Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Feasibility of virtual reality and comparison of its effectiveness to biofeedback in children with Duchenne and Becker muscular dystrophies.

INTRODUCTION/AIMS: The utilization of virtual reality (VR) and biofeedback training, while effective in diverse populations, remains limited in the treatment of Duchenne and Becker muscular dystrophies (D/BMD). This study aimed to determine the feasibility of VR in children with D/BMD and compare the effectiveness of VR and biofeedback in children with D/BMD. METHODS: The study included 25 children with D/BMD. Eight children in the control group participated in a routine follow-up rehabilitation program, while the remaining children were randomly assigned to the VR (n = 9) and biofeedback (n = 8) groups for a 12-week intervention. The following evaluations were performed before, during (week 6), and after treatment: Muscle pain and cramps, laboratory studies, muscle strength, timed performance, function (Motor Function Measurement Scale-32, Vignos, and Brooke Scales), and balance (Pediatric Functional Reach Test and Balance Master System). Motivation for rehabilitation was determined. RESULTS: The median ages were 9.00 (VR), 8.75 (biofeedback), and 7.00 (control) years. The study found no significant differences between groups in pretreatment assessments for most measures, except for tandem step width (p < .05). VR and biofeedback interventions significantly improved various aspects (pain intensity, cramp frequency, cramp severity, muscle strength, timed performance, functional level, and balance) in children with D/BMD (p < .05), while the conventional rehabilitation program maintained patients' current status without any changes. The study found VR and biofeedback equally effective, with VR maintaining children's motivation for rehabilitation longer (p < .05). DISCUSSION: The study showed that both VR and biofeedback appear to be effective for rehabilitation this population, but additional, larger studies are needed.

Artemisinin May Disrupt Hyphae Formation by Suppressing Biofilm-Related Genes of Candida albicans: In Vitro and In Silico Approaches.

This study aimed to assess the antifungal and antibiofilm efficacy of artemisinin against Candida (C.) species, analyze its impact on gene expression levels within C. albicans biofilms, and investigate the molecular interactions through molecular docking. The antifungal efficacy of artemisinin on a variety of Candida species, including fluconazole-resistant and -susceptible species, was evaluated by the microdilution method. The effect of artemisinin on C. albicans biofilm formation was investigated by MTT and FESEM. The mRNA expression of the genes related to biofilm was analyzed by qRT-PCR. In addition, molecular docking analysis was used to understand the interaction between artemisinin and C. albicans at the molecular level with RAS1-cAMP-EFG1 and EFG1-regulated genes. Artemisinin showed higher sensitivity against non-albicans Candida strains. Furthermore, artemisinin was strongly inhibitory against C. albicans biofilms at 640 µg/mL. Artemisinin downregulated adhesion-related genes ALS3, HWP1, and ECE1, hyphal development genes UME6 and HGC1, and hyphal CAMP-dependent protein kinase regulators CYR1, RAS1, and EFG1. Furthermore, molecular docking analysis revealed that artemisinin and EFG1 had the highest affinity, followed by UME6. FESEM analysis showed that the fluconazole- and artemisinin-treated groups exhibited a reduced hyphal network, unusual surface bulges, and the formation of pores on the cell surfaces. Our study suggests that artemisinin may have antifungal potential and showed a remarkable antibiofilm activity by significantly suppressing adhesion and hyphal development through interaction with key proteins involved in biofilm formation, such as EFG1.

Bayesian interpretation of the prefrontal P2 ERP component based on stimulus/response mapping uncertainty.

The brain can be seen as a predictive system continuously computing prior information to guess posterior probabilities minimizing sources of uncertainty. To test this Bayesian view of the brain, event-related potentials (ERP) methods have been used focusing on the well-known P3 component, traditionally associated with decision-making processes and sources of uncertainty regarding target probability. Another ERP component linked with decision-making is the prefrontal P2 (pP2) component, which has never been considered within the Bayesian framework. To test which source of uncertainty could be associated with the pP2, uncertainty induced by target probability and stimulus-response (S/R) mapping were modulated in three visuomotor tasks. Results showed that the pP2 had the largest amplitude in the task with the largest uncertainty regarding the S/R mapping and degraded as the S/R mapping became more predictable. The P3 was maximal in the tasks with larger uncertainty regarding the target probability. While we confirmed the P3 association with target probability, we extended our knowledge on the pP2 associating it with S/R mapping uncertainty. This component, which has been previously localized within the anterior insular cortex, may minimize S/R mapping uncertainty allowing response-related evidence accumulation and comparing current events with internal representations to extract action-related probabilities.

Effects of a Virtual Reality Reaction Training Protocol on Physical and Cognitive Skills of Young Adults and Their Neural Correlates: A Randomized Controlled Trial Study.

Increasing evidence shows that virtual reality (VR) training is highly effective in cognitive and motor rehabilitation. Another modern form of training is cognitive-motor dual-task training (CMDT), which has been demonstrated to rapidly improve physical and cognitive functions in real environments. This study aims to test whether a VR-based CMDT protocol can be used for motor and cognitive skill enhancement in young, healthy subjects. For this aim, 24 university students participated in a randomized control trial. The experimental group participated in a 5-week virtual reality reaction training (VRRT), performing 30 min sessions once a week. The control group did not receive any training but was tested twice with the same measures and temporal distance as the experimental group. Before and after the intervention, motor, cognitive, and electrophysiological measures were assessed. The results showed that following VRRT, the response time for both physical and cognitive tests was improved by about 14% and 12%, respectively, while the control group did not show significant changes. Moreover, electrophysiological data revealed a significant increase in anticipatory motor readiness in premotor brain areas in the experimental group only; however, cognitive top-down control tended to be increased in prefrontal areas after VRRT. This training protocol in a VR modality seems to be as effective as other CMDT methodologies carried out in a real modality. Still, it has the advantages of being more flexible and more user-friendly compared to standard training. The VRRT's efficacy on physical and cognitive functions indicates that virtual reality applications can be used by the young population, not only for entertainment purposes but also in the form of cognitive-motor training.

The Impact of Parent-Based Support Programs on Neurodevelopmental Prognosis: Second-Year Results from a Newly Established Neurodevelopmental Follow-Up Unit in a Tertiary Hospital.

This study aims to assess the neurodevelopmental progress of high-risk infants 2 years post implementation of the Neurodevelopmental Follow-Up Unit (NFU) program at our hospital and explore implementation challenges for insights. Infants were assessed using the Hammersmith Infant Neurological Examination (HINE), The Alberta Infant Motor Scale (AIMS), and Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). A multidisciplinary team provided comprehensive parent education covering neurologic cues, postural advice, and developmental instructions in accordance with the children's assessment findings. In addition, a pediatric physical therapist provided motor development training emphasizing age-appropriate milestones and functional independence, while child development specialists addressed delays identified through BSID-III assessments. A total of 121 high-risk babies were enrolled during a 2-year period. Results revealed that 9 infants exhibited suboptimal HINE scores at 3-4 months, with only 2 maintaining suboptimal scores at 12-15 months. Similarly, 2 infants with suboptimal AIMS scores at 3-4 months reached normal values at 12-15 months. Comparable improvements were observed in BSID-III scores. While no correlation between HINE and AIMS scores was found at the 3-4-month mark, a significant correlation emerged between AIMS and HINE scores at 6-9 months (r = 0.643, P < .001) and 12-15 months (r = 0.820, P < .001). Encouraging early family education alongside regular monitoring of high-risk newborns appears to have a positive impact on their motor and cognitive development. Consideration of clinical recommendations, such as tailored interventions and periodic assessments, may contribute to optimizing developmental outcomes.

Factors and Processes Facilitating Recovery from Coercion in Mental Health Services-A Meta-Ethnography.

BACKGROUND: Being subjected to or witnessing coercive measures in mental health services can have a negative impact on service users, carers and professionals, as they most often are experienced as dehumanising and traumatic. Coercion should be avoided, but when it does happen, it is important to understand how the experience can be processed so that its consequences are managed. METHOD: A systematic review and meta-ethnography was used to synthesise findings from qualitative studies that examined service users', staff's and relatives' experiences of recovery from being exposed to coercive measures in mental health care settings. We identified, extracted and synthesised, across 23 studies, the processes and factors that were interpreted as significant to process the experience. RESULTS: Recovery from coercion is dependent on a complex set of conditions that support a sense of dignity and respect, a feeling of safety and empowerment. Being in a facilitating environment, receiving appropriate information and having consistent reciprocal communication with staff are the means through which these conditions can be achieved. People employ strategies to achieve recovery, both during and after coercion, to minimise its impact and process the experience. CONCLUSIONS: The findings point to the importance of mental health care settings offering recovery-oriented environments and mental health professionals employing recovery-oriented practices, that would empower service users to develop strategies for managing their mental distress as well as their experiences in mental health care in a way that minimises traumatisation and fosters recovery.

Dual task impact on functional mobility and interaction of functional level and balance in patients with Duchenne muscular dystrophy.

BACKGROUND: Dystrophin, a protein crucial for various brain regions governing higher-order functions like learning and memory is notably absent in individuals with Duchenne muscular dystrophy (DMD). This absence of dystrophin in the brain is believed to underlie cognitive challenges in DMD. Cognitive and motor challenges observed in DMD could potentially hinder the execution of dual tasks. RESEARCH QUESTION: Is there a significant correlation between dual-task performance, functional mobility, and balance in children with DMD? METHOD: The study included 28 participants (14 DMD, 14 typical development). Timed Up and Go (TUG) test results were recorded for single and dual-task conditions (motor-motor, cognitive-motor). Functional level was assessed using Motor Function Measurement-32 (MFM-32), Brooke Upper Extremity Scale, and Vignos Scale. Balance was evaluated using Balance Master System and Pediatric Functional Reach Test (PFRT). RESULTS: Significant differences in TUG test scores across conditions were observed in both DMD and typical development groups (p < 0.05). Children with DMD exhibited longer completion times compared to typical development children (p < 0.05). Among children with DMD, there was a significant correlation between TUG scores in different task conditions and balance assessment (p < 0.05, r = 0.571 to -0.819). Lower MFM-32 scores in DMD children were correlated with worse TUG performance across conditions (p < 0.05, r = 0.586 to -0.868). SIGNIFIANCE: This study sheds light on the multifaceted nature of dual-tasking challenges in individuals with DMD, thereby contributing to a deeper understanding of the implications for rehabilitation strategies.

Identification of medically important yeasts by sequence analysis of the internal transcribed spacer and D1/D2 region of the large ribosomal subunit / Identificación de levaduras de interés médico mediante análisis de secuencia del espaciador interno transcrito y de la región D1/D2 de la subunidad ribosómica grande

Background: The prevalence of opportunistic yeast infections has increased in recent decades as the result of an increasing immunocompromised patient population. Aims: To evaluate ribosomal RNA (rRNA) gene sequence to identify medically important yeast species, to investigate the performance of both the rRNA gene internal transcribed spacer (ITS) and D1/D2 region in identifying clinically relevant yeasts, and to compare these results with those of a standard phenotypic method. Methods: Both regions from 50 yeast strains, comprising 45 clinical isolates and 5 reference strains, were amplified using PCR and then sequenced. The sequences were compared to reference data available from the GenBank database of the National Center for Biotechnology Information using the BLASTn tool. Results: Using ID32C, 88% (44/50) of all strains were identified accurately at the species level, although 6% were misidentified; two Candida eremophila isolates were identified as Candida glabrata and Candida tropicalis, and one Saprochaete clavata isolate was identified as Saprochaete capitata. Two of the four isolates identified by phenotypic methods as Trichosporon asahii were defined so by analyzing the ITS region, but the remaining two were not distinguishable from closely related species. Based on the D1/D2 region, these four isolates had 100% sequence identity with T. asahii, Trichosporon japonicum, and Trichosporon asteroides. The isolate identified as Trichosporon inkin using ID32C could not be distinguished from Trichosporon ovoides by analyzing the ITS and D1/D2 regions. Conclusions: Identifying medically important yeasts by sequencing the ITS and D1/D2 region is a rapid and reliable alternative to conventional identification methods. For a diagnostic algorithm, we suggest a two-step procedure integrating conventional methods (e.g. microscopic morphology on corn meal agar with Tween(R) 80 and API ID32C(R)) and sequence analysis of the ITS and D1/D2 region

Antecedentes: La prevalencia de infecciones oportunistas por levaduras ha aumentado en las últimas décadas como resultado de una población de pacientes inmunocomprometidos cada vez mayor. Objetivos: Evaluar la secuencia del gen del ARN ribosomal (ARNr) para identificar especies de levaduras médicamente importantes, investigar el rendimiento del espaciador transcrito interno del gen ARNr (ITS) y las regiones D1/D2 en la identificación de levaduras clínicamente relevantes, y comparar estos resultados con los de un método fenotípico estándar. Métodos: Ambas regiones del ARNr de 50 cepas de levaduras con 45 aislamientos clínicos y 5 cepas de referencia se amplificaron mediante PCR y posteriormente se secuenciaron. Las secuencias se compararon con los datos de referencia disponibles en la base de datos GenBank(R) del Centro Nacional de Información Biotecnológica mediante la herramienta BLASTn. Resultados: Mediante el método ID32C el 88% (44/50) de todas las cepas se identificaron con precisión y el 6% se identificaron erróneamente; dos aislamientos de Candida eremophila fueron identificados como Candida glabrata y Candida tropicalis, y un aislamiento de Saprochaete clavata fue identificado como Saprochaete capitata. Dos de los cuatro aislamientos identificados por métodos fenotípicos como Trichosporon asahii se catalogaron así al analizar la región ITS, pero las dos restantes no se distinguían de las especies estrechamente relacionadas. En base a la secuencia de la región D1/D2, estos cuatro aislamientos se identificaron, con un 100% de similitud, como T. asahii, Trichosporon japonicum y Trichosporon asteroides. El aislamiento identificado como Trichosporon inkin mediante ID32C no se pudo distinguir de Trichosporon ovoides al analizar las regiones ITS y D1/D2. Conclusiones: La identificación de levaduras de interés médico mediante la secuenciación de las regiones ITS y D1/D2 es una alternativa rápida y confiable a los métodos de identificación convencionales. Para un algoritmo de diagnóstico sugerimos un procedimiento de dos pasos que integre métodos convencionales (morfología microscópica en agar de harina de maíz con Tween(R) 80 y API ID32C(R)) y análisis de la secuencia de las regiones ITS y D1/D2

Lack of evidence of HPV etiology of prostate cancer following radical surgery and higher frequency of the Arg/Pro genotype in turkish men with prostate cancer

ABSTRACT Objectives The aim of this study was to assess the possible role of HPV in the development of prostate cancer (PCa) and investigate the distribution of the p53 codon 72 polymorphism in PCa in a Turkish population. Materials and methods A total of 96 tissues, which had been obtained using a radical surgery method, formalin-fixed and parafin-embedded, were used in this study. The study group consisted of 60 PCa tissues (open radical prostatectomy) and the control group contained 36 benign prostatic hyperplasia tissues (BPH) (transvesical open prostatectomy). The presence of HPV and the p53 codon 72 polymorphism was investigated in both groups using real-time PCR and pyrosequencing. Results The results of the real-time PCR showed no HPV DNA in any of the 36 BPH tissue samples. HPV-DNA was positive in only 1 of the 60 PCa samples (1.7%). The HPV type of this sample was identified as HPV-57. The distribution of the three genotypes, Arg/Arg, Arg/Pro and Pro/Pro was found to be 45.6, 45.6, and 8.8% in the PCa group and 57.1%, 34.3% and 8.6% in the control group, respectively. Compared with the control group, patients with PCa had a higher frequency of the Arg/Pro genotype and Proline allele (odds ratio (OR)=1.67, 95% confidence interval (CI)=0.68-4.09, p=0.044; OR=1.13, 95% CI=0.76-1.68, p=0.021, respectively). Conclusions The results of the study do not support the hyphothesis that prostate cancer is associated with HPV infection but indicated that Proline allele can be a risk factor in the development of PCa in the Turkish population.