Miracle-dz/UniFAR-FTUs huggingface dataset:
Therapeutic efficacy of equine botulism heptavalent antitoxin against all seven botulinum neurotoxins in symptomatic guinea pigs

Botulism neurotoxins are highly toxic and are potential agents for bioterrorism. The development of effective therapy is essential to counter the possible use of these toxins in military and bioterrorism scenarios, and to provide treatment in cases of natural intoxication. Guinea pigs were intoxicated with a lethal dose of botulinum neurotoxin serotypes A, B, C, D, E, F or G, and at onset of the clinical disease intoxicated animals were treated with either BAT® [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)–(Equine)] or placebo. BAT product treatment significantly (p<0.0001) enhanced survival compared to placebo for all botulinum neurotoxin serotypes and arrested or mitigated the progression of clinical signs of botulism intoxication. These results demonstrated the therapeutic efficacy of BAT product in guinea pigs and provided supporting evidence of effectiveness for licensure of BAT product under FDA 21 CFR Part 601 (Subpart H Animal Rule) as a therapeutic for botulism intoxication to serotypes A, B, C, D, E, F or G in adults and pediatric patients.
Numerical modeling of high-intensity focused ultrasound-mediated intraperitoneal delivery of thermosensitive liposomal doxorubicin for cancer chemotherapy

Abstract Although intraperitoneal chemotherapy (IPC) has been suggested as a promising method for the management of peritoneal dissemination (PD) of ovarian or colorectal cancers, the actual clinical use of this method has been restricted due to such problems as poor drug penetration into the tumor and high side effects. It is, therefore, necessary to develop new strategies to improve the efficacy of this approach. In the present work, a new strategy is proposed based on intraperitoneal (IP) injection of thermosensitive liposomal doxorubicin (TSL-Dox) with triggered release by mild hyperthermia induced by high intensity focused ultrasound (HIFU). A computational model is developed to evaluate the proposed drug delivery system. Results show an order of magnitude increase in drug penetration depth into the tumor compared to the conventional IP delivery. Furthermore, the effects of thermal conditions applied to the tumor, TSL size, tumor vessel permeability, and tumor size are investigated. Results indicate an improved efficiency of the drug delivery by expanding the heated region, yet, it increases the risk of unintentional TSL drug load release in the peritoneal cavity. Results also indicate that smaller TSLs have better treatment outcome. However, there is a significant reduction in treatment efficacy for TSLs with sizes smaller than the vessel wall pore size. Thus, tuning the size of TSL should be based on the tumor microvascular permeability. The simulation results suggest that the TSL-Dox delivery system in smaller tumors is far advantageous than larger ones. Results of our model can be used as guidelines for future preclinical studies.
MYCELIAL EFFECTS ON PHAGE RETENTION DURING TRANSPORT IN A MICROFLUIDIC PLATFORM.

Phages (i.e. viruses that infect bacteria) have been considered as good tracers for the hydrological transport of colloids and (pathogenic) viruses. Little, however, is known about interactions of phages with (fungal) mycelia as the prevalent soil microbial biomass. Forming extensive and dense networks, mycelia provide significant surfaces for phage-hyphal interactions. Here, we for the first time quantified the mycelial retention of phages in a microfluidic platform that allowed for defined fluid exchange around hyphae. Two common lytic tracer phages (Escherichia coli phage T4 and marine phage PSA-HS2) and two mycelia of differing surface properties (Coprionopsis cinerea, Pythium ultimum) were employed. Phage-hyphal interaction energies were approximated by the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) approach of colloidal interaction. Our data show initial hyphal retention of phages of up to ≈ 4 × 107 PFU mm-2 (≈ 2550 PFU mm-2 s-1) with a retention efficiency depending on the hyphal and, to a lesser extent, the phage surface properties. Experimental data were supported by XDLVO calculations, which revealed the highest attractive forces for the interaction between hydrophobic T4 phages and hydrophobic C. cinerea surfaces. Our data suggest that mycelia may be relevant for the retention of phages in the subsurface and need to be considered in subsurface phage tracer studies. Mycelia-phage interactions may further be exploited for the development of novel strategies to reduce or hinder the transport of undesirable (bio-)colloidal entities in environmental filter-systems.
Population-level surveillance of antibiotic resistance in Escherichia coli through sewage analysis

Introduction The occurrence of antibiotic resistance in faecal bacteria in sewage is likely to reflect the current local clinical resistance situation. Aim This observational study investigated the relationship between Escherichia coli resistance rates in sewage and clinical samples representing the same human populations. Methods E. coli were isolated from eight hospital (n = 721 isolates) and six municipal (n = 531 isolates) sewage samples, over 1 year in Gothenburg, Sweden. An inexpensive broth screening method was validated against disk diffusion and applied to determine resistance against 11 antibiotics in sewage isolates. Resistance data on E. coli isolated from clinical samples from corresponding local hospital and primary care patients were collected during the same year and compared with those of the sewage isolates by linear regression. Results E. coli resistance rates derived from hospital sewage and hospital patients strongly correlated (r2 = 0.95 for urine and 0.89 for blood samples), as did resistance rates in E. coli from municipal sewage and primary care urine samples (r2 = 0.82). Resistance rates in hospital sewage isolates were close to those in hospital clinical isolates while resistance rates in municipal sewage isolates were about half of those measured in primary care isolates. Resistance rates in municipal sewage isolates were more stable between sampling occasions than those from hospital sewage. Conclusion Our findings provide support for development of a low-cost, sewage-based surveillance system for antibiotic resistance in E. coli, which could complement current monitoring systems and provide clinically relevant antibiotic resistance data for countries and regions where surveillance is lacking.
The adaptive value of epigenetic mutation: Limited in large but high in small peripheral populations

The fate of populations during range expansions, invasions and environmental changes is largely influenced by their ability to adapt to peripheral habitats. Recent models demonstrate that stable epigenetic modifications of gene expression that occur more frequently than genetic mutations can both help and hinder adaptation in panmictic populations. However, these models do not consider interactions between epimutations and evolutionary forces in peripheral populations. Here, we use mainland–island mathematical models and simulations to explore how the faster rate of epigenetic mutation compared to genetic mutations interacts with migration, selection and genetic drift to affect adaptation in peripheral populations. Our model focuses on cases where epigenetic marks are stably inherited. In a large peripheral population, where the effect of genetic drift is negligible, our analyses suggest that epimutations with random fitness impacts that occur at rates as high as 10–3 increase local adaptation when migration is strong enough to overwhelm divergent selection. When migration is weak relative to selection and epimutations with random fitness impacts decrease adaptation, we find epigenetic modifications must be highly adaptively biased to enhance adaptation. Finally, in small peripheral populations, where genetic drift is strong, epimutations contribute to adaptation under a wider range of evolutionary conditions. Overall, our results suggest that epimutations can change outcomes of adaptation in peripheral populations, which has implications for understanding conservation and range expansions and contractions, especially of small populations.
Pseudomonas aeruginosa ExsA Regulates a Metalloprotease, ImpA, That Inhibits Phagocytosis of Macrophages

Pseudomonas aeruginosa is an opportunistic pathogenic bacterium whose type III secretion system (T3SS) plays a critical role in acute infections. Translocation of the T3SS effectors into host cells induces cytotoxicity. In addition, the T3SS promotes the intracellular growth of P. aeruginosa during host infections. The T3SS regulon genes are regulated by an AraC-type regulator, ExsA. In this study, we found that an extracellular metalloprotease encoded by impA (PA0572) is under the regulation of ExsA. ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogenic bacterium whose type III secretion system (T3SS) plays a critical role in acute infections. Translocation of the T3SS effectors into host cells induces cytotoxicity. In addition, the T3SS promotes the intracellular growth of P. aeruginosa during host infections. The T3SS regulon genes are regulated by an AraC-type regulator, ExsA. In this study, we found that an extracellular metalloprotease encoded by impA (PA0572) is under the regulation of ExsA. An ExsA consensus binding sequence was identified upstream of the impA gene, and direct binding of the site by ExsA was demonstrated via an electrophoretic mobility shift assay. We further demonstrate that secreted ImpA cleaves the macrophage surface protein CD44, which inhibits the phagocytosis of the bacterial cells by macrophages. Combined, our results reveal a novel ExsA-regulated virulence factor that cooperatively inhibits the functions of macrophages with the T3SS.
Switching to iGlarLixi Versus Continuing Daily or Weekly GLP-1 RA in Type 2 Diabetes Inadequately Controlled by GLP-1 RA and Oral Antihyperglycemic Therapy: The LixiLan-G Randomized Clinical Trial

OBJECTIVE Fixed-ratio combinations of basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1 RA) allow concomitant administration of two proven complementary injectable therapies for type 2 diabetes. This study investigated switching to a titratable fixed-ratio combination of insulin glargine plus lixisenatide (iGlarLixi) in patients with type 2 diabetes receiving daily or weekly GLP-1 RA therapy. RESEARCH DESIGN AND METHODS LixiLan-G, a randomized, open-label, 26-week trial, compared switching to iGlarLixi versus continuing prior GLP-1 RA in patients with type 2 diabetes and HbA1c 7–9% (53–75 mmol/mol) taking maximum tolerated doses of a GLP-1 RA daily (60% on liraglutide once daily or exenatide twice daily) or weekly (40% on dulaglutide, exenatide extended release, or albiglutide) with metformin with or without pioglitazone and with or without sodium–glucose cotransporter 2 inhibitors. Adherence to randomized treatment was closely monitored throughout the study. RESULTS iGlarLixi (n = 257) reduced HbA1c more than continued GLP-1 RA therapy (n = 257) from a baseline 7.8% (62 mmol/mol) in both to 6.7% (50 mmol/mol) and 7.4% (57 mmol/mol), respectively, at 26 weeks (least squares mean difference −0.6%; P < 0.0001). More iGlarLixi patients achieved HbA1c <7% (53 mmol/mol) (62% vs. 26%; P < 0.0001) and the composite of HbA1c <7% without documented symptomatic hypoglycemia (<54 mg/dL). Nausea and vomiting rates as well as numbers of documented symptomatic hypoglycemia events per patient-year were generally low but greater with iGlarLixi versus continued GLP-1 RA therapy. CONCLUSIONS Switching to iGlarLixi improves glucose control for patients with type 2 diabetes insufficiently controlled on a maximum tolerated dose of a GLP-1 RA plus oral antihyperglycemic agents.
T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces

Significance Cells respond to the mechanical properties of their environment, altering a range of cellular functions important to normal tissue function, disease progression, and repair. This mechanosensing ability has been studied predominantly with planar substrates which, while experimentally advantageous, do not capture the complexity of cellular interfaces. This report demonstrates that T cells respond to the mechanical resistance of microfabricated elastomer structures, identifying an aspect of mechanosensing that has implications from understanding cell–cell interactions to design of biomaterials. Cells have the remarkable ability to sense the mechanical stiffness of their surroundings. This has been studied extensively in the context of cells interacting with planar surfaces, a conceptually elegant model that also has application in biomaterial design. However, physiological interfaces are spatially complex, exhibiting topographical features that are described over multiple scales. This report explores mechanosensing of microstructured elastomer surfaces by CD4+ T cells, key mediators of the adaptive immune response. We show that T cells form complex interactions with elastomer micropillar arrays, extending processes into spaces between structures and forming local areas of contraction and expansion dictated by the layout of microtubules within this interface. Conversely, cytoskeletal reorganization and intracellular signaling are sensitive to the pillar dimensions and flexibility. Unexpectedly, these measures show different responses to substrate rigidity, suggesting competing processes in overall T cell mechanosensing. The results of this study demonstrate that T cells sense the local rigidity of their environment, leading to strategies for biomaterial design.
Are serum levels of ADAMTS5, TAS and TOS at 24–28 gestational weeks associated with adverse perinatal outcomes in gestational diabetic women?

Abstract We aimed to determine the role of placental A Disintegrin and Metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and maternal serum ADAMTS5, total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) levels at 24–28th gestational weeks in GDM. This study included 57 patients, who had been diagnosed as having GDM at their 24–28th gestational week, and 29 controls. The maternal blood samples were collected at the 24-28th gestational week and ADAMTS5 was studied with the enzyme-linked immunosorbent assay (ELISA) method, whereas an automated colorimetric method was used to study TAS, TOS, and OSI. The level of ADAMTS5 in maternal serum of patients with GDM were significantly lower than the controls (p = .017); whereas TOS and OSI levels were significantly higher (p = .003 and p = .008). Multivariable logistic regression analysis revealed ADAMTS5 and TOS levels were independently associated with adverse perinatal outcomes (p = .004 and p = .018). We found that serum ADAMTS5 levels decreased and TOS level increased in GDM pregnant at 24–28th gestational weeks. In addition, we found that increased levels of serum ADAMTS5 and decreased TOS levels at 24–28th weeks were associated with adverse perinatal outcomes independent of the mode of treatment in GDM. Impact statement What is already known on this subject? Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. The insulin resistance, which starts at the 24–28th gestational weeks, increases during gestation. GDM increases maternal complications like preeclampsia, cesarean rate, cardiovascular disease, obesity, and diabetes after pregnancy; and neonatal complications like macrosomia, hypoglycemia, hyperbilirubinemia, delivery trauma, shoulder dystocia, and adult-onset obesity, and diabetes. What the results of this study add? A significant relationship between ADAMTS5, TOS levels and adverse perinatal outcome. insulin resistance and was observed. What the implications are of these findings for clinical practice and/or further research? Based on this finding, we concluded that increased levels of oxidative stress and decreased ADAMTS5 levels are associated with GDM and predictive for adverse perinatal outcomes. The results of the present study were consistent with the previous reports and indicated that increased oxidative stress in GDM patients are related to adverse perinatal outcomes.
Detecting and measuring areas of choriocapillaris low perfusion in intermediate, non-neovascular age-related macular degeneration

Abstract. Age-related macular degeneration (AMD) is a vision-threatening disease that affects the outer retina and choroid of elderly adults. Because photoreceptors are found in the outer retina and rely primarily on the trophic support of the underlying choriocapillaris, imaging of flow or lack thereof in choriocapillaris by optical coherence tomography angiography (OCTA) has great clinical potential in AMD assessment. We introduce a metric using OCTA, named “focal perfusion loss” (FPL) to describe the effects of age and non-neovascular AMD on choriocapillaris flow. Because OCTA imaging of choriocapillaris is vulnerable to artifacts—namely motion, projections, segmentation errors, and shadows—they are removed by postprocessing software. The shadow detection software is a machine learning algorithm recently developed for the evaluation of the retinal circulation and here adapted for choriocapillaris analysis. It aims to exclude areas with unreliable flow signal due to blocking of the OCT beam by objects anterior to the choriocapillaris (e.g., drusen, retinal vessels, vitreous floaters, and iris). We found that both the FPL and the capillary density were able to detect changes in the choriocapillaris of AMD and healthy age-matched subjects with respect to young controls. The dominant cause of shadowing in AMD is drusen, and the shadow exclusion algorithm helps determine which areas under drusen retain sufficient signal for perfusion evaluation and which areas must be excluded. Such analysis allowed us to determine unambiguously that choriocapillaris density under drusen is indeed reduced.
Discovery of the Lyme Disease Agent

A detailed first-hand account of the events leading up to the discovery of the Lyme disease agent has been lacking. Nearly 40 years have elapsed since the discovery of the organism that was named Borrelia burgdorferi. There are thousands of articles in the scientific and medical literature on this organism and the disease that it causes. In the interval since the organism’s discovery, however, misconceptions have arisen regarding not only the disease but the discovery itself. ABSTRACT A detailed first-hand account of the events leading up to the discovery of the Lyme disease agent has been lacking. Nearly 40 years have elapsed since the discovery of the organism that was named Borrelia burgdorferi. There are thousands of articles in the scientific and medical literature on this organism and the disease that it causes. In the interval since the organism’s discovery, however, misconceptions have arisen regarding not only the disease but the discovery itself. Accordingly, with this paper, we aim to fill in the details of this episode in medical history with a joint introduction, first-person accounts by the two authors, a summary of contemporaneous events, and concluding comments. The history of the discovery of the Lyme disease agent has threads originating in different places in the United States. Studies on Long Island, NY, provided the epidemiological thread of studies on rickettsial diseases and babesiosis, linking the latter with the cutaneous manifestation of Lyme disease, now known as erythema migrans. The Long Island thread intersected Montana’s Rocky Mountain Laboratories thread of studies on a relapsing fever Borrelia and its cultivation and expertise in vector biology. This intersection made possible the discovery of the spirochete and its recovery from patients. This paper stresses that what may seem to have been an individual scientific discovery is actually the product of several threads coming together and is attributable to more people than appreciated.
Monitoring Tuberculosis Drug Activity in Live Animals by Using Near-Infrared Fluorescence Imaging

Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis. In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and fastidious procedure that delays the progression of drugs down the pipeline and towards the clinic. ABSTRACT Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis. In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and fastidious procedure that delays the progression of drugs down the pipeline and towards the clinic. In this investigation, we report the construction, optimization, and characterization of genetically engineered near-infrared (NIR) fluorescent reporter strains of the pathogens Mycobacterium marinum and Mycobacterium tuberculosis that enable the direct visualization of bacteria in infected zebrafish and mice, respectively. Fluorescence could be measured precisely in infected immunodeficient mice, while its intensity appeared to be below the limit of detection in immunocompetent mice, probably because of the lower bacterial load obtained in these animals. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by CFU enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals in real time. The NIR fluorescent imaging system disclosed here is a valuable resource for TB research and can serve to accelerate drug development.
Abnormal body weight and food-related behavior in school-aged children as measured by the Children’s Binge Eating Disorder Scale

Obesity in children is becoming a global epidemic. Health and emotional consequences can threaten life and health both during childhood and adulthood. In this study, we aimed to assess the coexistence of overweight and obesity, binge eating disorder and detrimental attitudes toward nutrition among school-age children. We also aimed to determine the usefulness of the Children’s Binge Eating Disorder Scale (C-BEDS) as a screening tool. We examined a group of over 550 healthy children aged 6–12. In all, 15% were overweight, and 6% were obese. A total of 12% of the children presented an increased risk of eating disorders. The examined group of children significantly differed in the number of positive C-BEDS responses compared with the authors of the test. Test reliability as measured by the Cronbach’s alpha coefficient was . 008. Preliminary results indicate that the problem of excessive body weight affects every fifth child, consistent with previous reports. The C-BEDS used in this study did not permit the identification of children, neither with the risk of Binge Eating Disorder (BED) nor subthreshold BED. This may be due to the relatively low internal consistency of the questions contained in the scale.