Miracle-dz/UniFAR-FTUs huggingface dataset:
Retinal Ganglion Cell Replacement: Current Status and Challenges Ahead

The neurons of the retina can be affected by a wide variety of inherited or environmental degenerations that can lead to vision loss and even blindness. Retinal ganglion cell (RGC) degeneration is the hallmark of glaucoma and other optic neuropathies that affect millions of people worldwide. Numerous strategies are being trialed to replace lost neurons in different degeneration models, and in recent years, stem cell technologies have opened promising avenues to obtain donor cells for retinal repair. Stem cell–based transplantation has been most frequently used for the replacement of rod photoreceptors, but the same tools could potentially be used for other retinal cell types, including RGCs. However, RGCs are not abundant in stem cell–derived cultures, and in contrast to the short‐distance wiring of photoreceptors, RGC axons take a long and intricate journey to connect with numerous brain nuclei. Hence, a number of challenges still remain, such as the ability to scale up the production of RGCs and a reliable and functional integration into the adult diseased retina upon transplantation. In this review, we discuss the recent advancements in the development of replacement therapies for RGC degenerations and the challenges that we need to overcome before these technologies can be applied to the clinic. Developmental Dynamics 248:118–128, 2019. © 2018 Wiley Periodicals, Inc.
Development of Phonological, Lexical, and Syntactic Abilities in Children With Cochlear Implants Across the Elementary Grades.

Purpose This study assessed phonological, lexical, and morphosyntactic abilities at 6th grade for a group of children previously tested at 2nd grade to address 4 questions: (a) Do children with cochlear implants (CIs) demonstrate deficits at 6th grade? (b) Are those deficits greater, the same, or lesser in magnitude than those observed at 2nd grade? (c) How do the measured skills relate to each other? and (d) How do treatment variables affect outcome measures? Participants Sixty-two 6th graders (29 with normal hearing, 33 with CIs) participated, all of whom had their language assessed at 2nd grade. Method Data are reported for 12 measures obtained at 6th grade, assessing phonological, lexical, and morphosyntactic abilities. Between-groups analyses were conducted on 6th-grade measures and the magnitude of observed effects compared with those observed at 2nd grade. Correlational analyses were performed among the measures at 6th grade. Cross-lagged analyses were performed on specific 2nd- and 6th-grade measures of phonological awareness, vocabulary, and literacy to assess factors promoting phonological and lexical development. Treatment effects of age of 1st CI, preimplant thresholds, and bimodal experience were evaluated. Results Deficits remained fairly consistent in type and magnitude across elementary school. The largest deficits were found for phonological skills and the least for morphosyntactic skills, with lexical skills intermediate. Phonological and morphosyntactic skills were largely independent of each other; lexical skills were moderately related to phonological skills but not morphosyntactic skills. Literacy acquisition strongly promoted both phonological and lexical development. Of the treatment variables, only bimodal experience affected outcomes and did so positively. Conclusions Congenital hearing loss puts children at continued risk of language deficits, especially for phonologically based skills. Two interventions that appear to ameliorate that risk are providing a period of bimodal stimulation and strong literacy instruction.
Metabolic marker gene mining provides insight in global mcrA diversity and, coupled with targeted genome reconstruction, sheds further light on metabolic potential of the Methanomassiliicoccales

Over the past years, metagenomics has revolutionized our view of microbial diversity. Moreover, extracting near-complete genomes from metagenomes has led to the discovery of known metabolic traits in unsuspected lineages. Genome-resolved metagenomics relies on assembly of the sequencing reads and subsequent binning of assembled contigs, which might be hampered by strain heterogeneity or low abundance of a target organism. Here we present a complementary approach, metagenome marker gene mining, and use it to assess the global diversity of archaeal methane metabolism through the mcrA gene. To this end, we have screened 18,465 metagenomes for the presence of reads matching a database representative of all known mcrA proteins and reconstructed gene sequences from the matching reads. We use our mcrA dataset to assess the environmental distribution of the Methanomassiliicoccales and reconstruct and analyze a draft genome belonging to the ‘Lake Pavin cluster’, an uncultivated environmental clade of the Methanomassiliicoccales. Analysis of the ‘Lake Pavin cluster’ draft genome suggests that this organism has a more restricted capacity for hydrogenotrophic methylotrophic methanogenesis than previously studied Methanomassiliicoccales, with only genes for growth on methanol present. However, the presence of the soluble subunits of methyltetrahydromethanopterin:CoM methyltransferase (mtrAH) provide hypothetical pathways for methanol fermentation, and aceticlastic methanogenesis that await experimental verification. Thus, we show that marker gene mining can enhance the discovery power of metagenomics, by identifying novel lineages and aiding selection of targets for in-depth analyses. Marker gene mining is less sensitive to strain heterogeneity and has a lower abundance threshold than genome-resolved metagenomics, as it only requires short contigs and there is no binning step. Additionally, it is computationally cheaper than genome resolved metagenomics, since only a small subset of reads needs to be assembled. It is therefore a suitable approach to extract knowledge from the many publicly available sequencing projects.
Impact of direct acting antiviral (DAA) treatment on glucose metabolism and reduction of pre-diabetes in patients with chronic hepatitis C.

BACKGROUND AND AIM With the development of direct acting antiviral agents (DAA) chronic hepatitis C virus (HCV) infection has become curable in most patients. Since HCV infection is known to have direct and/or indirect effects on glucose metabolism, successful HCV treatment may have an impact in reducing glucose level, pre-diabetes, the need of treatment for diabetes, and ultimately diabetes-associated morbidity. We investigated the association of DAA treatment and glucose metabolism in the context of development or resolution of hepatic fibrosis in a large cohort of HCV- infected patients. METHODS In this retrospective single-center observational study, we investigated 281 patients receiving all-oral DAA therapy for fasting plasma glucose, HbA1c, liver enzymes and general clinical chemistry, measured during a 52-week follow-up. In addition, elastography, FIB-4- and APRI-calculation were used to assess hepatic fibrosis non-invasively. RESULTS Successful elimination of HCV through DAA treatment was associated with a significant drop in fasting glucose level and a reduced rate of impaired fasting plasma glucose (FPG). Interestingly, this metabolic change was BMI-independent. In addition, long-term glucose levels also decreased after successful DAA treatment. A significant APRI-score reduction was associated with a persistent improvement of FPG. However, DAA did not have an impact on glucose metabolism in patients suffering from liver cirrhosis. CONCLUSION This study highlights the beneficial impact of successful HCV therapy on glucose metabolism and identifies patients with liver cirrhosis as a collective in need of intensified surveillance with regard to diabetes progression despite HCV eradication.
QSPR modelling of in vitro degradation half-life of acyl glucuronides

Abstract Acyl glucuronidation is an important Phase II biotransformation, which is an efficient detoxification mechanism for the metabolism of carboxylic acid group-containing drugs. However, the reactivity of acyl glucuronide (AG) metabolites associated with short half-lives may be an indication of idiosyncratic drug toxicity. The degradation half-lives of AGs elucidate several important reactions such as hydrolysis, acyl migration and covalent binding to proteins. Prediction of degradation half-life using computational methods is a promising alternative approach to costly and time-consuming experiments, enabling a priori evaluation of the properties of drug candidates during the drug design process. The main objective of the present study was to develop a linear model for the quantitative prediction of half-lives of acyl glucuronidated drug-like compounds. The proposed model revealed that the number of total quaternary carbons, the complexity of the ring in the compound, Sanderson electronegativities, and dipole moment of the compound are important molecular features in predicting the half-life of an AG. The rigorously validated model can contribute to a better understanding of molecular features of these drugs to predict degradation half-lives.
Achieving target levels for vascular risk parameters in Polish school-age children with type 1 diabetes – a single center study

Abstract Background Therapeutic goals have been established to decrease the risk of long-term complications of type 1 diabetes (T1DM). The effects of these guidelines should be constantly evaluated. Hence, the present study examines the frequency at which children with T1DM treated by one of the Polish reference centers complied with the therapeutic targets issued in 2014 by the International Society for Pediatric and Adolescent Diabetes (ISPAD) and by the Diabetes Poland (PTD). Methods A retrospective analysis (years 2011–2014) was performed in patients with T1DM aged 6.5–18 years, with diabetes duration >12 months and no change of insulin regimen within 6 months. Collected data included insulin therapy regimen, weight, height, blood pressure, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and glycated hemoglobin (HbA1c) level from the last hospitalization. Results The records of 447 patients (260 boys, 299 treated with insulin pump) were analyzed. All ISPAD goals were achieved by 123 (27.5%) patients, but only 43 (9.6%) met all PTD targets. Optimal HbA1c was achieved by 224 (50.1%) according to ISPAD criteria (HbA1c<7.5%) and by 87 (19.6%) patients according to PTD (HbA1c≤6.5%). Obesity was diagnosed in 11.6% of the patients; 19.7% of the patients were overweight. In logistic regression, patient age was the only independent predictor of failing to achieve complete T1DM control (p=0.001, OR=1.12 [1.05–1.23]) and optimal HbA1c (p=0.01, OR=1.1 [1.0–1.2]) according to ISPAD guidelines. Moreover, girls had a greater risk of failing body mass index (BMI) targets (PTD: p=0.002, OR=2.16; ISPAD: p=0.0001, OR=3.37) and LDL-C targets (p=0.005, OR=1.8) than boys. Conclusions Overall, control of vascular risk factors in Polish children with T1DM is unsatisfactory. While too few children are achieving the HbA1c target set by PTD, it is possible that such strict national target helps half of the Polish school-age patients achieve ISPAD-issued aim which is more liberal. High prevalence of overweight among children with T1DM warrants initiatives focused not only on glycemic control but also on motivation of patients to lead a healthy lifestyle.
A classification of product sampling for software product lines

The analysis of software product lines is challenging due to the potentially large number of products, which grow exponentially in terms of the number of features. Product sampling is a technique used to avoid exhaustive testing, which is often infeasible. In this paper, we propose a classification for product sampling techniques and classify the existing literature accordingly. We distinguish the important characteristics of such approaches based on the information used for sampling, the kind of algorithm, and the achieved coverage criteria. Furthermore, we give an overview on existing tools and evaluations of product sampling techniques. We share our insights on the state-of-the-art of product sampling and discuss potential future work.
Autophagy in Adipose Tissue Physiology and Pathophysiology.

SIGNIFICANCE Alterations in adipose tissue function have profound consequences on whole body energy homeostasis because this tissue is central for fat accumulation, energy expenditure, glucose and insulin metabolism, and hormonal regulation. With the obesity reaching epidemic proportions globally, it is important to understand the mechanisms leading to adipose tissue malfunction. Recent Advances: Autophagy has originally been viewed as an adaptive response to cellular stress, but in recent years this process was shown to regulate important cellular processes. In adipose tissue, autophagy is a key regulator of white adipose tissue (WAT) and brown adipose tissue (BAT) adipogenesis, and dysregulated autophagy impairs fat accumulation both in vitro and in vivo. Animal studies have also suggested an important role for autophagy and mitophagy during the transition from beige to white fat. Human studies have provided evidence for altered autophagy in WAT, and these alterations correlated with the degree of insulin resistance. CRITICAL ISSUES Despite these important advances in the study of autophagy in adipose tissue, we still do not understand the physiological role of autophagy in mature white and brown adipocytes. Furthermore, several human studies involving autophagy assessment were performed on whole adipose tissue, which complicates the interpretation of the results considering the cellular heterogeneity of this tissue. FUTURE DIRECTIONS Future studies will undoubtedly expand our understanding of the role of autophagy in fully differentiated adipocytes, and uncover novel cross-talks between this tissue and other organs in regulating lipid metabolism, redox signaling, energy homeostasis, and insulin sensitivity. Antioxid. Redox Signal. 00, 000-000.
Infrared Coagulation: A Treatment Option for Cervical Intraepithelial Neoplasia

In their recent article in Journal of Global Oncology, after meticulous evaluation of current literature and experience, Jeronimo et al present guidelines for secondary prevention of cervical cancer. Among those is the recommended treatment of grade 3 or greater cervical intraepithelial neoplasia (CIN) lesions with loop electrosurgical excision procedure (LEEP). Although LEEP is a common, well-studied, and effective procedure, it has complications, including cervical bleeding, stenosis, and pregnancy-related adverse outcomes. Thus, bridging knowledge from anal surgery, we propose the use of infrared coagulation (IRC) as a treatment option for CIN lesions to diminish or even eliminate complications. IRC effectively ablates anal lesions in an area (anus) with denser sensory innervation and microbial load than the cervix and in an area that experiencesdaily functional tissue stretching asa result of normal defecation, which does not occur in the cervical area. As a result of all these negative characteristics of the anal area, there have been no attempts to use LEEP in the anus because severemorbidity would result. However, using the friendly energy of IRC, anal dysplasia is treated effectively, especially when anal intraepithelial neoplasia covers a limited surface of the anal canal epithelium. This result is attributed to the fact that IRC penetrates fully the epithelium, which is the locum of intraepithelial lesions, leavingdeeper tissuesunaffected,which is not the case with LEEP.
Synthesis and Characterization of Poly(Vinyl Alcohol)-Chitosan-Hydroxyapatite Scaffolds: A Promising Alternative for Bone Tissue Regeneration

Scaffolds can be considered as one of the most promising treatments for bone tissue regeneration. Herein, blends of chitosan, poly(vinyl alcohol), and hydroxyapatite in different ratios were used to synthesize scaffolds via freeze-drying. Mechanical tests, FTIR, swelling and solubility degree, DSC, morphology, and cell viability were used as characterization techniques. Statistical significance of the experiments was determined using a two-way analysis of variance (ANOVA) with p < 0.05. Crosslinked and plasticized scaffolds absorbed five times more water than non-crosslinked and plasticized ones, which is an indicator of better hydrophilic features, as well as adequate resistance to water without detriment of the swelling potential. Indeed, the tested mechanical properties were notably higher for samples which were undergone to crosslinking and plasticized process. The presence of chitosan is determinant in pore formation and distribution which is an imperative for cell communication. Uniform pore size with diameters ranging from 142 to 519 µm were obtained, a range that has been described as optimal for bone tissue regeneration. Moreover, cytotoxicity was considered as negligible in the tested conditions, and viability indicates that the material might have potential as a bone regeneration system.
Understanding vulnerabilities in plugin-based web systems: an exploratory study of wordpress

A common software product line strategy involves plugin-based web systems that support simple and quick incorporation of custom behaviors. As a result, they have been widely adopted to create web-based applications. Indeed, the popularity of ecosystems that support plugin-based development (e.g., WordPress) is largely due to the number of customization options available as community-contributed plugins. However, plugin-related vulnerabilities tend to be recurrent, exploitable and hard to be detected and may lead to severe consequences for the customized product. Hence, there is a need to further understand such vulnerabilities to enable preventing relevant security threats. Therefore, we conducted an exploratory study to characterize vulnerabilities caused by plugins in web-based systems. To this end, we went over WordPress vulnerability bulletins cataloged by the National Vulnerability Database as well as associated patches maintained by the WordPress plugins repository. We identified the main types of vulnerabilities caused by plugins as well as their impact and the size of the patch to fix the vulnerability. Moreover, we identified the most common security-related topics discussed among WordPress developers. We observed that, while plugin-related vulnerabilities may have severe consequences and might remain unnoticed for years before being fixed, they can commonly be mitigated with small and localized changes to the source code. The characterization helps to provide an understanding on how typical plugin-based vulnerabilities manifest themselves in practice. Such information can be helpful to steer future research on plugin-based vulnerability detection and prevention.
Model-based product line development with EASy-producer using VIL and VTL

EASy-Producer is an open-source research toolset for engineering product lines, variability-rich software ecosystems, and dynamic software product lines. In this tutorial, we will focus on its model-based development and implementation capabilities, which are realized by the Variability Instantiation Language (VIL) and the Variability Template Language (VTL). Further, we will provide a basic introduction into the Integrated Variability Modeling Language (IVML) in order to use the provided information of IVML variability models and configurations during instantiation defined with VIL and as part of the templates created with VTL.
Steroids and nonsteroidal anti‐inflammatory drugs in the postoperative regime after trabeculectomy – which provides the better outcome? A systematic review and meta‐analysis

Surgical outcome after trabeculectomy depends on maintaining a functional bleb which requires a delicate balance between incomplete wound healing to prevent fibrosis and enough wound healing to prevent hyperfiltration. Thus, controlling the inflammatory response is essential. We conducted a systematic review and meta‐analysis to compare the effectiveness of different formulations of steroids (topical, systemic and depot) and nonsteroidal anti‐inflammatory drugs (NSAIDs) in achieving long‐term pressure control with fewer antiglaucomatous medications, preserving visual acuity and visual fields while considering surgical and postoperative complications. We used the PubMed, EMBASE and Cochrane Libraries to identify randomized controlled trials (RCTs) comparing the effect of different formulations of steroids (topical, systemic or depot) to NSAIDs. Data on prespecified outcomes from eligible references were entered into a meta‐analysis using the Review Manager 5.3 program. We identified seven RCTs with a total of 342 included patients. Topical steroids were superior to placebo in controlling intraocular pressure (IOP) and reducing the risk of complications. Supplementing topical steroids with a perioperative steroid depot (subtenon or intracamerally) or systemic steroids in the early postoperative period did not provide better outcome or a change in the risk of complications. Addition of topical NSAIDs to topical steroids in patients undergoing trabeculectomy did not change the outcome or risk profile. For patients undergoing phacotrabeculectomy and topical NSAID, there was a nonsignificant trend towards better intermediate IOP control and a reduced need for antiglaucomatous medications compared to topical steroids but there was no difference in effect for patients undergoing trabeculectomy. In conclusion, there is a low level of evidence to support the clinician in deciding which postoperative regime provides a more favourable outcome because of inconsistency in the reported outcomes between studies and a low number of patients for each comparable intervention and outcome. It does seem that topical steroids are better than no anti‐inflammatory treatment after glaucoma surgery, but further research is recommended.
Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer

Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.