stimulation in PD patients eliminated the significant (p < 0.05) alterations existing in stride asymmetry and in stride variability. When comparing the effects of post-plantar stimulation with the respective basal level, considered as 100% in both groups, we observed a significant (p = 0.019, Mann–Whitney test) increase in stride length compared to basal in the PD group and control group. No significant effects of foot plantar stimulation were observed in any of the gait parameters in the control group. Plantar foot stimulation has a positive effect on the step and stride length, and has a positive effect on walking stability, measured by the increase in stride length. No significant effect was observed on bradykinesia because it did not improve walking velocity. These findings indicate that foot plantar stimulation using a 3D printing insole seems to generate a more stable walking pattern in PD patients, with an interesting applicability, and a low-cost, for reducing gait impairment in PD patients.
Screening of Deletion Variants within the Goat PRDM6 Gene and Its Effects on Growth Traits

Simple Summary Genome-wide association studies found that the PR/SET Domain 6 (PRDM6) gene mutation was associated with bone development, bone density, and body mass index. This study found a 12 bp deletion variation within the PRDM6 gene in Shaanbei white cashmere goats in a large sample size (n = 1044). This variation polymorphism was associated with multiple goat growth traits in the yearling period, including heart girth (p = 0.027), cannon circumference (p = 0.008), chest depth (p = 2.10 × 10−5), chest width (p = 0.004), body height (p = 0.032), body length (p = 0.044), and hip-width (p = 0.014). The effects of the 12 bp variation were found to make no difference on adult goat growth traits. Taken together, these results demonstrate that the 12 bp deletion variant plays an important role in the early growth and development of goats and could be considered as a useful and effective molecular marker for goat breeding selection in the growth stage. Abstract By genome-wide association studies, the PRDM6 gene has been shown to affect multiple, apparently unrelated inherited traits, including bone density and body mass index. Therefore, it is considered a potentially pleiotropic gene. In this study, we identified a 12 bp deletion variant (NC_030814.1:rs651603667, g: 79985625-79985636delTTGACTGATCCA) within the PRDM6 gene in a large sample (SBWC goats; n = 1044). All goat samples were collected in Shaanxi province in July 2018. The frequency of the wt allele was higher than the frequency of the del allele, and this mutation polymorphism confirmed to be consistent with the Hardy–Weinberg equilibrium (p > 0.05). Further results showed that in a group of goats in the yearling period (18 months old, n = 567), this deletion variant of the PRDM6 gene was associated with heart girth (p = 0.027), cannon circumference (p = 0.008), chest depth (p = 2.10 × 10−5), chest width (p = 0.004), body height (p = 0.032), body length (p = 0.044) and hip-width (p = 0.014). For adult SBWC goats (36 months old, n = 477), the effects of the 12 bp variation on growth-related traits were found to make no difference. These findings show that the 12 bp deletion within the goat PRDM6 gene plays an important role in the early growth and development of goats. Using the 12 bp mutation, breeders can quickly and effectively select excellent individual goats at an early stage.
A Randomized Clinical Trial to Evaluate the Efficacy and Safety of the ACTLIFE Exercise Program for Women with Post-menopausal Osteoporosis: Study Protocol

Osteoporosis (OP) is a systemic disease of the skeleton characterized by increased risk of fracture. There is a general consensus on the efficacy of physical activity in the prevention of bone loss, falls and fractures, but there is no agreement on the best setting to exercise. The aim of the study is to evaluate the efficacy of a 12-months exercise protocol for women with post-menopausal OP when administered as individual home training (IHT) versus gym group training (GGT). The study is a randomized trial with two parallel groups. Sedentary patients with primary post-menopausal osteoporosis are recruited at the Istituto Ortopedico Rizzoli of Bologna. In the first group, the 12-month ACTLIFE program is performed as IHT, while in the second as GGT. The program is aimed at improving joint mobility, muscle force, balance, motor coordination and endurance. The study is single blinded. Patients are assessed at baseline and after 6 and 12 months. The primary outcome is the modification of quality of life measured with the Short Osteoporosis Quality of Life Questionnaire (ECOS-16). The findings of this study will highlight advantages and disadvantages of exercising in the two different settings and provide evidence on how to increase physical activity in osteoporotic women.
Health Behaviors and Psychological Distress Among Conscripts of the Lithuanian Military Service: A Nationally Representative Cross-Sectional Study

The decline in healthy behavior in young people is a concern for public health in general and for country’s defense. The aim of this study is to identify and compare health behaviors and psychological distress between male conscripts enlisted and rejected for military service. This cross-sectional study included 1243 men aged 19–26 years (mean age 22.50 ± 2.43 years). We assessed health behaviors (physical activity, adherence to healthy eating patterns, cigarette smoking, and alcohol consumption) and psychological distress. Among all conscripts, 44.7% were physically inactive, 50.2% had low adherence to healthy nutrition, 9.6% were heavy drinkers, 62.3% were current smokers, and 9.1% had high psychological distress level. Compared with physically inactive conscripts, physically active conscripts were more likely to be enlisted (adjusted odds ratio (OR) = 1.42; 95% confidence interval (CI) 1.11–2.03). Compared with current nonsmokers, current smokers were less likely to be enlisted (OR = 0.58; CI 0.39–0.86). Compared with conscripts with a high distress level, those with a low distress level were almost four times more likely to be enlisted (OR = 0.26; 95% CI 0.12–0.55). Adherence to guidelines for healthy eating and alcohol consumption was not significantly related to enlistment. These findings suggest that health behaviors in male conscripts are unsatisfactory. That is, about half are physically inactive, have a poor diet, and smoke, and nearly one in 10 is a heavy drinker and has a high psychological distress level. The enlisted conscripts were more likely to be sufficiently physically active and less likely to be a current smoker or have a high distress level. Early intervention programs to provide a heathier population of young men for conscription should focus on mental well-being and target health-related behaviors such as physical activity and not smoking. Preferably, these should be implemented as health education programs in schools to help prevent the development of adverse health behaviors among young men. Governmental policies and strategies are required to enable intersectional collaboration and shared responsibility among the education, military and health sectors.
Synthesis, Biological Assessment, and Structure Activity Relationship Studies of New Flavanones Embodying Chromene Moieties

Novel flavanones that incorporate chromene motifs are synthesized via a one-step multicomponent reaction. The structures of the new chromenes are elucidated by using IR, 1H-NMR, 13C-NMR, 1H-1H COSY, HSQC, HMBC, and elemental analysis. The new compounds are screened for their in vitro antimicrobial and cytotoxic activities. The antimicrobial properties are investigated and established against seven human pathogens, employing the agar well diffusion method and the minimum inhibitory concentrations. A majority of the assessed derivatives are found to exhibit significant antimicrobial activities against most bacterial strains, in comparison to standard reference drugs. Moreover, their cytotoxicity is appraised against four different human carcinoma cell lines: human colon carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), human breast adenocarcinoma (MCF-7), and adenocarcinoma human alveolar basal epithelial cell (A-549). All the desired compounds are subjected to in-silico studies, forecasting their drug likeness, bioactivity, and the absorption, distribution, metabolism, and excretion (ADME) properties prior to their synthetic assembly. The in-silico molecular docking evaluation of all the targeted derivatives is undertaken on gyrase B and the cyclin-dependent kinase. The in-silico predicted outcomes were endorsed by the in vitro studies.
Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism.
Iron(II) Spin Crossover Complexes with 4,4′-Dipyridylethyne—Crystal Structures and Spin Crossover with Hysteresis

Three new iron(II) 1D coordination polymers with cooperative spin crossover behavior showing thermal hysteresis loops were synthesized using N2O2 Schiff base-like equatorial ligands and 4,4′-dipyridylethyne as a bridging, rigid axial linker. One of those iron(II) 1D coordination polymers showed a 73 K wide hysteresis below room temperature, which, upon solvent loss, decreased to a still remarkable 30 K wide hysteresis. Single crystal X-ray structures of two iron(II) coordination polymers and T-dependent powder XRD patterns are discussed to obtain insight into the structure property relationship of those materials.
Spousal influence: A study of women with eating and body image concerns

Eating disorder literature often overlooks those exhibiting eating and body image concerns without an eating disorder diagnosis. Supportive spouses may ameliorate negative body image and eating behavior, but spouses who exhibit both supportive and non-supportive behaviors concurrently (ambivalent) may send mixed messages. Eating disorder behaviors and spousal interactions were assessed in 61 women who demonstrated eating disordered behavior and body dissatisfaction but were not clinically diagnosed with an eating disorder. Spouses mostly provided messages of reassurance. However, some women were unable to overcome their internalized negative body image. Feelings of social comparison were seen with ambivalent spouses. Supportive relationships may be protective, but actual interventions may be needed to change negative body image.
High-Order Harmonic Generation in Au Nanoparticle-Contained Plasmas

Gold nanoparticles (NPs) have a wide range of applications in various fields. Here, we present high-order nonlinear optical studies of the plasmas produced from ablation of Au bulk targets and Au NP films deposited on paper and glass substrates. Experimentally, we analyze high-order harmonic generation (HHG) from gold NPs-containing plasmas. The HHG is produced by 35-fs pulses at 800 and 400 nm, while the plasmas are produced by femtosecond (35 fs, 800 nm), picosecond (200 ps, 800 nm), and nanosecond (5 ns, 1064 nm) pulses, respectively. High-order harmonics produced from ablated Au NPs on paper were 40 times stronger than the HHG from that ablated from the Au bulk targets. Through molecular dynamic simulations, we investigate the formation of gold NPs during laser ablation of a metal surface under different conditions.
A new molecular method for the rapid subtyping of bovine herpesvirus 1 field isolates

Bovine herpesvirus 1 (BoHV-1) causes several clinical syndromes in cattle worldwide. There are 3 subtypes of BoHV-1: 1.1, 1.2a, and 1.2b. Several molecular methods are commonly used in the detection and characterization of BoHV-1. Among them, restriction endonuclease analysis (REA) and single-nucleotide polymorphism (SNP) analysis of the complete viral genome allow classification of BoHV-1 into different subtypes. However, developing countries need simpler and cheaper screening assays for routine testing. We designed a standard multiplex PCR followed by a REA assay allowing straightforward subclassification of all BoHV-1 isolates tested into 1.1, 1.2a, and 1.2b subtypes based on the analysis of fragment length polymorphism. Our standard multiplex PCR-REA was used to analyze 33 field strains of BoHV-1 isolated from various tissues. The assay confirmed the subtype identified previously by REA. In addition, non-polymorphic or undigested fragments were sequenced in order to confirm the mutation affecting the RE HindIII site. Our PCR-REA method is an affordable and rapid test that will subtype all BoHV-1 strains.
Adaptive and Mutational Responses to Peptide Dendrimer Antimicrobials in Pseudomonas aeruginosa

Colistin (polymyxin E) is a last-resort antibiotic against multidrug-resistant isolates of Pseudomonas aeruginosa. However, the nephro-toxicity of colistin limits its use, spurring the interest in novel antimicrobial peptides (AMP). Here, we show that the synthetic AMP-dendrimer G3KL (MW 4,531.38 Da, 15 positive charges, MIC = 8 mg/liter) showed faster killing than polymyxin B (Pmx-B) with no detectable resistance selection in P. aeruginosa strain PA14. ABSTRACT Colistin (polymyxin E) is a last-resort antibiotic against multidrug-resistant isolates of Pseudomonas aeruginosa. However, the nephro-toxicity of colistin limits its use, spurring the interest in novel antimicrobial peptides (AMP). Here, we show that the synthetic AMP-dendrimer G3KL (MW 4,531.38 Da, 15 positive charges, MIC = 8 mg/liter) showed faster killing than polymyxin B (Pmx-B) with no detectable resistance selection in P. aeruginosa strain PA14. Spontaneous mutants selected on Pmx-B, harboring loss of function mutations in the PhoQ sensor kinase gene, showed increased Pmx-B MICs and arnB operon expression (4-amino-l-arabinose addition to lipid A), but remained susceptible to dendrimers. Two mutants carrying a missense mutation in the periplasmic loop of the PmrB sensor kinase showed increased MICs for Pmx-B (8-fold) and G3KL (4-fold) but not for the dendrimer T7 (MW 4,885.64 Da, 16 positive charges, MIC = 8 mg/liter). The pmrB mutants showed increased expression of the arnB operon as well as of the speD2-speE2-PA4775 operon, located upstream of pmrAB, and involved in polyamine biosynthesis. Exogenous supplementation with the polyamines spermine and norspermine increased G3KL and T7 MICs in a phoQ mutant background but not in the PA14 wild type. This suggests that both addition of 4-amino-l-arabinose and secretion of polyamines are required to reduce susceptibility to dendrimers, probably neutralizing the negative charges present on the lipid A and the 2-keto-3-deoxyoctulosonic acid (KDO) sugars of the lipopolysaccharide (LPS), respectively. We further show by transcriptome analysis that the dendrimers G3KL and T7 induce adaptive responses through the CprRS two-component system in PA14.