Miracle-dz/UniFAR-FTUs huggingface dataset:
Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.
Elucidating the Possible Involvement of Maize Aquaporins and Arbuscular Mycorrhizal Symbiosis in the Plant Ammonium and Urea Transport under Drought Stress Conditions

This study investigates the possible involvement of maize aquaporins which are regulated by arbuscular mycorrhizae (AM) in the transport in planta of ammonium and/or urea under well-watered and drought stress conditions. The study also aims to better understand the implication of the AM symbiosis in the uptake of urea and ammonium and its effect on plant physiology and performance under drought stress conditions. AM and non-AM maize plants were cultivated under three levels of urea or ammonium fertilization (0, 3 µM or 10 mM) and subjected or not to drought stress. Plant aquaporins and physiological responses to these treatments were analyzed. AM increased plant biomass in absence of N fertilization or under low urea/ ammonium fertilization, but no effect of the AM symbiosis was observed under high N supply. This effect was associated with reduced oxidative damage to lipids and increased N accumulation in plant tissues. High N fertilization with either ammonium or urea enhanced net photosynthesis (AN) and stomatal conductance (gs) in plants maintained under well-watered conditions, but 14 days after drought stress imposition these parameters declined in AM plants fertilized with high N doses. The aquaporin ZmTIP1;1 was up-regulated by both urea and ammonium and could be transporting these two N forms in planta. The differential regulation of ZmTIP4;1 and ZmPIP2;4 with urea fertilization and of ZmPIP2;4 with NH4+ supply suggests that these two aquaporins may also play a role in N mobilization in planta. At the same time, these aquaporins were also differentially regulated by the AM symbiosis, suggesting a possible role in the AM-mediated plant N homeostasis that deserves future studies.
D-Index-Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial.

PURPOSE Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.
Peripheral monocyte count is an independent predictor of all-cause mortality in type 2 diabetes with macro-vascular complications

Abstract The relationship between monocyte count and mortality seemed to be varied in different diseases, and it remains unclear in type 2 diabetes (T2D). We conducted a prospective study to investigate whether monocyte count predict all-cause mortality in patients with T2D. In this prospective study, a total of 1073 patients with T2D were enrolled at baseline and 880 patients completed the follow up. The median follow-up time was 47 months. At baseline, clinical characteristics including height, weight, waist circumference, blood pressure were recorded. Biochemical parameters including counts of white blood cells (WBCC), neutrophil (NC) and monocyte (MC), lipid profiles, glycated hemoglobin (HbA1c), serum creatinine were measured. Charlson comorbidity index (CCI) was calculated based on age and comorbidities. Participants were stratified into low, median, and high tertiles according to the baseline MC. Regression models were used to analyze the associations of peripheral MC and the all-cause mortality. Compared to the survived subjects, the baseline MC was significantly higher in patients who deceased during the follow-up (0.45 ± 0.16 vs 0.37 ± 0.15 × 109/L, P = .003). In the multivariate Cox hazard models, subjects in higher MC tertile showed higher risks of all-cause mortality (low tertile as the reference, hazard ratio [HR] 95%CI 2.65 [0.84,8.31] and 3.73 [1.14,12.24] for middle and high MC tertile, respectively) after adjusted for gender, body mass index, CCI, duration of T2D, history of hypertension and metabolic syndrome, drugs, levels of high-sensitivity C-reactive protein, systolic blood pressure, HbA1c, WBCC, and NC. In T2D patients with macro-vascular complications at baseline, 1-SD increment of MC resulted in 1.92-fold higher risk of all-cause mortality. However, the relationship disappeared in subjects without macro-vascular complications at baseline (1.13 [0.72, 1.78], P = .591). Peripheral monocyte count is an independent predictor of all-cause mortality in T2D, especially for subjects with macro-vascular complications.
Absence of GIP secretion alleviates age-related obesity and insulin resistance

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP−/−) and heterozygous (GIP+/−) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP−/− mice compared to that in WT and GIP+/− mice from 38 weeks of age, while there was no significant difference between WT and GIP+/− mice. Visceral and s.c. fat mass were also significantly lower in GIP−/− mice compared to those in WT and GIP+/− mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP−/− mice than those in WT and GIP+/− mice. During insulin tolerance test, GIP−/− mice showed higher insulin sensitivity than that of WT and GIP+/− mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP−/− mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.
I-Block: a simple Escherichia coli-based assay for studying sequence-specific DNA binding of proteins

Abstract We have developed a simple method called I-Block assay, which can detect sequence-specific binding of proteins to DNA in Escherichia coli. The method works by detecting competition between the protein of interest and RNA polymerase for binding to overlapping target sites in a plasmid-borne lacI promoter variant. The assay utilizes two plasmids and an E. coli host strain, from which the gene of the Lac repressor (lacI) has been deleted. One of the plasmids carries the lacI gene with a unique NheI restriction site created in the lacI promoter. The potential recognition sequences of the tested protein are inserted into the NheI site. Introduction of the plasmids into the E. coliΔlacI host represses the constitutive β-galactosidase synthesis of the host bacterium. If the studied protein expressed from a compatible plasmid binds to its target site in the lacI promoter, it will interfere with lacI transcription and lead to increased β-galactosidase activity. The method was tested with two zinc finger proteins, with the lambda phage cI857 repressor, and with CRISPR-dCas9 targeted to the lacI promoter. The I-Block assay was shown to work with standard liquid cultures, with cultures grown in microplate and with colonies on X-gal indicator plates.
Nuclear envelope attachment of telomeres limits TERRA and telomeric rearrangements in quiescent fission yeast cells

Abstract Telomere anchoring to nuclear envelope (NE) is a key feature of nuclear genome architecture. Peripheral localization of telomeres is important for chromatin silencing, telomere replication and for the control of inappropriate recombination. Here, we report that fission yeast quiescent cells harbor predominantly a single telomeric cluster anchored to the NE. Telomere cluster association to the NE relies on Rap1–Bqt4 interaction, which is impacted by the length of telomeric sequences. In quiescent cells, reducing telomere length or deleting bqt4, both result in an increase in transcription of the telomeric repeat-containing RNA (TERRA). In the absence of Bqt4, telomere shortening leads to deep increase in TERRA level and the concomitant formation of subtelomeric rearrangements (STEEx) that accumulate massively in quiescent cells. Taken together, our data demonstrate that Rap1–Bqt4-dependent telomere association to NE preserves telomere integrity in post-mitotic cells, preventing telomeric transcription and recombination. This defines the nuclear periphery as an area where recombination is restricted, creating a safe zone for telomeres of post-mitotic cells.
A Literature Review and Gap Analysis of Emerging Technologies and New Trends in Gambling

There have been significant changes in the gambling landscape particularly relating to gambling in the digital age. As the gambling landscape changes, regulation of gambling also needs to change. In 2018, the Office of Responsible Gambling in New South Wales, Australia, commissioned a gap analysis to inform their research objectives and priority focus areas. This included an identification of gaps in our understanding of emerging technologies and new trends in gambling. A gap analysis of the peer-reviewed literature published since 2015 was undertaken, identifying 116 articles. The main area of focus was Internet gambling, followed by articles exploring the relationship between video gaming and gambling, the expansion of the sports betting market, Electronic Gambling Machines characteristics and articles exploring new technologies and trends in advertising and inducements. Key gaps related to the need for more research in general, as well as research focusing on subpopulations such as those using different gambling formats, those with varying levels of problem gambling, and vulnerable populations. From a methods perspective, researchers saw the need for longitudinal studies, more qualitative research and improved outcome measures. The development and testing of a public health approach to addressing the harms associated with gambling in these areas is needed.
Reducing Sedentary Time among Older Adults in Assisted Living: Perceptions, Barriers, and Motivators

Older adults accumulate more sedentary time (ST) than any other age group, especially those in assisted living residences (ALRs). Reducing prolonged ST could help maintain function among older adults. However, to develop effective intervention strategies, it is important to understand the factors that influence sedentary behavior. The purpose of this study was to explore perceptions of ST as well as barriers and motivators to reducing ST among older adults in assisted living, in the context of the Social Ecological Model (SEM). Using a qualitative description approach, we sought to learn about participants’ perceptions of sedentary time in their daily lives. Semi-structured focus groups were held at six ALRs with 31 participants (84% women, 83.5 ± 6.5 years). Data were transcribed and coded using an inductive thematic approach. Themes were categorized based on four levels of the SEM: individual, social, physical environment, and organization. Many reported barriers were at the individual level (e.g., lack of motivation, pain, fatigue) while others were associated with the organization or social environment (e.g., safety concerns, lack of activities outside of business hours, and social norms). These findings suggest that there are unique challenges and opportunities to consider when designing ST interventions for assisted living.
Pediatric Emergency Department Return Visits: An Innovative and Systematic Approach to Promote Quality Improvement and Patient Safety.

OBJECTIVES Emergency department (ED) return visits (RVs) leading to hospital admission are a quality measure that can potentially signal gaps in patient care. Systematic capture and investigation of RVs at a case level can provide an understanding of patient- and visit-level factors associated with RVs, and thus inform system-level quality improvement (QI) opportunities. Our objective is to describe the development of a database that enables tracking and analyzing of all pediatric ED RVs, to understand recurring themes and inform QI initiatives. METHODS A single-center retrospective cohort study was conducted at a quaternary care children's hospital during a 3-year period (December 2013 to November 2016). All 72-hour RVs were audited for patient- and visit-level variables and clinicians completed root-cause analyses of their RVs. Using descriptive statistics, variables associated with RVs and system-level quality themes were identified. RESULTS Of 214,047 ED patient visits, 1546 (0.7%) patients returned within 72 hours and were admitted. The RV patients had higher acuity scores on both visits compared with all ED visits, and the RV group had a higher proportion of children younger than 12 months than the overall ED visit group (25.0% vs 16.2%). The underlying cause for the majority of RVs was determined to be natural disease progression (63%), whereas 9% were callbacks for positive blood cultures or discrepant radiology results, and 6% were categorized as misdiagnoses. Several successful QI initiatives were completed as a result of the program. CONCLUSIONS Systematic monitoring and investigation of all ED RVs provides an innovative and effective approach to seeking provider- and system-level improvement opportunities.
Influence of comorbid knee osteoarthritis on surgical outcome and sagittal spinopelvic/lower-extremity alignment in elderly patients with degenerative lumbar spondylolisthesis undergoing transforaminal lumbar interbody fusion.

OBJECTIVE This retrospective study aimed to clarify the influence of comorbid severe knee osteoarthritis (KOA) on surgical outcome in terms of sagittal spinopelvic/lower-extremity alignment in elderly patients with degenerative lumbar spondylolisthesis (DLS). METHODS In total, 110 patients aged at least 65 years (27 men, 83 women; mean age 74.0 years) who underwent short-segment lumbar fusion were included in the present study. Using the Kellgren-Lawrence (KL) grading system, patients were categorized into those with no to mild KOA (the mild-OA group: KL grades 0-2), moderate KOA (moderate-OA group: KL grade 3), or severe KOA (severe-OA group: KL grade 4). Surgical results were assessed using the Japanese Orthopaedic Association (JOA) scoring system, and spinopelvic/lower-extremity parameters were compared among the 3 groups. Adjacent-segment disease (ASD) was assessed over a mean follow-up period of 4.7 years (range 2-8.1 years). RESULTS The study cohort was split into the mild-OA group (42 patients), the moderate-OA group (28 patients), and the severe-OA group (40 patients). The severe-OA group contained significantly more women (p = 0.037) and patients with double-level listhesis (p = 0.012) compared with the other groups. No significant differences were found in mean postoperative JOA scores or recovery rate among the 3 groups. The mean postoperative JOA subscore for restriction of activities of daily living was only significantly lower in the severe-OA group compared with the other groups (p = 0.010). The severe-OA group exhibited significantly greater pelvic incidence, pelvic tilt, and knee flexion angle (KFA), along with a smaller degree of lumbar lordosis than the mild-OA group both pre- and postoperatively (all p < 0.05). Overall, the rate of radiographic ASD was observed to be higher in the severe-OA group than in the mild-OA group (p = 0.015). Patients with ASD in the severe-OA group exhibited significantly greater pelvic tilt, pre- and postoperatively, along with less lumbar lordosis, than the patients without ASD postoperatively (all p < 0.05). CONCLUSIONS A lack of lumbar lordosis caused by double-level listhesis and knee flexion contracture compensated for by far greater pelvic retroversion is experienced by elderly patients with DLS and severe KOA. Therefore, corrective lumbar surgery and knee arthroplasty may be considered to improve sagittal alignment, which may contribute to the prevention of ASD, resulting in favorable long-term surgical outcomes.
Effectiveness of Tocilizumab in juvenile patients with refractory Takayasu arteritis

Abstract Rationale: Takayasu arteritis (TA) is a systemic large-vessel vasculitis which can be accompanied by the symptoms associated with vascular stenosis. Patient concerns: We describe 2 female juveniles with TA who presented with progressive intermittent claudication. Diagnosis: Contrast-enhanced computed tomography (CT) revealed the stenosis of femoral arteries and increased levels of C-reactive protein (CRP), and serum amyloid A (SAA) were noted in both patients. According to European league against rheumatism consensus criteria for the diagnosis of TA was confirmed in both patients. Interventions: Both patients had shown resistance to glucocorticoids and treated with tocilizumab (TCZ) (subcutaneous injections, 162 mg/week). Outcomes: These treatments improved claudication symptoms. Follow-up imaging by enhanced CT revealed restoration of advanced stenosis of the femoral arteries in both patients. They achieved normalization of levels of the acute-phase reactants CRP and SAA. Serum levels of interleukin-6 were increased transiently after TCZ injection, but declined to within normal ranges at 12 weeks. Lessons: Juvenile patients with TA presenting with advanced stenosis of the femoral arteries are not rare. The clinical courses of our patients suggested the beneficial effects of TCZ against the progressive vascular stenosis observed in refractory TA.
Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome

Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.