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Abstract The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches.

Primary ciliary defects cause a group of developmental conditions known as ciliopathies. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for mouse model lacking the ciliary protein Mks1. In vivo loss of Mks1 sensitises cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. We identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalised, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. We demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1).

Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.

This paper is concerned with the second order differential equation with not necessarily linear nonlocal boundary condition. The existence of solutions is obtained using the properties of the Leray–Schauder degree. The results generalize and improve some known results with linear nonlocal boundary conditions.

In this paper we study the nonlocal Neumann boundary value problem of the following form $$ u'' =f(t,u,u'),\quad u'(0)=0, \quad u'(1)=\int_{0 }^{1}u'(s)dg(s), $$ where $f:[0,1]\times\mathbb R^n\times\mathbb R^n\to\mathbb R^n$ and $g=\mbox{diag}(g_1,\ldots,g_n)$ with $g_i:[0,1]\to\mathbb R$, $i=1,\ldots,n$. The case when the function $f$ does not depend on $u'$ is also considered. The existence of solutions is obtained by means of the generalized Miranda theorem. The main results can be applied to many problems of this type depending on which conditions will be imposed upon the function $f$.

The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.

In this article we show the existence of at least one solution to the system of nonlocal resonant boundary-value problem $$ x''=f(t,x), \quad x'(0)=0, \quad x'(1)=\int_{0 }^{1}x'(s)\,dg(s), $$ where $f:[0,1]\times\mathbb{R}^k\to\mathbb{R}^k$, $g:[0,1]\to\mathbb{R}^k$.

Meckel–Gruber syndrome (MKS) is a lethal autosomal recessive congenital anomaly syndrome caused by mutations in genes encoding proteins that are structural or functional components of the primary cilium. Conditions that are caused by mutations in ciliary genes are collectively termed the ciliopathies, and MKS represents the most severe condition in this group of disorders. The primary cilium is a microtubule-based organelle, projecting from the apical surface of vertebrate cells. It acts as an “antenna” that receives and transduces chemosensory and mechanosensory signals, but also regulates diverse signaling pathways, such as Wnt and Shh, that have important roles during embryonic development. Most MKS proteins localize to a distinct ciliary compartment called the transition zone (TZ) that regulates the trafficking of cargo proteins or lipids. In this review, we provide an up-to-date summary of MKS clinical features, molecular genetics, and clinical diagnosis. MKS has a highly variable phenotype, extreme genetic heterogeneity, and displays allelism with other related ciliopathies such as Joubert syndrome, presenting significant challenges to diagnosis. Recent advances in genetic technology, with the widespread use of multi-gene panels for molecular testing, have significantly improved diagnosis, genetic counseling, and the clinical management of MKS families. These include the description of some limited genotype–phenotype correlations. We discuss recent insights into the molecular basis of disease in MKS, since the functions of some of the relevant ciliary proteins have now been determined. A common molecular etiology appears to be disruption of ciliary TZ structure and function, affecting essential developmental signaling and the regulation of secondary messengers.

Extracellular vesicles (EVs) play a possible role in cell–cell communication and are found in various body fluids and cell conditioned culture media. The aim of this study was to isolate and characterize EVs in culture medium conditioned by bovine embryos in group and to verify if these EVs are functionally active. Initially, ultracentrifuged bovine serum albumin (BSA) containing medium was selected as suitable EV-free embryo culture medium. Next, EVs were isolated from embryo conditioned culture medium by OptiPrepTM density gradient ultracentrifugation. Isolated EVs were characterized by nanoparticle tracking analysis, western blotting, transmission, and immunoelectron microscopy. Bovine embryo-derived EVs were sizing between 25–230 nm with an average concentration of 236.5 ± 1.27 × 108 particles/mL. Moreover, PKH67 EV pre-labeling showed that embryo-secreted EVs were uptaken by zona-intact bovine embryos. Since BSA did not appear to be a contaminating EV source in culture medium, EV functionality was tested in BSA containing medium. Individual embryo culture in BSA medium enriched with EVs derived from conditioned embryo culture medium showed significantly higher blastocyst rates at day 7 and 8 together with a significantly lower apoptotic cell ratio. In conclusion, our study shows that EVs play an important role in inter embryo communication during bovine embryo culture in group.

We provide an existence result for a Neumann nonlinear boundary value problem posed on the half-line. Our main tool is the multi-valued version of the Miranda Theorem.

We prove the existence of at least one solution to a nonlinear second-order differential equation on the half-line, with the boundary conditions $x'(0)=0$ and with the first derivative vanishing at infinity. Our main tool is the multi-valued version of the Miranda Theorem.

The aim of this study is the presentation of novel water treatment systems based on ozonation combined with ceramic membranes for the treatment of refractory organic compounds found in natural water sources such as groundwater. This includes, firstly, a short review of possible membrane based hybrid processes for water treatment from various sources. Several practical and theoretical aspects for the application of hybrid membrane-ozonation systems are discussed, along with theoretical background regarding the transformation of target organic pollutants by ozone. Next, a novel ceramic membrane contactor, bringing into contact the gas phase (ozone) and water phase without the creation of bubbles (bubbleless ozonation), is presented. Experimental data showing the membrane contactor efficiency for oxidation of atrazine, endosulfan, and methyl tert-butyl ether (MTBE) are shown and discussed. Almost complete endosulfan degradation was achieved with the use of the ceramic contactor, whereas atrazine degradation higher than 50% could not be achieved even after 60 min of reaction time. Single ozonation of water containing MTBE could not result in a significant MTBE degradation. MTBE mineralization by O3/H2O2 combination increased at higher pH values and O3/H2O2 molar ratio of 0.2 reaching a maximum of around 65%.

Silica monoliths featuring either mesopores or flow-through macropores and mesopores in their skeleton are prepared by combining spinodal phase separation and sol-gel condensation. The macroporous network is first generated by phase separation in acidic medium in the presence of polyethyleneoxides while mesoporosity is engineered in a second step in alkaline medium, possibly in the presence of alkylammonium cations as surfactants. The mesoporous monoliths, also referred as aerogels, are obtained in the presence of alkylpolyethylene oxides in acidic medium without the use of supercritical drying. The impact of the experimental conditions on pore architecture of the monoliths regarding the shape, the ordering, the size and the connectivity of the mesopores is comprehensively discussed based on a critical appraisal of the different models used for textural analysis.

Objective: The purpose of the article is to answer the following questions: What are the problems faced by university managers responsible for managing multigenerational work teams? Is it possible, and if so, what are good practices in integrating the potential of multigenerational teams of employees? What is the overall assessment of multigenerational teams – do university executives see them as an opportunity or a burden? Research Design & Methods: Qualitative research in the form of a case study was carried out. This method included seven individual interviews with executives at the Faculty of Organization and Management at Lodz University of Technology. Findings: Executives at the selected university identify various types of problems in managing multigenerational teams, while recognising opportunities to integrate the potential inherent in age-diverse teams. Respondents are mostly positive about intergenerational teams, but they also note some difficulties for managers related to having a multigenerational team. Implications / Recommendations: The role of people responsible for leading multigenerational teams is becoming increasingly demanding. Striving to achieve equal involvement of representatives of all generations in the work is one of the most difficult challenges faced by university managers today. The effort, however, is worth making, as any diversity can positively influence the team and foster improvements in knowledge management. Contribution: The article adds to the characterisation of each generation of employees with aspects from a knowledge management perspective.

Introduction: Artificial Intelligence (AI) has emerged as a seminal force in healthcare, fundamentally transforming various aspects of medical practice and patient care. This review explores the transformative impact of AI on the treatment of cardiovascular diseases (CVDs). State of Knowledge: AI has revolutionized diagnostic accuracy, treatment precision, and patient management in the realm of cardiovascular care. It enhances diagnostic processes, enabling the early detection of CVDs through advanced imaging analysis and interpretation. Additionally, AI facilitates precision in risk stratification, identifying high-risk patient cohorts with heightened accuracy and informing personalized treatment strategies. Furthermore, AI optimizes drug selection and dosage regimens through pharmacogenomics, maximizing therapeutic efficacy while minimizing adverse drug reactions. Moreover, AI improves precision and safety during interventional procedures, guiding clinicians in real-time decision-making and enhancing procedural outcomes. Conclusions: AI is poised to revolutionize cardiovascular care, fostering innovation and improving patient outcomes.

Introduction and purpose: Chronic inflammation in the oral cavity poses significant risks to both the heart and the circulatory system. A growing number of studies indicate a correlation between periodontal health and the likelihood of developing cardiovascular conditions, including myocardial infarction, coronary artery disease, hypertension, and stroke. This review aims to summarize recent reports, define current state of knowledge, and propose optimal treatment and prevention strategies. State of knowledge: Risk factors such as obesity, smoking, and genetic predisposition contribute to the development of both PD and cardiovascular diseases (CVDs). Inflammation serves as a common factor linking the two conditions, with periodontal pathogens directly affecting cardiovascular health. Epigenetic mechanisms, particularly in response to environmental stimuli, further exacerbate the relationship between PD and CVDs. Additionally, the oral microbiome plays a crucial role, with periodontal pathogens infiltrating systemic circulation and triggering immune-inflammatory responses that promote cardiovascular damage. Conclusions: People with periodontitis have a higher risk of CVDs, especially when other risk factors such as smoking and obesity are present. Periodontal treatment has been demonstrated to enhance cardiovascular health parameters. Implementing preventive strategy, addressing both periodontitis and cardiovascular risk factors, could potentially decrease morbidity and mortality associated with cardiovascular disease.

Introduction: Parkinson's disease (PD) is one of the most common neurodegenerative diseases that mainly affects older people over 60 years of age. Since life expectancy is increasing not only in Europe but also around the world, the number of people suffering from PD will gradually increase. State of knowledge: One of the newest techniques used to study the mechanisms of diseases of the nervous system, which allows monitoring the activity of neurons by modifying their functions, is optogenetics. This method involves controlling neuronal activity using light. The sensitivity of cells to light is achieved by introducing into the body the genes of ion channels from algae or bacteria, which are incorporated into the cell membrane and then become excited when exposed to light. Depending on the gene used, the activity of a nerve cell can be intensified or inhibited. An important advantage of the method is the possibility of using it in vivo and recording the results in real time. Summary: This publication aims to present the basics of optogenetics and is a review of works related to its use in the study of PD pathomechanism. For this purpose, the PubMed and Google Scholar databases were verified using the following words: "Parkinson optogenetic", "optogenetic stimulation", "channelrhodopsin".

Background: Creatine, a naturally occurring compound plays a crucial role in cellular energy metabolism, particularly in tissues with high energy demands like muscles and the brain. Beyond its well-established role in physical performance enhancement, recent research has revealed its potential benefits for cognitive functions and mood regulation. This review paper aims to comprehensively analyze the existing literature on creatine supplementation's effects on cognitive functions and mood. State of Knowledge: Findings suggest that creatine supplementation enhances memory, attention, and executive functions, especially under conditions of stress or sleep deprivation. Moreover, it exhibits mood-stabilizing effects, potentially offering relief for symptoms of depression and fatigue. Creatine's ability to augment brain energy metabolism, alongside its neuroprotective properties, underlies its cognitive and mood-enhancing effects. While generally safe, caution is advised, particularly in populations with kidney diseases or those using medications affecting kidney function. Summary: Creatine emerges as a promising adjunct therapy for enhancing cognitive functions and promoting emotional well-being beyond its traditional role in physical performance.The review underscores the need for further research to elucidate the precise mechanisms of creatine's effects and explore its synergistic potential with other cognitive-enhancing supplements.

Introduction: Neurodegenerative diseases pose a significant diagnostic challenge due to the increasing elderly population and the rising prevalence of these conditions. State of Knowledge: Differential diagnosis among these diseases is particularly challenging; thus, numerous clinical trials have been conducted to identify markers that could facilitate accurate disease diagnosis. Among various diagnostic approaches, imaging techniques play a crucial role, especially magnetic resonance imaging (MRI), which includes advanced modalities such as proton magnetic resonance spectroscopy (¹H-MRS). ¹H-MRS offers a non-invasive assessment of neurometabolite profiles, providing critical information that aids in precise diagnosis. Conclusions: With ongoing clinical trials, the importance of ¹H-MRS in diagnosing neurodegenerative diseases continues to grow. This paper reviews the results of recent and relevant clinical trials examining changes in ¹H-MRS in the most prevalent neurodegenerative diseases.

Introduction: Children with chronic kidney disease (CKD) require a specialized diet to manage their condition and support healthy growth and development. A proper diet for children with CKD aims to control the intake of certain nutrients, such as protein, lipid, calcium, phosphorus, potassium, sodium, and vitamin D, while ensuring they receive adequate nutrition for growth and development. Aim of the study: This article discusses the epidemiology, causes and pathomechanism of CKD in children. It also presents existing clinical trials and dietary recommendations from societies such as Kidney Disease: Improving Global Outcomes (KDIGO) 2024, Kidney Disease Outcomes Quality Initiative (KDOQI) and Pediatric Renal Nutrition Taskforce (PRNT) and identifies potential sources of selected macronutrients and micronutrients in children's diets. Materials and methods: Comprehensive literature searches were performed across the main electronic databases of PubMed, Google Scholar, KDIGO2024, KDQQI and PRNT recommendations for studies published in the English language about dietary recommendations for children with CKD. Results: The approach to nutrition for children with CKD is still evolving, and specific macronutrient and micronutrient ratios should be established based on the clinical condition, the child's age, and body weight. Care should be taken to ensure that the child's diet is varied, and a healthy eating style should be promoted.

Intruduction and purpose: Patients with severe asthma account for approximately 3% to 10% of all asthma patients. They have higher hospital utilization rates and treatment costs than patients with non-severe asthma. Previously, treatment options for these patients were limited due to unacceptable side effects. However, the advent of biologic therapies has provided promising targeted therapy for these patients. State of knowledge: Biologic therapies target inflammatory modulators that play a key role in the pathogenesis of asthma, particularly in patients with high T2 cells. These therapies have shown promising results in reducing asthma symptoms, improving lung function, decreasing the use of oral corticosteroids, and enhancing patients' quality of life. Conclusions: This article reviews the mechanism of action, efficacy, and indications of currently approved biologic drugs available in Poland, as well as potential therapeutic targets for the future.

Introduction and Purpose: In last years gene modification technologies such as CRISPR/Cas9 has had a revolutionary impact on the treatment of inherited diseases. Technologies developed from bacterial defense mechanisms, has become a basic tools in scientific research and medical therapies. In our article we provided an overview of applications of gene modifications technologies, directly focusing on CRISPR/Cas9, in genetic disease treatment. State of Knowledge: New applications of CRISPR/Cas9 are still being explored. Treating inherited diseases such as cystic fibrosis, Duchenne muscular dystrophy, thalassemia, hemophilia, Huntington's disease, Crigler-Najjar syndrome, sickle cell anemia, Marfan syndrome, and phenylketonuria, is feasible with this novel technique. A comparative analysis with other gene editing methods highlights CRISPR/Cas9's efficacy, ease of use, and multiplexing capabilities. Summary: CRISPR/Cas9 is a groundbreaking technology with broad applications in genetic research and therapy. Its ease of use, cost-effectiveness, and ability to target multiple genes simultaneously position it as a preferred method. However, there are some challenges associated with precision issues and ethical considerations in human embryo gene editing. As CRISPR/Cas9 continues to evolve, responsible application and ethical considerations are important for maximizing its potential in treatment of genetic diseases.

Introduction and purpose: Gaucher's Disease (GD), a rare genetic disorder, is a difficult challenge in genetic and metabolic disorders. The aim of this review is to provide an exploration of GD, spanning its pathophysiology to the latest advancements in diagnostic and therapeutic innovations. In this review we aimed to underscore the challenges it presents and the ongoing efforts to overcome them. State of knowledge: GD, characterized by the accumulation of glucocerebroside, involves molecular, cellular, and systemic dysfunctions. At the molecular level, mutations in the GBA gene give rise to diverse manifestations, influencing disease severity. Cellular disruptions lead to lysosomal dysfunction, altered calcium homeostasis, and chronic inflammation, impacting various organ systems. Diagnostic approaches involve biomarkers, genetic testing, and imaging studies, each playing a crucial role in confirming the disease type and assessing its grade. Summary: Management and treatment strategies for GD have evolved, with enzyme replacement therapy and substrate reduction therapy serving as the basics. However, challenges persist, including limited efficacy in treating neurological symptoms and the high cost of treatments. The review highlights ongoing research and future perspectives in GD therapy.

Precipitation is an important factor that influences the quality of surface water in many regions of the world. The pollution of stormwater runoff from roads and parking lots is an understudied area in water quality research. Therefore, a comprehensive analysis of the physicochemical properties of rainwater flowing from parking lots was carried out, considering heavy metals and organic micropollutants. High concentrations of zinc were observed in rainwater, in addition to alkanes, e.g., tetradecane, hexadecane, octadecane, 2,6,10-trimethyldodecane, 2-methyldodecane; phenolic derivatives, such as 2,6-dimethoxyphenol and 2,4-di-tertbutylphenol; and compounds such as benzothiazole. To remove the contaminants present in rainwater, adsorption using silica carriers of the MCF (Mesostructured Cellular Foams) type was performed. Three groups of modified carriers were prepared, i.e., (1) SH (thiol), (2) NH2 (amino), and (3) NH2/SH (amine and thiol functional groups). The research problem, which is addressed in the presented article, is concerned with the silica carrier influence of the functional group on the adsorption efficiency of micropollutants. The study included an evaluation of the effects of adsorption dose and time on the efficiency of the contaminant removal process, as well as an analysis of adsorption isotherms and reaction kinetics. The colour adsorption from rainwater was 94–95% for MCF-NH2 and MCF-NH2/SH. Zinc adsorbance was at a level of 90% for MCF-NH2, and for MCF-NH2/SH, 52%. Studies have shown the high efficacy (100%) of MCF-NH2 in removing organic micropollutants, especially phenolic compounds and benzothiazole. On the other hand, octadecane was the least susceptible to adsorption in each case. It was found that the highest efficiency of removal of organic micropollutants and zinc ions was obtained through the use of functionalized silica NH2.

Background: The symbiotic relationship between the gut microbiota and cardiovascular health has become a main point in contemporary research, offering valuable insights into the pathogenesis of cardiovascular diseases (CVDs). This review aims to comprehensively examine the bidirectional communication between gut microbial communities and the cardiovascular system, explaining the intricate mechanisms that connect gut dysbiosis to the initiation and progression of CVDs. Material and Methods: A systematic literature review was conducted to compile and analyze relevant studies investigating the impact of the gut microbiota on cardiovascular health. Emphasis was placed on explaining the molecular and physiological mechanisms underlying the interaction between gut microbes and cardiovascular function. Results: Our review confirmed evidence linking gut microbiota-derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide and lipopolysaccharides to vascular function and inflammation. Additionally, we explored the modulation of host metabolism and immune responses by gut microbes, providing insights into their roles in atherosclerosis and hypertension. The review highlight the influence of diet and lifestyle on shaping the gut microbiome and, consequently, cardiovascular outcomes. Conclusions: Gut microbiota plays a crucial role in cardiovascular health and is involved in the start and development of various heart diseases. The identified molecular and physiological mechanisms highlight the need for complete understanding of the gut-cardiovascular axis. Moreover, the review emphasizes the potential of microbiota-targeted interventions, including probiotics and fecal microbiota transplantation, as innovative strategies for preventing and managing CVDs.