Miracle-dz/UniFAR-FTUs huggingface dataset:
A Therapeutic Game for Sexually Abused Children and Adolescents (Vil Du?!): Exploratory Mixed Methods Evaluation

Background Talking about experiences of sexual abuse in therapy is difficult for children and adolescents. Possible reasons for this difficulty are a lack of vocabulary to describe the situation or feelings of shame, fear, and self-blame associated with sexual abuse. The serious game Vil Du? was developed to help children open up about their sexual abuse experiences. Vil Du? is a nonverbal communication game that resembles a dress-up game in which children can show the therapist what happened to them. Objective This exploratory evaluation study examines which working elements of the game could be identified in therapy with victims of sexual abuse (aim 1). In addition, this study examines how therapists evaluate the acceptability of the game (aim 2). Methods The therapists completed 23 web-based surveys on the use of Vil Du? In addition, semistructured interviews were conducted with 10 therapists. The data were analyzed in NVivo following previously reported stepwise guidelines. Results Regarding aim 1, therapists mentioned various working elements of Vil Du? ; for instance, Vil Du? puts the child in control of the situation. In addition, Vil Du? reduces barriers to disclosure because there is no need to talk or have eye contact with the therapist. Regarding aim 2, Vil Du? was generally evaluated more positively than negatively by the therapists. For instance, therapists indicated that using Vil Du? is time efficient and might make the treatment process less confronting and difficult for the client. According to therapists, most clients indeed experienced less tension and more positive (or neutral) emotions than negative emotions when using Vil Du? Conclusions The most important working elements of Vil Du? , according to therapists, are that it enables children to regain control over their sexual abuse experiences and reduces barriers to disclosing sexual abuse experiences. The more positive evaluation of Vil Du? indicates the acceptability of the game for therapists as well as their clients.
Identification of oral precancerous and cancerous tissue by swept source optical coherence tomography

Distinguishing cancer from precancerous lesions is critical and challenging in oral medicine. As a noninvasive method, optical coherence tomography (OCT) has the advantages of real‐time, in vivo, and large‐depth imaging. Texture information hidden in OCT images can provide an important auxiliary effect for improving diagnostic accuracy. The aim of this study is to explore a reliable and accurate OCT‐based method for the screening and diagnosis of human oral diseases, especially oral cancer.
Prevalence of Early Childhood Caries in South Africa: Protocol for a Systematic Review

Background Young children are at the highest risk of developing dental caries as they have a lack of autonomy over their diet and oral hygiene practices. Dental caries develops over time due to demineralization of tooth substance (enamel), which results from acid production during sugar metabolism by bacteria. Early onset of dental caries often results in asymptomatic presentation, but if left untreated, it can result in severe pain, infection, and dentoalveolar abscesses. Early childhood caries (ECC) is defined as dental caries in children aged 6 years and younger and is a significant public health problem in South Africa. According to the Global Burden of Disease study, untreated dental caries of primary teeth affects 532 million children. Untreated dental caries has many detrimental effects which can affect the physical development and reduce the quality of life of affected children. Furthermore, long-term untreated dental caries can result in school absenteeism, low BMI, and poor educational outcomes. Objective The purpose of this study was to determine the prevalence and severity of ECC in South Africa in children under the age of 6 years. Methods All cross-sectional studies documenting the prevalence and severity of dental disease (decayed, missing, and filled teeth scores) will be included. Various databases will be searched for eligible studies. Only studies conducted on South African children aged 6 years and under will be included. There will be no restriction on the time or language of publication. The quality of all eligible studies will be analyzed by a risk of bias tool developed by the Joanna Briggs Institute. The results will be presented narratively, and if possible, a meta-analysis will be conducted. Results The protocol is registered with PROSPERO. The literature search was initially conducted in November 2018 and was repeated in November 2020. Conclusions The results of this study will be used to advise stakeholders of the prevalence and severity of dental disease in children under 6 years of age in South Africa. Trial Registration PROSPERO CRD42018112161; International Registered Report Identifier (IRRID) DERR1-10.2196/25795
Engineering mechanobiology through organoids‐on‐chip: A strategy to boost therapeutics

The mechanical environment of living cells is as critical as chemical signaling. Mechanical stimuli play a pivotal role in organogenesis and tissue homeostasis. Unbalances in mechanotransduction pathways often lead to diseases, such as cancer, cystic fibrosis, and neurodevelopmental disorders. Despite its inherent relevance, there is a lack of proper mechanoresponsive in vitro study systems. In this context, there is an urge to engineer innovative, robust, dynamic, and reliable organotypic technologies to better connect cellular processes to organ‐level function and multi‐tissue cross‐talk. Mechanically active organoid‐on‐chip has the potential to surpass this challenge. These systems converge microfabrication, microfluidics, biophysics, and tissue engineering fields to emulate key features of living organisms, hence, reducing costs, time, and animal testing. In this review, we intended to present cutting‐edge organ‐on‐chip platforms that integrate biomechanical stimuli as well as novel multicellular culture, such as organoids. We focused on its application in two main fields: precision medicine and drug development. Moreover, we also discussed the state of the art for the development of an engineered model to assess patient‐derived tumor organoid metastatic potential. Finally, we highlighted the current drawbacks and emerging opportunities to match the industry needs. We envision the use of mechanoresponsive organotypic‐on‐chip microdevices as an indispensable tool for precision medicine, drug development, disease modeling, tissue engineering, and developmental biology.
Infantile spasms‐linked Nedd4‐2 mediates hippocampal plasticity and learning via cofilin signaling

Individuals affected by infantile spasms (IS), such as those carrying mutations in an IS‐linked gene, neural precursor cell expressed developmentally downregulated gene 4‐like (Nedd4‐2), exhibit developmental delays and learning disabilities, but the underlying mechanism is unknown. Using conditional Nedd4‐2 knockout mice, we uncover that Nedd4‐2 functions to maintain the excitatory synapses in hippocampal neurons and allows for late‐phase long‐term synaptic potentiation (L‐LTP) at Schaffer collateral synapses in the hippocampus. We also find that Nedd4‐2 is required for multiple forms of hippocampus‐dependent learning and memory. Mechanistically, we show that loss of Nedd4‐2 leads to a decrease in actin polymerization caused by reduced phosphorylation of the actin depolymerizing protein cofilin. A cell‐permeable peptide promoting phosphorylation of endogenous cofilin in Nedd4‐2 knockout neurons restores the number of hippocampal excitatory synapses and hippocampal L‐LTP and partially restores hippocampus‐dependent learning in mice. Taken together, our results reveal a novel mechanism underlying IS‐associated learning disabilities and may provide information for future therapeutic strategies for IS.
Species-Specific Endotoxin Stimulus Determines Toll-Like Receptor 4- and Caspase 11-Mediated Pathway Activation Characteristics

Macrophages and monocytes are innate immune cells playing an important role in orchestrating the initial innate immune response to bacterial infection and the tissue damage. This response is facilitated by specific receptors on the cell surface and intracellularly. ABSTRACT The innate immune system is the body’s first line of defense against pathogens and its protection against infectious diseases. On the surface of host myeloid cells, Toll-like receptor 4 (TLR4) senses lipopolysaccharide (LPS), the major outer membrane component of Gram-negative bacteria. Intracellularly, LPS is recognized by caspase 11 through the noncanonical inflammasome to induce pyroptosis—an inflammatory form of lytic cell death. While TLR4-mediated signaling perturbations result in secretion of cytokines and chemokines that help clear infection and facilitate adaptive immunity, caspase 11-mediated pyroptosis leads to the release of damage-associated molecular patterns and inflammatory mediators. Although the core signaling events and many associated proteins in the TLR4 signaling pathway are known, the complex signaling events and protein networks within the noncanonical inflammasome pathway remain obscure. Moreover, there is mounting evidence for pathogen-specific innate immune tuning. We characterized the major LPS structures from two different pathogens, modeled their binding to the surface receptors, systematically examined macrophage inflammatory responses to these LPS molecules, and surveyed the temporal differences in global protein secretion resulting from TLR4 and caspase 11 activation in macrophages using mass spectrometry (MS)-based quantitative proteomics. This integrated strategy, spanning functional activity assays, top-down structural elucidation of endotoxins, and secretome analysis of stimulated macrophages, allowed us to identify crucial differences in TLR4- and caspase 11-mediated protein secretion in response to two Gram-negative bacterial endotoxins. IMPORTANCE Macrophages and monocytes are innate immune cells playing an important role in orchestrating the initial innate immune response to bacterial infection and the tissue damage. This response is facilitated by specific receptors on the cell surface and intracellularly. One of the bacterial molecules recognized is a Gram-negative bacteria cell wall component, lipopolysaccharide (LPS). The structure of LPS differs between different species. We have characterized the innate immune responses to the LPS molecules from two bacteria, Escherichia coli and Bordetella pertussis, administered either extracellularly or intracellularly, whose structures we first determined. We observed marked differences in the temporal dynamics and amounts of proteins secreted by the innate immune cells stimulated by any of these molecules and routes. This suggests that there is specificity in the first line of response to different Gram-negative bacteria that can be explored to tailor specific therapeutic interventions.
Identification of a GrgA-Euo-HrcA Transcriptional Regulatory Network in Chlamydia

Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in underdeveloped areas as well as some developed countries. Chlamydia carries genes that encode a limited number of known transcription factors. While Euo is thought to be critical for early chlamydial development, the functions of GrgA and HrcA in the developmental cycle are unclear. ABSTRACT Chlamydia trachomatis is an obligate intracellular bacterium whose unique developmental cycle consists of an infectious elementary body and a replicative reticulate body. Progression of this developmental cycle requires temporal control of the transcriptome. In addition to the three chlamydial sigma factors (σ66, σ28, and σ54) that recognize promoter sequences of genes, chlamydial transcription factors are expected to play crucial roles in transcriptional regulation. Here, we investigate the function of GrgA, a Chlamydia-specific transcription factor, in C. trachomatis transcriptomic expression. We show that 10 to 30 min of GrgA overexpression induces 13 genes, which likely comprise the direct regulon of GrgA. Significantly, σ66-dependent genes that code for two important transcription repressors are components of the direct regulon. One of these repressors is Euo, which prevents the expression of late genes during early phases. The other is HrcA, which regulates molecular chaperone expression and controls stress response. The direct regulon also includes a σ28-dependent gene that codes for the putative virulence factor PmpI. Furthermore, overexpression of GrgA leads to decreased expression of almost all tRNAs. Transcriptomic studies suggest that GrgA, Euo, and HrcA have distinct but overlapping indirect regulons. These findings, together with temporal expression patterns of grgA, euo, and hrcA, indicate that a transcriptional regulatory network of these three transcription factors plays critical roles in C. trachomatis growth and development. IMPORTANCE Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in underdeveloped areas as well as some developed countries. Chlamydia carries genes that encode a limited number of known transcription factors. While Euo is thought to be critical for early chlamydial development, the functions of GrgA and HrcA in the developmental cycle are unclear. Activation of euo and hrcA immediately following GrgA overexpression indicates that GrgA functions as a master transcriptional regulator. In addition, by broadly inhibiting tRNA expression, GrgA serves as a key regulator of chlamydial protein synthesis. Furthermore, by upregulating pmpI, GrgA may act as an upstream virulence determinant. Finally, genes coregulated by GrgA, Euo, and HrcA likely play critical roles in chlamydial growth and developmental control.
Impact of pseudouridylation, substrate fold, and degradosome organization on the endonuclease activity of RNase E

The conserved endoribonuclease RNase E dominates the dynamic landscape of RNA metabolism and underpins control mediated by small regulatory RNAs in diverse bacterial species. We explored the enzyme's hydrolytic mechanism, allosteric activation, and interplay with partner proteins in the multicomponent RNA degradosome assembly of Escherichia coli. RNase E cleaves single-stranded RNA with preference to attack the phosphate located at the 5′ nucleotide preceding uracil, and we corroborate key interactions that select that base. Unexpectedly, RNase E activity is impeded strongly when the recognized uracil is isomerized to 5-ribosyluracil (pseudouridine), from which we infer the detailed geometry of the hydrolytic attack process. Kinetics analyses support models for recognition of secondary structure in substrates by RNase E and for allosteric autoregulation. The catalytic power of the enzyme is boosted when it is assembled into the multienzyme RNA degradosome, most likely as a consequence of substrate capture and presentation. Our results rationalize the origins of substrate preferences of RNase E and illuminate its catalytic mechanism, supporting the roles of allosteric domain closure and cooperation with other components of the RNA degradosome complex.
Uptake of Genetic Testing Among Patients with Cancer At Risk for Lynch Syndrome in the National Health Interview Survey

Genetic testing uptake for colorectal cancer and endometrial cancer has not increased over a 10-year period in spite of universal screening guidelines. More genetic testing education is needed at the provider and patient level to improve screening strategies for cancer patients who are most at risk for Lynch syndrome. Lynch syndrome is the most common inherited cancer syndrome that increases the risk of developing colorectal and endometrial cancer. Universal screening guidelines were first recommended by the Centers for Disease Control and Prevention (CDC) in 2009 and are updated annually by multiple societies. Therefore, one would expect genetic testing rates to increase over time. But testing remains underutilized among those with colorectal or endometrial cancer, even though early detection can improve prognosis and survival rates. In this study, we aimed to understand differences in genetic testing uptake among those with colorectal cancer or endometrial cancer from 2005, 2010, 2015, using data from the National Health Interview Survey (NHIS). We examined genetic testing uptake across cancer-type, age (≤50 or ≥51), sex, race, insurance, and education using a χ2 statistical analysis. Despite an upward genetic testing trend in 2010, we found no significant differences in genetic testing uptake over time. In 2010, non-White individuals experienced the highest increase from 2005 in comparison with White individuals. However, genetic testing rates declined for both groups by 2015. Our findings show that genetic testing for colorectal cancer and endometrial cancer did not increase over a 10-year period in spite of guidelines that recommend testing. Prevention Relevance: Genetic testing uptake for colorectal cancer and endometrial cancer has not increased over a 10-year period in spite of universal screening guidelines. More genetic testing education is needed at the provider and patient level to improve screening strategies for cancer patients who are most at risk for Lynch syndrome.
Balance between bacterial extracellular matrix production and intramacrophage proliferation by a Salmonella‐specific SPI‐2‐encoded transcription factor

Biosynthesis and secretion of a complex extracellular matrix (EM) is a hallmark of Salmonella biofilm formation, impacting on its relationship with both the environment and the host. Cellulose is a major component of Salmonella EM. It is considered an anti‐virulence factor because it interferes with Salmonella proliferation inside macrophages and virulence in mice. Its synthesis is stimulated by CsgD, the master regulator of biofilm formation in enterobacteria, which in turn is under the control of MlrA, a MerR‐like transcription factor. In this work, we identified a SPI‐2‐encoded Salmonella‐specific transcription factor homolog to MlrA, MlrB, that represses transcription of its downstream gene, orf319, and of csgD inside host cells. MlrB is induced in laboratory media mimicking intracellular conditions and inside macrophages, and it is required for intramacrophage proliferation. An increased csgD expression is observed in the absence of MlrB inside host cells. Interestingly, inactivation of the CsgD‐controlled cellulose synthase‐coding gene restored intramacrophage proliferation to rates comparable to wild‐type bacteria in the absence of MlrB. These data indicate that MlrB represses CsgD expression inside host cells and suggest that this repression lowers the activation of the cellulose synthase. Our findings provide a novel link between biofilm formation and Salmonella virulence.
Families’ Health Behavior: Validity and Reliability of the Turkish Version of the Family Health Climate Scale

ABSTRACT This study aims to adapting the Family Health Climate Scale (FHC Scale) into Turkish and to conduct its validity and reliability analyses. The FHC Scale consists of two subscales, the Physical Activity Scale (FHC-PA) and the Nutrition Scale (FHC-NU). The validity and reliability analyzes of the scales were done separately. The sample included 789 participants (263 students, 263 mothers, 263 fathers). The sample was randomly allocated to two groups. Explanatory Factor Analysis (EFA) was performed on Sample I (132 students, 132 mothers, 132 fathers); and Confirmatory Factor Analysis (CFA) on sample II (131 students, 131 mothers, 131 fathers). As a result of the EFA it was determined that three factors FHC-PA Scale; and four factors FHC-NU Scale were included. The CFA result it was determined that scale models had good fit values. The FHC-Scale could be used as a reliable and valid measurement tool in Turkey.
Easy and reliable maximum a posteriori Bayesian estimation of pharmacokinetic parameters with the open‐source R package mapbayr

Pharmacokinetic (PK) parameter estimation is a critical and complex step in the model‐informed precision dosing (MIPD) approach. The mapbayr package was developed to perform maximum a posteriori Bayesian estimation (MAP‐BE) in R from any population PK model coded in mrgsolve. The performances of mapbayr were assessed using two approaches. First, “test” models with different features were coded, for example, first‐order and zero‐order absorption, lag time, time‐varying covariates, Michaelis–Menten elimination, combined and exponential residual error, parent drug and metabolite, and small or large inter‐individual variability (IIV). A total of 4000 PK profiles (combining single/multiple dosing and rich/sparse sampling) were simulated from each test model, and MAP‐BE of parameters was performed in both mapbayr and NONMEM. Second, a similar procedure was conducted with seven “real” previously published models to compare mapbayr and NONMEM on a PK outcome used in MIPD. For the test models, 98% of mapbayr estimations were identical to those given by NONMEM. Some discordances could be observed when dose‐related parameters were estimated or when models with large IIV were used. The exploration of objective function values suggested that mapbayr might outdo NONMEM in specific cases. For the real models, a concordance close to 100% on PK outcomes was observed. The mapbayr package provides a reliable solution to perform MAP‐BE of PK parameters in R. It also includes functions dedicated to data formatting and reporting and enables the creation of standalone Shiny web applications dedicated to MIPD, whatever the model or the clinical protocol and without additional software other than R.
High‐resolution MRI of the human palatine tonsil and its schematic anatomic 3D reconstruction

The palatine tonsils form an important part of the human immune system. Together with the other lymphoid tonsils of Waldeyer's tonsillar ring, they act as the first line of defense against ingested or inhaled pathogens. Although histologically stained sections of the palatine tonsil are widely available, they represent the tissue only in two dimensions and do not provide reference to three‐dimensional space. Such a representation of a tonsillar specimen based on imaging data as a 3D anatomical reconstruction is lacking both in scientific publications and especially in textbooks. As a first step in this direction, the objective of the present work was to image a resected tonsil specimen with high spatial resolution in a 9.4 T small‐bore pre‐clinical MRI and to combine these data with data from the completely sectioned and H&E stained same palatine tonsil. Based on the information from both image modalities, a 3D anatomical sketch was drawn by a scientific graphic artist. In perspective, such studies could help to overcome the difficulty of capturing the spatial extent and arrangement of anatomical structures from 2D images and to establish a link between three‐dimensional anatomical preparations and two‐dimensional sections or illustrations, as they have been found so far in common textbooks and anatomical atlases.