Piezo2 voltage-block regulates mechanical pain sensitivity.

PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurones in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved Arginine (R2756). Using genome engineering in mice we generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurones isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain of function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurones that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurones innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurones essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurones. Consistently, Piezo2 knock-in mice showed substantial behaviourally hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels.

Measuring mental wellbeing in clinical and non-clinical adolescents using the COMPAS-W Wellbeing Scale.

Introduction: Adolescence is a key period of vulnerability for poor mental health as the brain is still developing and may be more sensitive to the negative impacts of stress and adversity. Unfortunately, few measures comprehensively assess wellbeing in adolescents. Methods: The 26-item COMPAS-W Wellbeing Scale for adults was validated in a sample of 1,078 adolescents aged 13-17 years old (51.67% male, 79.13% non-clinical vs 20.87% psychiatric or developmental clinical cases). The six COMPAS-W sub-scales and total scale were examined in this sample using second-order confirmatory factor analysis, and psychometric testing. Results: The 23-item COMPAS-W demonstrated the best fit for this sample according to goodness-of-fit indices (χ 2 (220, 1078) = 1439.395, p < 0.001, CFI = 0.893, TLI = 0.877, RMSEA = 0.070, SRMR = 0.095). Internal reliability for the confirmed 23-item COMPAS-W model was run for the total scale (α = 0.912) and sub-scales (Composure, α = 0.735; Own-worth, α = 0.601; Mastery, α = 0.757; Positivity, α = 0.721; Achievement, α = 0.827; and Satisfaction, α = 0.867). Test-retest reliability over 6 weeks was also good for the total scale at r = 0.845 and the sub-scales: Composure (r = 0.754), Own-worth (r = 0.743), Mastery (r = 0.715), Positivity (r = 0.750), Achievement (r = 0.750), and Satisfaction (r = 0.812). Compared with non-clinical participants' wellbeing (M = 90.375, SE = 0.400), those with clinical diagnoses reported lower wellbeing, both for those with developmental diagnoses (M = 85.088, SE = 1.188), or psychiatric diagnoses (M = 78.189, SE = 1.758), or combined developmental and psychiatric diagnoses (M = 77.079, SE = 2.116). Yet, when wellbeing category scores were considered by diagnosis group, both non-clinical and clinical groups demonstrated incidence across all three categories of languishing, moderate and flourishing wellbeing, in support of the dual-continua model of mental health. On average, younger adolescents' (13-14 years) wellbeing did not differ from older adolescents' (15-17 years) wellbeing; however, for sex, males scored 1.731 points significantly higher in wellbeing compared with females (p = 0.028); and American participants scored 3.042 points significantly higher in wellbeing compared with Australian participants (p < 0.001). Discussion: In conclusion, the 23-item COMPAS-W is a reliable measure of wellbeing for adolescents, both for those with and without developmental and psychiatric diagnoses.

Genetic constraint at single amino acid resolution in protein domains improves missense variant prioritisation and gene discovery.

BACKGROUND: One of the major hurdles in clinical genetics is interpreting the clinical consequences associated with germline missense variants in humans. Recent significant advances have leveraged natural variation observed in large-scale human populations to uncover genes or genomic regions that show a depletion of natural variation, indicative of selection pressure. We refer to this as "genetic constraint". Although existing genetic constraint metrics have been demonstrated to be successful in prioritising genes or genomic regions associated with diseases, their spatial resolution is limited in distinguishing pathogenic variants from benign variants within genes. METHODS: We aim to identify missense variants that are significantly depleted in the general human population. Given the size of currently available human populations with exome or genome sequencing data, it is not possible to directly detect depletion of individual missense variants, since the average expected number of observations of a variant at most positions is less than one. We instead focus on protein domains, grouping homologous variants with similar functional impacts to examine the depletion of natural variations within these comparable sets. To accomplish this, we develop the Homologous Missense Constraint (HMC) score. We utilise the Genome Aggregation Database (gnomAD) 125 K exome sequencing data and evaluate genetic constraint at quasi amino-acid resolution by combining signals across protein homologues. RESULTS: We identify one million possible missense variants under strong negative selection within protein domains. Though our approach annotates only protein domains, it nonetheless allows us to assess 22% of the exome confidently. It precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD). It is also methodologically independent of these, adding power to predict variant pathogenicity when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly significantly associated with DD that could act through an altered-function mechanism. CONCLUSIONS: Grouping variants of comparable functional impacts is effective in evaluating their genetic constraint. HMC is a novel and accurate predictor of missense consequence for improved variant interpretation.

Lymphocytic Choriomeningitis Virus Infections in Hungary between 2017-2023-Investigation of the First Congenital Infections.

Lymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne arenavirus, primarily spread by common house mouse species. Acquired human infections range from asymptomatic to mild flu-like symptoms and self-resolving neurological diseases. In contrast, intrauterine LCMV infection is associated with high mortality and morbidity. Infection of the fetus often leads to fetal death, and surviving fetuses may develop vision impairment and central nervous system developmental disorders. LCMV is mainly diagnosed by serological methods using in-house indirect immunofluorescence assays. LCMV nucleic acid is detected by the nested RT-PCR method and confirmed by Sanger sequencing. In Hungary, 23 acquired lymphocytic choriomeningitis cases were diagnosed between 2017 and 2023. Ten out of 23 confirmed patients proved to be positive by the PCR method. Two cases of intrauterine LCMV infections were detected in 2019 and 2021, respectively. The IgG antibody titers measured in the infant's serum samples were much higher than the IgG titers of the maternal serum samples. Both IgM and IgA antibodies were detectable in the infants' sera. As the microbiological diagnosis of LCMV is rather challenging and the symptoms are very similar to the clinical picture of other common teratogenic pathogens such as cytomegalovirus or Toxoplasma gondii, intrauterine LCMV infections might still be underdiagnosed.

Fragile X Syndrome and FMR1 premutation: results from a survey on associated conditions and treatment priorities in Italy.

BACKGROUND AND OBJECTIVES: Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children's Hospital, conducted a survey among Italian participants. METHOD: Here, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities. RESULTS: Anxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM. CONCLUSION: FXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

The engagement of temporal attention in left spatial neglect.

Previous literature showed how left spatial neglect arises from an asymmetrical distribution of spatial attention. However, it was also suggested that left spatial neglect might be partially caused or at least worsened by non-spatial attention disorders of the right-lateralized stimulus-driven attentional fronto-parietal network. Here, we psychophysically tested the efficiency of temporal attentional engagement of foveal perception through meta-contrast (Experiment 1) and "attentional" masking (Experiment 2) tasks in patients with right-hemisphere stroke with left neglect (N+), without left neglect (N-) and matched healthy controls (C). In both experiments, N+ patients showed higher thresholds, not only than Cs, but also than N- patients. Temporal engagement was clinically impaired in all N+ patients and highly correlated with their typical inability to direct spatial attention towards stimuli on the left side. Our findings suggest that a temporal impairment of attentional engagement is a relevant deficit of left spatial neglect.

Combined HRAS and NRAS ablation induces a RASopathy phenotype in mice.

BACKGROUND: HRASKO/NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. METHODS: Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. RESULTS: The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. CONCLUSIONS: Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS.

Association of preterm birth and birth size status with neurodevelopmental and psychiatric disorders in spontaneous births.

Preterm birth (PTB) or small birth size are risk factors for certain neurodevelopmental disorders. The magnitude of these associations in spontaneous births, and of associations for combined PTB and birth size status on neurodevelopmental and psychiatric disorders is unexplored. We investigated whether PTB and small/large for gestational age (SGA/LGA), separately or combined, in spontaneous births, are associated with a wide spectrum of neurodevelopmental and psychiatric disorders. In this population-based registry cohort study, all singleton spontaneous births in Finland from 1996 to 2014 were followed until 2018 (n = 819 764). We show that PTB across gestational ages, and SGA, were associated with higher risks for anxiety disorders, intellectual disabilities, specific developmental disorders (SDD), autism spectrum disorders (ASD), attention-deficit/hyperactivity disorders (ADHD) and other emotional and behavioural disorders (F98). Most of these associations were not attributed to familial factors. Larger effect sizes were observed with lower gestational ages. Extremely PTB was associated at highest risks with intellectual disabilities (HR, 10.70 [95%CI, 8.69-13.17]) and SDD (HR, 8.91 [95%CI, 8.18-9.71]). Moreover, very preterm birth combined with SGA was associated with a higher risk for SDD (HR, 7.55 [95%CI, 6.61-8.62]) than that of very preterm or SGA birth alone. Conversely, LGA birth lowered the risk for SDD and other emotional and behavioural disorders among individuals born very preterm. In conclusion, PTB along with SGA is associated with higher risks for SDD than one exposure alone, whereas LGA lowers the risks for SDD and other emotional and behavioural disorders in individuals born spontaneously.

Barriers and facilitators to achieving employment in mainstream settings in adults with autism spectrum disorder without intellectual developmental disorders: A scoping review.

Autistic people without Intellectual Developmental Disorders (IDD) have a significantly lower employment rate compared to the general population even though employment favors social integration and quality of life. AIMS: To examine the barriers and facilitators to employability in mainstream settings for autistic adults without intellectual disability. METHODS: Following the scoping review guidelines, we searched the Cochrane, PubMed and PsycINFO databases for references published between 01/01/2000 to 01/08/2023. RESULTS: A review of the 44 identified articles suggests the existence of multiple individual and environmental factors influencing job access and retention. CONCLUSIONS: This is the first review to assess the facilitators and barriers to employment support for autistic people without intellectual disability. The results underline the need for studying strategies to promote access to employment and job retention for autistic people. Future research should explore the mediating and moderating factors leading to the improvement of employability of autistic people WIDD.

Evaluation of autism awareness and knowledge levels among Syrian migrants living in Türkiye.

This study was conducted to evaluate the autism knowledge level and awareness of individuals over the age of 18 who applied to immigrant health centers in Istanbul, Gaziantep and Kilis, where the Syrian immigrant population is dense. This cross-sectional study was conducted between December 2022 and April 2023 in 896 immigrants. The sample of the research consists of immigrants residing in Türkiye and who applied to the immigrant health centers in Istanbul, Gaziantep and Kilis for any reason at the time of the research. A questionnaire consisting of three parts was applied to the immigrant people face-to-face. While 38.4% of the participants were female, 61.6% were male. The mean age of the participants is 34.63 ± 10.74. It was determined that people's place of residence, whether they have children, marital status and income status have significant effects on autism knowledge levels (p < 0.001). Since the importance of early diagnosis in autism is known, it is of great importance for people to have knowledge and awareness on this issue. This study will investigate the awareness of the immigrant population, who are faced with traumatic events such as war and migration, and will shed light on future intervention studies.

A mHealth application for the training of caregivers of children with developmental disorders in South Africa: rationale and initial piloting.

Background: Evidence-based mobile health (mHealth) interventions have been successful for an array of physical and mental health conditions. Children with developmental disorders (DD) often have secondary speech and language disorders. The lack of high-quality medical and educational services in low- and middle-income countries limits the opportunities for children with DD to succeed in life. South Africa currently offers limited access to education, social, and health services. Methods: Twelve caregivers of twelve children with DD between the ages of 3 and 6 years who already received monthly early childhood therapy participated in this study. A mHealth app, called Nna'Le'wena, a Setswana phrase meaning "Me and You", was designed, developed, installed, and tested on tablets. The app provided a systematic framework and guidance to the caregivers in order to use evidence-based communication interaction strategies with the children over a twelve-week period. The app could be used offline and provided audio instructions in English and Setswana, two dominant languages in South Africa. The app automatically generated log files and collected answers to weekly surveys. At the end of the study, caregivers were asked to evaluate the app by using relevant portions of the Mobile App Rating Scale (MARS). Results: Caregivers were able to successfully interact and use the app. The app was well-received and liked by the caregivers. Caregivers listened to the instructional audios in English and Setswana during the 12-week period. They were able to provide communication opportunities to their children during daily living activities, especially during play- and mealtime activities. Conclusions: The Nna'Le'wena app was successfully deployed and used by caregivers of children with DD. mHealth solutions can be effective and are relatively affordable solutions that can enhance health care and educational delivery in different settings, including in low-and middle-income countries with limited Internet capabilities.

Forensic interviews conducted with autistic adults in Japan: a review of the literature and directions for future research.

The interviewing of victims, witnesses and suspects is important in helping resolve criminal investigations. In Japan, developments have recently occurred in the training of the police and their public prosecutors in these key tasks. Whilst literature exists on autism in Japan, studies examining police/public prosecutor interviews with autistic adults conducted in that country (and indeed, any other) remain scant. As elsewhere in the world, identification of those who manifest characteristics prevalent on the autism spectrum disorder (ASD) scale, has been found to be problematical to criminal justice professionals. To help address this deficit in understanding, we provide an overview of the literature concerning contemporary understanding of the challenges facing autistic adults as they attempt to reveal their verbal accounts, as well as suggested techniques when interviewing adults on the ASD scale during criminal investigations, offering lessons learned from research conducted around the world that provide potentially promising solutions for Japan.

Clustering of predicted loss-of-function variants in genes linked with monogenic disease can explain incomplete penetrance.

BACKGROUND: Genetic variants that severely alter protein products (e.g. nonsense, frameshift) are often associated with disease. For some genes, these predicted loss-of-function variants (pLoFs) are observed throughout the gene, whilst in others, they occur only at specific locations. We hypothesised that, for genes linked with monogenic diseases that display incomplete penetrance, pLoF variants present in apparently unaffected individuals may be limited to regions where pLoFs are tolerated. To test this, we investigated whether pLoF location could explain instances of incomplete penetrance of variants expected to be pathogenic for Mendelian conditions. METHODS: We used exome sequence data in 454,773 individuals in the UK Biobank (UKB) to investigate the locations of pLoFs in a population cohort. We counted numbers of unique pLoF, missense, and synonymous variants in UKB in each quintile of the coding sequence (CDS) of all protein-coding genes and clustered the variants using Gaussian mixture models. We limited the analyses to genes with ≥ 5 variants of each type (16,473 genes). We compared the locations of pLoFs in UKB with all theoretically possible pLoFs in a transcript, and pathogenic pLoFs from ClinVar, and performed simulations to estimate the false-positive rate of non-uniformly distributed variants. RESULTS: For most genes, all variant classes fell into clusters representing broadly uniform variant distributions, but genes in which haploinsufficiency causes developmental disorders were less likely to have uniform pLoF distribution than other genes (P < 2.2 × 10-6). We identified a number of genes, including ARID1B and GATA6, where pLoF variants in the first quarter of the CDS were rescued by the presence of an alternative translation start site and should not be reported as pathogenic. For other genes, such as ODC1, pLoFs were located approximately uniformly across the gene, but pathogenic pLoFs were clustered only at the end, consistent with a gain-of-function disease mechanism. CONCLUSIONS: Our results suggest the potential benefits of localised constraint metrics and that the location of pLoF variants should be considered when interpreting variants.

The PAX Genes: Roles in Development, Cancer, and Other Diseases.

Since their 1986 discovery in Drosophila, Paired box (PAX) genes have been shown to play major roles in the early development of the eye, muscle, skeleton, kidney, and other organs. Consistent with their roles as master regulators of tissue formation, the PAX family members are evolutionarily conserved, regulate large transcriptional networks, and in turn can be regulated by a variety of mechanisms. Losses or mutations in these genes can result in developmental disorders or cancers. The precise mechanisms by which PAX genes control disease pathogenesis are well understood in some cases, but much remains to be explored. A deeper understanding of the biology of these genes, therefore, has the potential to aid in the improvement of disease diagnosis and the development of new treatments.

The relationship between object play, language, and visual and motor skills in children at risk of developmental disorders between 12 and 37 months.

BACKGROUND: Exploratory object play is a primary strategy in amassing knowledge about one's environment and determines the development of language skills at a later age. However, still much remains unknown about how object play is related to visual and language development in children at risk of developmental disorders. PARTICIPANTS AND PROCEDURE: Forty-four children at risk of developmental disorders aged 13 to 37 months took part in the study. The measurement of object play relied on observation of children manipulating novel objects. Language skills were assessed by the Mullen Scales. RESULTS: The results indicate that there is a correlation between specific object play behaviours, language and visual skills. CONCLUSIONS: The findings from this study support the hypothesis that the relationship between visual and language skills and object play in children at risk of developmental disorders is different in younger and older children.

Evaluation of a Problem-Solving Program on Developmental Disorders: A Qualitative Appraisal.

Background In Japan, effective educational methods to promote understanding of developmental disorders (DD) among young people have not been established, something that is necessary for an inclusive society. Aims This paper aimed to identify both the positive aspects and areas for improvement in a problem-solving program for middle and high school students on the topic of DD called inochi Gakusei Innovators Program (i-GIP). The study also sought to determine the changes in attitudes toward DD that occurred as a result of participating in the program. Method Semi-structured interviews were conducted online, with middle and high school students who participated in i-GIP, university students who helped manage the program, and cooperators with DD or their families. Inductive thematic analysis was conducted, and codes and themes were identified. Results Positive aspects of i-GIP included its project-based learning approach, raising awareness and understanding of developmental disorders, and the proactive attitude of the students. Areas for improvement in the program were identified, including program administration and addressing challenges related specifically to DD. Changes in attitudes and behavior toward DD were reported, along with improvements in interpersonal relationships. Conclusions and implications This study suggests that incorporating a project-based approach can be a useful manner to learn about DD among young people.

BRCA1 protein dose-dependent risk for embryonic oxidative DNA damage, embryopathies and neurodevelopmental disorders with and without ethanol exposure.

Although widely known as a tumor suppressor, the breast cancer 1 susceptibility protein (BRCA1) is also important in development, where it regulates fetal DNA repair pathways that protect against DNA damage caused by physiological and drug-enhanced levels of reactive oxygen species (ROS). We previously showed that conditional heterozygous (+/-) knockout (cKO) mouse embryos with a minor 28% BRCA1 deficiency developed normally in culture, but when exposed to the ROS-initiating drug, alcohol (ethanol, EtOH), exhibited embryopathies not evident in wild-type (+/+) littermates. Herein, we characterized a directBrca1 +/- knockout (KO) model with a 2-fold greater (58%) reduction in BRCA1 protein vs. the cKO model. We also characterized and compared learning & memory deficits in both the cKO and KO models. Even saline-exposed Brca1 +/- vs. +/+ KO progeny exhibited enhanced oxidative DNA damage and embryopathies in embryo culture and learning & memory deficits in females in vivo, which were not observed in the cKO model, revealing the potential pathogenicity of physiological ROS levels. The embryopathic EtOH concentration for cultured direct KO embryos was half that for cKO embryos, and EtOH affected Brca1 +/+ embryos only in the direct KO model. The spectrum and severity of EtOH embryopathies in culture were greater in both Brca1 +/- vs. +/+ embryos, and direct KO vs. cKO +/- embryos. Motor coordination deficits were evident in both male and female Brca1 +/- KO progeny exposed in utero to EtOH. The results in our direct KO model with a greater BRCA1 deficiency vs. cKO mice provide the first evidence for BRCA1 protein dose-dependent susceptibility to developmental disorders caused by physiological and drug-enhanced oxidative stress.

Insight into the function of tetranectin in human diseases: A review and prospects for tetranectin-targeted disease treatment.

Tetranectin (TN), a serum protein, is closely associated with different types of cancers. TN binds plasminogen and promotes the proteolytic activation of plasminogen into plasmin, which suggests that TN is involved in remodeling the extracellular matrix and cancer tissues during cancer development. TN is also associated with other diseases, such as developmental disorders, cardiovascular diseases, neurological diseases, inflammation, and diabetes. Although the functional mechanism of TN in diseases is not fully elucidated, TN binds different proteins, such as structural protein, a growth factor, and a transcription regulator. Moreover, TN changes and regulates protein functions, indicating that TN-binding proteins mediate the association between TN and diseases. This review summarizes the current knowledge of TN-associated diseases and TN functions with TN-binding proteins in different diseases. In addition, potential TN-targeted disease treatment by inhibiting the interaction between TN and its binding proteins is discussed.

Speech-language pathologists' professional stress level and factors affecting it in the Republic of Serbia.

BACKGROUND: In the Republic of Serbia, to our knowledge, there has been no research dedicated to the professional stress faced by speech-language pathologists (SLPs). Since speech therapy belongs to the helping professions, SLPs might experience professional stress. OBJECTIVE: To examine the levels of professional stress in SLPs concerning sociodemographic characteristics and terms of the workplace. METHODS: The research was conducted online, using a questionnaire designed to determine professional stress in speech-language pathologists - Speech-Language Pathologist Stress Inventory. The voluntary sample consisted of 185 employed SLPs from the Republic of Serbia. The stress level was observed concerning marital status, years of working experience, age, educational degree, caseload size, job sector, job setting, type of patients' diagnosis, and type of service which SLPs provide. RESULTS: The results showed that SLPs experience mild to moderate levels of professional stress and that there is a statistically significant difference in the stress level concerning years of working experience, age, job sector, and job setting. Applying Generalized Linear Mixed Model revealed that two-way interaction (Years of working experience * Marital status) and three-way interaction (Age * Job Setting * Type of patients' diagnosis) dominated on the model. CONCLUSION: Since it is noted that SLPs are experiencing mild to moderate levels of professional stress, it is important to emphasize the need for adaptation of existing work terms as well as to provide additional support to speech therapists in order to improve their mental health.