Miracle-dz/UniFAR-FTUs huggingface dataset:
A De Novo Mutation in COL1A1 in a Holstein Calf with Osteogenesis Imperfecta Type II

Simple Summary Skeletal connective tissue disorders represent a heterogeneous group of inherited disorders mostly monogenically inherited. Heritable connective tissue disorders such as osteogenesis imperfecta (OI) belong to this group. Herein, an affected calf showing congenital bone lesions such as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis resembling OI type II is reported. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL1A1 gene. The COL1A1 gene is known to be associated with dominant inherited OI type II forms in humans and sporadically in dogs and cattle, but so far, a variant in the fibrillar collagen NC1 domain has not been shown to cause a similar phenotype in domestic animals. We assume that the herein identified most-likely causative variant occurred either within the parental germlines or post-zygotically in the developing embryo. Rare lethal disorders such as OI in livestock are usually not diagnosed to the molecular level, mainly because of the lack of resources and diagnostic tools. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders. Abstract Osteogenesis imperfecta (OI) type II is a genetic connective tissue disorder characterized by bone fragility, severe skeletal deformities and shortened limbs. OI usually causes perinatal death of affected individuals. OI type II diagnosis in humans is established by the identification of heterozygous mutations in genes coding for collagens. The purpose of this study was to characterize the pathological phenotype of an OI type II-affected neonatal Holstein calf and to identify the causative genetic variant by whole-genome sequencing (WGS). The calf had acute as well as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis. Genetic analysis revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals. Furthermore, this study highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for rare lethal genetic disorders in cattle.
Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS has emerged as an attractive anti-virulence target for therapeutic design. The T3SS is a multiprotein molecular syringe that enables pathogens to inject effector proteins into host cells. These effectors modify host cell mechanisms in a variety of ways beneficial to the pathogen. Due to the T3SS’s complex nature, there are numerous ways in which it can be targeted. This review will be focused on the direct targeting of components of the T3SS, including the needle, translocon, basal body, sorting platform, and effector proteins. Inhibitors will be considered a direct inhibitor if they have a binding partner that is a T3SS component, regardless of the inhibitory effect being structural or functional.
Is Periodontitis a Predictor for an Adverse Outcome in Patients Undergoing Coronary Artery Bypass Grafting? A Pilot Study

Periodontitis is a risk factor for atherosclerosis and coronary vascular disease (CVD). This research evaluated the relationship between periodontal conditions and postoperative outcome in patients who underwent coronary artery bypass grafting (CABG). A total of 101 patients with CVD (age 69 years, 88.1% males) and the necessity of CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the Centers for Disease Control and Prevention (CDC, 2007). Additionally, periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) were determined. Multivariate survival analyses were carried out after a one-year follow-up period with Cox regression. All study subjects suffered from periodontitis (28.7% moderate, 71.3% severe). During the follow-up period, 14 patients (13.9%) experienced a new cardiovascular event (11 with angina pectoris, 2 with cardiac decompensation, and 1 with cardiac death). Severe periodontitis was not significant associated with the incidence of new events (adjusted hazard ratio, HR = 2.6; p = 0.199). Other risk factors for new events were pre-existing peripheral arterial disease (adjusted HR = 4.8, p = 0.030) and a history of myocardial infarction (HR = 6.1, p = 0.002). Periodontitis was not found to be an independent risk factor for the incidence of new cardiovascular events after CABG surgery.
Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

Simple Summary Metastatic urothelial cell carcinoma (UCC) is a significant public health burden with a median survival estimated at about 15 months. The use of immunotherapy with immune checkpoint inhibitors has greatly improved outcomes but only benefits a minority (~20%) of patients. In this review we discuss the evidence showing how a key molecular pathway known as Wnt/β-catenin signaling can be a driver of immunotherapy resistance and how these insights can serve as lessons for improving future treatment of urothelial carcinoma. Abstract Urothelial cell carcinoma (UCC) is a significant public health burden. It accounts for approximately 90 percent of all bladder cancers with an estimated 200,000 annual deaths globally. Platinum based cytotoxic chemotherapy combinations are the current standard of care in the frontline setting for metastatic UCC. Even with these treatments the median overall survival is estimated to be about 15 months. Recently, immune checkpoint inhibitors (ICIs) have demonstrated superior clinical benefits compared to second line chemotherapy in UCC treatment. However only a minority of patients (~20%) respond to ICIs, which highlights the need to better understand the mechanisms behind resistance. In this review, we (i) examine the pathophysiology of Wnt/β-catenin signaling, (ii) discuss pre-clinical evidence that supports the combination of Wnt/β-catenin inhibitors and ICI, and (iii) propose future combination treatments that could be investigated through clinical trials.
The Effectiveness of an Educational Intervention on Knowledge, Attitudes and Reported Practices on Antibiotic Use in Humans and Pigs: A Quasi-Experimental Study in Twelve Villages in Shandong Province, China

Our aim was to evaluate the effectiveness of an intervention for residents in rural China on knowledge, attitudes and reported practices (KAP) on antibiotic use in humans and pigs. A quasi-experimental study was conducted in 12 villages in rural Shandong province, divided into intervention and control groups, covering a two-year period from July 2015 to June 2017. A package of health education-based interventions including training sessions, speakerphone messages, posters and handbooks for residents was developed and implemented over a one-year period to improve the use of antibiotics in humans and pigs. The intervention net effects were evaluated by Difference-in-Difference (DID) analysis based on responses to a questionnaire concerning KAP towards antibiotic use in humans and pigs. A total of 629 participants completed both baseline and post-trial questionnaires, including 127 participants with backyard pig farms. Significant improvements were found in KAP towards antibiotic use in humans, but changes related to antibiotic use for pigs were not significant. Participants who were in the intervention group (p < 0.001) were more likely to have improved their knowledge on antibiotic use in humans. Participants who had higher attitude scores were less likely to report self-medicating with stored antibiotics in the previous year (p < 0.001). Our results suggest that our health education-based intervention was effective in improving KAP on human antibiotic use, but it had little effect regarding antibiotic use for pigs.
Ketoanalogs’ Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease (Medika2 Study)

Nutritional therapy (NT) is a therapeutic option in the conservative treatment of chronic kidney disease (CKD) patients to delay the start of dialysis. The aim of this study was to evaluate the specific effect of ketoanalogs (KA)-supplemented diets for gut microbiota modulation. In a previous study we observed that the Mediterranean diet (MD) and a KA-supplemented very-low-protein diet (VLPD) modulated beneficially gut microbiota, reducing indoxyl- and p-cresyl-sulfate (IS, PCS) serum levels, and ameliorating the intestinal permeability in CKD patients. In the current study, we added a third diet regimen consisting of KA-supplemented MD. Forty-three patients with CKD grades 3B–4 continuing the crossover clinical trial were assigned to six months of KA-supplemented MD (MD + KA). Compared to MD, KA-supplementation in MD + KA determined (i) a decrease of Clostridiaceae, Methanobacteriaceae, Prevotellaceae, and Lactobacillaceae while Bacteroidaceae and Lachnospiraceae increased; (ii) a reduction of total and free IS and PCS compared to a free diet (FD)—more than the MD, but not as effectively as the VLPD. These results further clarify the driving role of urea levels in regulating gut integrity status and demonstrating that the reduction of azotemia produced by KA-supplemented VLPD was more effective than KA-supplemented MD in gut microbiota modulation mainly due to the effect of the drastic reduction of protein intake rather than the effect of KA.
A Review of Vat Photopolymerization Technology: Materials, Applications, Challenges, and Future Trends of 3D Printing

Additive manufacturing (3D printing) has significantly changed the prototyping process in terms of technology, construction, materials, and their multiphysical properties. Among the most popular 3D printing techniques is vat photopolymerization, in which ultraviolet (UV) light is deployed to form chains between molecules of liquid light-curable resin, crosslink them, and as a result, solidify the resin. In this manuscript, three photopolymerization technologies, namely, stereolithography (SLA), digital light processing (DLP), and continuous digital light processing (CDLP), are reviewed. Additionally, the after-cured mechanical properties of light-curable resin materials are listed, along with a number of case studies showing their applications in practice. The manuscript aims at providing an overview and future trend of the photopolymerization technology to inspire the readers to engage in further research in this field, especially regarding developing new materials and mathematical models for microrods and bionic structures.
Normal Versus Slowly Processed Pasta and Post-Prandial Glucose Homeostasis in Healthy Subjects: A Pilot Study

Nutritional science is gaining increasing attention due to the implicit potential to prevent cardio-metabolic diseases. It is also becoming clear that food-making process might influence the metabolic response to the meal. We have conducted a proof-of-concept study to investigate whether slowly processed pasta might positively impact glucose homeostasis. A total of 14 healthy male volunteers underwent two different mixed-meal tests in a randomized order. One meal was composed of 100 g of normally processed pasta and the other 100 g of slowly processed pasta. Each meal was completed with 10 g of olive oil and 10 g of parmesan cheese. Glucose, insulin, and incretin post-prandial responses were assessed at 15, 30, 60, 90, 120, 150, and 180 min. Glucose tolerance, insulin, and incretin response were unaffected by the two different pasta types. However, a slight difference was evident in the shape of the curve of post-prandial insulin (i.e., mildly delayed with the slowly processed pasta). Despite the common belief of a different impact of normally processed and slowly processed pasta on glucose metabolism, they show a superimposable post-prandial metabolic response after a single meal in male healthy individuals. Further studies are required to confirm these results also in chronic, real-life settings and then to translate them to metabolically impaired individuals.
Novel Protein-Based Vaccine against Self-Antigen Reduces the Formation of Sporadic Colon Adenomas in Mice

Simple Summary Colorectal cancer remains a leading cause of cancer-related mortality worldwide. However, high-risk populations with a genetic predisposition for colorectal cancer could benefit greatly from novel and efficacious immunopreventive strategies that afford long-lasting protection. The achaete-scute family bHLH transcription factor 2 (Ascl2) has been identified as a promising target for immunoprevention of colorectal cancer, based on its induction during the formation and progression of colorectal tumors and its minimal expression observed in healthy tissue. The goal of the present study was to determine the efficacy of a protein-based vaccine targeting Ascl2 in combination with an anti-PD-1 treatment in a spontaneous colorectal cancer mouse model. This novel vaccine strategy promotes potent tumor-specific immunity, and prevents the formation of colon adenomas in mice. The results demonstrate that Ascl2 is a promising target for immunoprevention for individuals at elevated risk of developing colorectal cancer. Abstract Novel immunopreventive strategies are emerging that show great promise for conferring long-term protection to individuals at high risk of developing colorectal cancer. The KISIMA vaccine platform utilizes a chimeric protein comprising: (1) a selected tumor antigen; (2) a cell-penetrating peptide to improve antigen delivery and epitope presentation, and (3) a TLR2/4 agonist to serve as a self-adjuvant. This study examines the ability of a KISIMA vaccine against achaete-scute family bHLH transcription factor 2 (Ascl2), an early colon cancer antigen, to reduce colon tumor formation by stimulating an anti-tumor immune response. Vaccine administrations were well-tolerated and led to circulating antibodies and antigen-specific T cells in a mouse model of colorectal cancer. To assess preventive efficacy, the vaccine was administered to mice either alone or in combination with the immune checkpoint inhibitor anti-PD-1. When delivered to animals prior to colon tumor formation, the combination strategy significantly reduced the development of colon microadenomas and adenomas, as compared to vehicle-treated controls. This response was accompanied by an increase in the intraepithelial density of CD3+ T lymphocytes. Together, these data indicate that the KISIMA-Ascl2 vaccine shows great potential to be a safe and potent immunopreventive intervention for individuals at high risk of developing colorectal cancer.
Increased Risk of Migraine in Patients with Chronic Periodontitis: A Population-Based Cohort Study

Migraine is considered to be a neurovascular disease that manifests as a throbbing headache, possibly caused by the activation of the trigeminovascular system. Several studies have supported the role of inflammation in the pathogenesis of migraine. Chronic periodontitis (CP) is an infectious inflammatory disease triggered by bacterial products evoking an immune response which could result in the destruction of the periodontium. However, little is known about the longitudinal association between CP and migraine. In this study, we designed a nationwide population-based cohort study to investigate the risk of migraine and CP exposure in Taiwan. In total, 68,282 patients with CP were identified from the National Health Insurance Research Database (NHIRD), and 68,282 comparisons were randomly captured and matched by age, sex, monthly income, urbanization and comorbidities. The association between CP exposure and migraine risk was evaluated by Cox proportional hazards regression models. In this study, 785 migraine patients were identified in the CP cohort, and 641 migraine cases were found in the non-CP cohort. The incidence rate of migraine was significantly higher in the CP cohort than the non-CP cohort (adjusted HR: 1.21, 95% CI: 1.09–1.34, p < 0.001) during the 13-year follow-up period. Females had a 2.69-fold higher risk for migraine than males (95% CI: 2.38–3.04, p < 0.001). In summary, CP is associated with an increased risk of subsequent migraine in Taiwan.
Nanomaterials for Biomedical Applications: Production, Characterisations, Recent Trends and Difficulties

Designing of nanomaterials has now become a top-priority research goal with a view to developing specific applications in the biomedical fields. In fact, the recent trends in the literature show that there is a lack of in-depth reviews that specifically highlight the current knowledge based on the design and production of nanomaterials. Considerations of size, shape, surface charge and microstructures are important factors in this regard as they affect the performance of nanoparticles (NPs). These parameters are also found to be dependent on their synthesis methods. The characterisation techniques that have been used for the investigation of these nanomaterials are relatively different in their concepts, sample preparation methods and obtained results. Consequently, this review article aims to carry out an in-depth discussion on the recent trends on nanomaterials for biomedical engineering, with a particular emphasis on the choices of the nanomaterials, preparation methods/instruments and characterisations techniques used for designing of nanomaterials. Key applications of these nanomaterials, such as tissue regeneration, medication delivery and wound healing, are also discussed briefly. Covering this knowledge gap will result in a better understanding of the role of nanomaterial design and subsequent larger-scale applications in terms of both its potential and difficulties.
An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications

Understanding the causality of the post-traumatic osteoarthritis (PTOA) disease process of the knee joint is important for diagnosing early disease and developing new and effective preventions or treatments. The aim of this review was to provide detailed clinical data on inflammatory and other biomarkers obtained from patients after acute knee trauma in order to (i) present a timeline of events that occur in the acute, subacute, and chronic post-traumatic phases and in PTOA, and (ii) to identify key factors present in the synovial fluid, serum/plasma and urine, leading to PTOA of the knee in 23–50% of individuals who had acute knee trauma. In this context, we additionally discuss methods of simulating knee trauma and inflammation in in vivo, ex vivo articular cartilage explant and in vitro chondrocyte models, and answer whether these models are representative of the clinical inflammatory stages following knee trauma. Moreover, we compare the pro-inflammatory cytokine concentrations used in such models and demonstrate that, compared to concentrations in the synovial fluid after knee trauma, they are exceedingly high. We then used the Bradford Hill Framework to present evidence that TNF-α and IL-6 cytokines are causal factors, while IL-1β and IL-17 are credible factors in inducing knee PTOA disease progresssion. Lastly, we discuss beneficial infrastructure for future studies to dissect the role of local vs. systemic inflammation in PTOA progression with an emphasis on early disease.
Personalized Consideration of Admission-Glucose Gap between Estimated Average and Initial Glucose Levels on Short-Term Stroke Outcome

Background: Poststroke hyperglycemia is associated with poor outcomes. Most prior studies used initial glucose as an indicator of poststroke hyperglycemia without considering glycemic control status at the time of stroke occurrence. We aimed to investigate the effect of an admission-glucose gap on short-term functional outcomes in acute ischemic stroke (AIS). Methods: We enrolled patients with AIS or transient ischemic attack who had been admitted within 7 days of symptom onset to three stroke centers from May 2016 to December 2019. The admission-glucose gap between estimated average glucose levels (eAG) and initial glucose level (eAG–initial glucose) was categorized into four groups. The short-term functional outcome was evaluated using the modified Rankin Scale (mRS) score at 3 months after stroke onset and was dichotomized. Results: Among 1332 included subjects, 548 (41.1%) had poor short-term functional outcomes. After adjusting for multiple variables, a severe negative glucose gap (eAG–initial glucose ≤ −50 mg/dL) was significantly associated with poor short-term functional outcome (OR, 1.573; 95% CI, 1.101–2.248). After dichotomizing glycemic control status, its significance was only maintained in the good glycemic control group (HbA1c < 6.5%) (OR, 1.914; 95% CI, 1.155–3.169). Conclusions: An elevated admission-glucose gap, in which the initial glucose level was much higher than the estimated glucose level was based on HbA1c, was associated with poor stroke prognosis. In addition to admission-glucose levels, glycemic control status at the time of stroke onset should be considered when predicting short-term stroke outcomes.
Western Corn Rootworm, Plant and Microbe Interactions: A Review and Prospects for New Management Tools

Simple Summary Over 90 million acres of US cropland are planted with corn, Zea mays, annually. The western corn rootworm, Diabrotica virgifera virgifera, causes significant economic damage by feeding on corn roots and the insect has populations that have adapted to nearly all management techniques in some regions. Additional tools are needed. Significant research on the basic biology of this pest has added new possibilities. Here, we summarize research that we believe has potential for future management of this major pest. Abstract The western corn rootworm, Diabrotica virgifera virgifera LeConte, is resistant to four separate classes of traditional insecticides, all Bacillius thuringiensis (Bt) toxins currently registered for commercial use, crop rotation, innate plant resistance factors, and even double-stranded RNA (dsRNA) targeting essential genes via environmental RNA interference (RNAi), which has not been sold commercially to date. Clearly, additional tools are needed as management options. In this review, we discuss the state-of-the-art knowledge about biotic factors influencing herbivore success, including host location and recognition, plant defensive traits, plant-microbe interactions, and herbivore-pathogens/predator interactions. We then translate this knowledge into potential new management tools and improved biological control.