Miracle-dz/UniFAR-FTUs huggingface dataset:
Anti-Virulence Strategy against the Honey Bee Pathogenic Bacterium Paenibacillus larvae via Small Molecule Inhibitors of the Bacterial Toxin Plx2A

American Foulbrood, caused by Paenibacillus larvae, is the most devastating bacterial honey bee brood disease. Finding a treatment against American Foulbrood would be a huge breakthrough in the battle against the disease. Recently, small molecule inhibitors against virulence factors have been suggested as candidates for the development of anti-virulence strategies against bacterial infections. We therefore screened an in-house library of synthetic small molecules and a library of flavonoid natural products, identifying the synthetic compound M3 and two natural, plant-derived small molecules, Acacetin and Baicalein, as putative inhibitors of the recently identified P. larvae toxin Plx2A. All three inhibitors were potent in in vitro enzyme activity assays and two compounds were shown to protect insect cells against Plx2A intoxication. However, when tested in exposure bioassays with honey bee larvae, no effect on mortality could be observed for the synthetic or the plant-derived inhibitors, thus suggesting that the pathogenesis strategies of P. larvae are likely to be too complex to be disarmed in an anti-virulence strategy aimed at a single virulence factor. Our study also underscores the importance of not only testing substances in in vitro or cell culture assays, but also testing the compounds in P. larvae-infected honey bee larvae.
NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.
Protocadherin 19 Clustering Epilepsy and Neurosteroids: Opportunities for Intervention

Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these individuals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefit.
Physiological and Disease Models of Respiratory System Based on Organ-on-a-Chip Technology

The pathogenesis of respiratory diseases is complex, and its occurrence and development also involve a series of pathological processes. The present research methods are have difficulty simulating the natural developing state of the disease in the body, and the results cannot reflect the real growth state and function in vivo. The development of microfluidic chip technology provides a technical platform for better research on respiratory diseases. The size of its microchannel can be similar to the space for cell growth in vivo. In addition, organ-on-a-chip can achieve long-term co-cultivation of multiple cells and produce precisely controllable fluid shear force, periodically changing mechanical force, and perfusate with varying solute concentration gradient. To sum up, the chip can be used to analyze the specific pathophysiological changes of organs meticulously, and it is widely used in scientific research on respiratory diseases. The focus of this review is to describe and discuss current studies of artificial respiratory systems based on organ-on-a-chip technology and to summarize their applications in the real world.
Underdiagnosis of Major Depressive Episodes in Hemodialysis Patients: The Need for Screening and Patient Education

This article aims to identify the reasons why patients with major depressive episode (MDE) do not seek treatment for their mental disorder. 89 out of 208 persons screened were diagnosed with major depressive episode using the Mini-International Neuropsychiatric Interview. 85 individuals with untreated depression filled out the following questionnaires: Beck Depression Inventory, List of Explanations of Well-Being (LEWB), Brief Measure to Assess Perception of Self-Influence on the Course of the Disease, Coping Inventory for Stressful Situations, Brief Method of Evaluating Coping with Disease, and Metacognitions Questionnaire. There were 43 women (50.6%) and 42 men (49.4%), aged 24 to 93 years (Mean (M) = 68.26 years; Standard Deviation (SD) = 14.19 years), with dialysis vintage ranging from 1 month to 33 years (M = 70.63 months; SD = 75.26 months). Among study patients, 70.6% declared that depression was the cause of their poor well-being, 75.3% attributed their depressive symptoms to kidney failure, and 49.4%, more specifically, to hemodialysis. A total of 64.7% of patients had a low perception of self-influence on the course of their kidney disease, and 58.5% presented a coping style focused on emotions. The most frequent dysfunctional metacognitive beliefs were negative beliefs about not controlling one’s own thoughts. This attitude was related to the low perception of self-influence on the course of the disease, maladaptive coping styles, and dysfunctional metacognitive beliefs.
A Path Model for Burnout in Community Mental Health Professionals

The purpose of this research is to identify a path model to explain burnout in community mental health professionals based on the compassion satisfaction–compassion fatigue (CS-CF) model. A total of 125 mental health professionals, including nurses, social professionals, and psychologists working in mental health welfare centers in various regions across South Korea were surveyed using a structured questionnaire. A path analysis was conducted using SPSS 24.0 and AMOS 24.0. The results showed that compassion satisfaction and compassion fatigue are significant predictors of burnout (β = −0.20, p = 0.011; β = 0.40, p < 0.001, respectively). The indirect pathways associated with burnout included occupational stress (β = 0.21, p = 0.021) and experience with aggressive behavior in the workplace (β = 0.33, p = 0.004) through maladaptive cognitive emotion regulation and compassion satisfaction. The total effect of the variables on burnout via compassion fatigue and compassion satisfaction explained 62.5% of burnout among mental health professionals. These findings indicate that providing nursing interventions might reduce compassion fatigue and increase compassion satisfaction to reduce burnout. Furthermore, intervention programs that help to reduce the use of maladaptive cognitive emotion regulation strategies are necessary to effectively reduce burnout in mental health professionals.
Fabrication of Humidity-Resistant Optical Fiber Sensor for Ammonia Sensing Using Diazo Resin-Photocrosslinked Films with a Porphyrin-Polystyrene Binary Mixture

Ammonia gas sensors were fabricated via layer-by-layer (LbL) deposition of diazo resin (DAR) and a binary mixture of tetrakis(4-sulfophenyl)porphine (TSPP) and poly(styrene sulfonate) (PSS) onto the core of a multimode U-bent optical fiber. The penetration of light transferred into the evanescent field was enhanced by stripping the polymer cladding and coating the fiber core. The electrostatic interaction between the diazonium ion in DAR and the sulfonate residues in TSPP and PSS was converted into covalent bonds using UV irradiation. The photoreaction between the layers was confirmed by UV-vis and Fourier transform infrared spectroscopy. The sensitivity of the optical fiber sensors to ammonia was linear when exposed to ammonia gases generated from aqueous ammonia solutions at a concentration of approximately 17 parts per million (ppm). This linearity extended up to 50 ppm when the exposure time (30 s) was shortened. The response and recovery times were reduced to 30 s with a 5-cycle DAR/TSPP+PSS (as a mixture of 1 mM TSPP and 0.025 wt% PSS in water) film sensor. The limit of detection (LOD) of the optimized sensor was estimated to be 0.31 ppm for ammonia in solution, corresponding to approximately 0.03 ppm of ammonia gas. It is hypothesized that the presence of the hydrophobic moiety of PSS in the matrix suppressed the effects of humidity on the sensor response. The sensor response was stable and reproducible over seven days. The PSS-containing U-bent fiber sensor also showed superior sensitivity to ammonia when examined alongside amine and non-amine analytes.
Fractal Dimension and Texture Analysis of Lesion Autofluorescence in the Evaluation of Oral Lichen Planus Treatment Effectiveness

Background: Oral Lichen planus (OLP) is a chronic inflammatory disease. Topical steroids are used as the treatment of choice. The alternative is photodynamic therapy (PDT). The study aimed to fabricate optimal biodegradable matrices for methylene blue or triamcinolone acetonide because of a lack of currently commercially available carriers that could adhere to the mucous. Methods: The study was designed as a 12-week single-blind prospective randomized clinical trial with 30 patients, full contralateral split-mouth design. Matrices for steroid and photosensitizer and laser device were fabricated. Fractal and texture analysis of photographs, taken in 405, 450, 405 + 450 nm wavelength, of lesions was performed to increase the objectivity of the assessment of treatment. Results: We achieved two total responses for treatment in case of steroid therapy and one in the case of PDT. Partial response was noted in 17 lesions treated using local steroid therapy and 21 in the case of PDT. No statistically significant differences were found between the effectiveness of both used methods. Statistically significant differences in fractal dimension before and after treatment were observed only in the analysis of photographs taken in 405 + 450 nm wavelength. Conclusions: Photodynamic therapy and topical steroid therapy are effective methods for treating OLP. Using a carrier offers the possibility of a more predictable and effective method of drug delivery into the mucous membrane. Autofluorescence enables the detection of lesions especially at the early stage of their development.
Structural Insight into La0.5Ca0.5Mn0.5Co0.5O3 Decomposition in the Methane Combustion Process

Perovskite-like solid solution La0.5Ca0. 5Mn0.5Co0. 5O3 was tested during the total methane combustion reaction. During the reaction, there is a noticeable decrease in methane conversion, the rate of catalyst deactivation increasing with an increase in temperature. The in situ XRD and HRTEM methods show that the observed deactivation occurs as a result of the segregation of calcite and cobalt oxide particles on the perovskite surface. According to the TGA, the observed drop in catalytic activity is also associated with a large loss of oxygen from the perovskite structure.
An Experimental Study on Mechanical Properties for the Static and Dynamic Compression of Concrete Eroded by Sulfate Solution

The mechanical properties of the static and dynamic compression of concrete eroded by a 15% sodium sulfate solution were explored with a 70-mm-diameter true triaxial static-dynamic comprehensive loading test system, and an analysis of the weakening mechanisms for the degree of macroscopic damage and microscopic surface changes of eroded concrete were conducted in combination with damage testing based on relevant acoustic characteristics and SEM scanning. The experience obtained in this paper is used to analyze and solve the problem that the bearing capacity of concrete buildings is weakened due to the decrease in durability under the special conditions of sulfate erosion. The results showed that, in a short time, the properties of concrete corroded by sulfate solution were improved to a certain extent due to continuous hydration. When the corrosion time was prolonged, the internal concrete structure was destroyed after it was eroded by sulfate, and its dynamic and static strength, deformability, and energy absorption were reduced to differing degrees, thus greatly inhibiting the overall mechanical performance of concrete; the dynamic compressive strength changed with strain that exhibited a significant strain rate effect; and, under the influence of sulfate erosion and hydration, the longitudinal wave velocity increased first and then decreased. The longitudinal wave velocity was slower than that of concrete under normal environment and distilled water immersion condition. SEM and acoustic wave analysis indicated that the internal concrete structure was destroyed after it was eroded by sulfate, and its dynamic and static strength, deformability, and energy absorption were reduced to differing degrees, thus greatly inhibiting the overall mechanical performance of concrete.
Osteosarcoma in Children: Not Only Chemotherapy

Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS.
HuD Regulates mRNA-circRNA-miRNA Networks in the Mouse Striatum Linked to Neuronal Development and Drug Addiction

Simple Summary Gene expression controls all aspects of life, including that of humans. Genes are expressed by copying the information stored in the DNA into RNA molecules, and this process is regulated in part by multiple RNA-binding proteins (RBPs). One such protein, HuD, plays a critical role in the development of neurons and has been implicated in childhood brain tumors, neurodegenerative disorders (Parkinson’s, Alzheimer’s, and ALS), and drug abuse. In addition, HuD participates in neuronal remodeling mechanisms in the mature brain and promotes regeneration of peripheral nerves. HuD primarily binds to transcribed messenger RNAs, which are then stabilized for translation into proteins. However, recent studies demonstrate that HuD also regulates the expression of non-coding RNAs, such as circular RNAs (circRNAs) and microRNAs (miRNAs). In this study, we examined the role of HuD in the control of non-coding RNA expression in the mouse striatum, a brain region associated both with normal behaviors and pathological conditions such as drug abuse. Our results show that HuD regulates mRNA-circRNA-miRNA networks involved in the expression of genes associated with brain development and remodeling of neuronal connections. These findings suggest the possibility of new mechanisms controlling brain development, neurodegenerative diseases, and substance use disorders. Abstract The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology.
The Antifungal Action Mode of N-Phenacyldibromobenzimidazoles

Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (5e–f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-β-d-glucosaminide and 4-nitrophenyl-β-d-N,N′,N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing β-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors.
Sphingolipid and Endocannabinoid Profiles in Adult Attention Deficit Hyperactivity Disorder

Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
The Road from Pathological Narcissism to Suicidality in Adolescence: An Empirical Study

Background: Clinical and empirical research evidenced a complex link between pathological narcissism and the suicidal process in adulthood. Given the relevance of suicidality and the peculiar narcissistic vicissitudes of adolescence, the proposed research investigated the relationship between pathological narcissism analyzed from the multi-dimensional perspective of the Diagnostic Interview for Narcissism (DIN) and suicidal ideation conducted in a sample of Italian Adolescents. Methods: One hundred and three Italian male and female adolescents between 12 and 18 were administered the DIN, SCIDII, CSSRS, and Kiddie-SADS with six months follow-up. Results: The correlation, t-test, multiple regression analyses evidenced the association of narcissistic affective states and mood with both suicidal ideation and lethality of conduct. The increase in the dimension of grandiosity is associated with the passage to potentially highly lethal suicidal gestures. Conclusions: Suicidal ideation and conduct seem to serve the function of restoring a sense of control and self-esteem in narcissistic individuals experiencing a state of affective dysregulation. Narcissistic pathological functioning seems to play an important role in the adolescent suicidal process, quite like adulthood. Assessing an adolescent’s narcissistic functioning may provide useful clinical information in understanding and managing the suicidal risk in this phase of life.