Diabetes mellitus (DM) je endokrinní onemocnění s rychle rostoucí celosvětovou prevalencí. Neoptimální léčba DM, zejména diabetu 1. typu (DM 1. typu), může vést k hypoglykemii – stavu charakterizovanému nízkou hladinou glukózy v krvi. Tento stav může negativně ovliv- nit funkce nezbytné pro jemné motorické dovednosti, jako je řízení, a tím zvýšit riziko dopravních nehod. Je proto klíčové hypoglykemii předcházet nebo ji efektivně řešit a zároveň zavést odpovídající legislativní opatření, která zajistí bezpečnost na silnicích. Tento článek se zaměřuje na problematiku hypoglykemie jako rizikového faktoru při řízení motorových vozidel v Indii a diskutuje možnosti pro budoucí zlepšení.
Diabetes mellitus (DM) is an endocrine disorder rapidly growing in global prevalence. Poor management of DM (primarily type 1 DM) may result in low blood glucose – hypoglycaemia. This condition can impair functions essential for fine skills like driving, thereby increasing the risk of motor accidents. Therefore, it is important to prevent or manage this complication judiciously, and to have appropriate legislations to ensure public road safety. In this article, we examine these aspects of hypoglycaemia as a driving risk in India and discuss possible goals for the future.
INTRODUCTION: Human and animal skin is colonized by a complex microbial population. An imbalance of these microorganisms is often associated with dermatological diseases. METHODS: The aim of this work was to describe the skin bacterial microbiota composition of healthy dogs and dogs with inflammatory skin lesions. Genomic DNA was sequenced using primers that target the V4 region of the bacterial 16S rRNA gene. Superficial skin swabs were collected from eight body areas of six healthy dogs (n = 48) and directly from inflammatory altered canine skin (n = 16). RESULTS: The skin of healthy dogs was predominantly colonized by phylum Bacillota (34.4 ± 27.2%), followed by Actinomycetota (32.2 ± 20.3%), Pseudomonadota (16.4 ± 12.2%), and Bacteroidota (8.7 ± 11.6%). At the level of genera, Streptococcus spp. (19.4 ± 26.1%) was the most abundant genus across all samples collected from healthy skin, followed by Curtobacterium (5.4 ± 12.1%), Bacteroides (5.2 ± 11.1%) and Corynebacterium_1 (4.3 ± 13.2%). More specifically, Streptococcus spp. was the most abundant on the chin (49.0 ± 35.5%), nose (37.9 ± 32.1%), perianal region (21.1 ± 28.2%), abdomen (11.0 ± 12.8%), dorsal back (12.4 ± 10.3%) and interdigital area (5.5 ± 2.2%). Curtobacterium spp. was predominant on inner pinna (17.8 ± 24.8%) and axilla (6.7 ± 10.8%). Alpha diversity analysis (Shannon index) showed maximum on interdigital area but minimum on a chin (p-value: 0.0416). Beta diversity analysis showed clustering across samples from the individual skin sites but also across samples collected from individual dogs. Staphylococcus spp. was the most abundant genus in 12/16 samples collected from inflammatory skin. In addition, a lower bacterial diversity was observed in samples from skin lesions compared to samples from healthy canine skin. DISCUSSION: The results confirm the fact that the microbiome of healthy skin is very diverse. Compared to other studies, streptococci predominated on healthy canine skin. Shannon index showed only minor differences in diversity between different parts of canine skin. Results of beta-diversity showed the fact that the main force driving the skin microbiota composition is the individual, followed by the skin site. On the area of skin lesions, dysbiosis was observed with a significant predominance of staphylococci.
- Publication type
- Journal Article MeSH
Impaired awareness of hypoglycemia remains an issue even in the era of modern technologies, as patients with type 1 diabetes (T1DM) face stricter requirements for glycemic targets. The evaluation of hypoglycemia awareness can be accomplished using questionnaires (Clarke and Gold scores) in combination with clinical appearance and sensor data. A 45-year-old man with T1DM was referred to our clinic in July 2019 due to impaired hypoglycemia awareness and repeated severe hypoglycemic episodes resulting in unconsciousness. At that time, he was driving both a car and a motorcycle. Despite good compliance, increased target values and implementation of continuous glucose monitoring (CGM) with alarms, prolonged hypoglycemias were not eliminated. Therefore, the patient was referred for pancreatic islet transplantation, but he decided not to undergo. In May 2021, his driving license was suspended, which eventually led him to accept treatment with a hybrid closed-loop insulin pump (AID). Shortly after initiation, he achieved satisfactory glycemic control, reduced time spent in hypoglycemia, and had no severe hypoglycemic episodes. According to the questionnaires, the hypoglycemia awareness has improved and his driving license was reinstated. This case study highlights the critical importance of identifying impaired awareness of hypoglycemia, its potential social impacts, and the opportunities for using new technologies to reverse this complication.
- Publication type
- Journal Article MeSH
- Case Reports MeSH
The brain's complex organization spans from molecular-level processes within neurons to large-scale networks, making it essential to understand this multiscale structure to uncover brain functions and address neurological disorders. Multiscale brain modeling has emerged as a transformative approach, integrating computational models, advanced imaging, and big data to bridge these levels of organization. This review explores the challenges and opportunities in linking microscopic phenomena to macroscopic brain functions, emphasizing the methodologies driving progress in the field. It also highlights the clinical potential of multiscale models, including their role in advancing artificial intelligence (AI) applications and improving healthcare technologies. By examining current research and proposing future directions for interdisciplinary collaboration, this work demonstrates how multiscale brain modeling can revolutionize both scientific understanding and clinical practice.
- Publication type
- Journal Article MeSH
- Review MeSH
A large body of evidence suggests that hypoxia drives aggressive molecular features of malignant cells irrespective of cancer type. Non-Hodgkin lymphomas (NHL) are the most common hematologic malignancies characterized by frequent involvement of diverse hypoxic microenvironments. We studied the impact of long-term deep hypoxia (1% O2) on the biology of lymphoma cells. Only 2 out of 6 tested cell lines (Ramos, and HBL2) survived ≥ 4 weeks under hypoxia. The hypoxia-adapted (HA)b Ramos and HBL2 cells had a decreased proliferation rate accompanied by significant suppression of both oxidative phosphorylation and glycolytic pathways. Transcriptome and proteome analyses revealed marked downregulation of genes and proteins of the mitochondrial respiration complexes I and IV, and mitochondrial ribosomal proteins. Despite the observed suppression of glycolysis, the proteome analysis of both HA cell lines showed upregulation of several proteins involved in the regulation of glucose utilization including the active catalytic component of prolyl-4-hydroxylase P4HA1, an important druggable oncogene. HA cell lines demonstrated increased transcription of key regulators of auto-/mitophagy, e.g., neuritin, BCL2 interacting protein 3 (BNIP3), BNIP3-like protein, and BNIP3 pseudogene. Adaptation to hypoxia was further associated with deregulation of apoptosis, namely upregulation of BCL2L1/BCL-XL, overexpression of BCL2L11/BIM, increased binding of BIM to BCL-XL, and significantly increased sensitivity of both HA cell lines to A1155463, a BCL-XL inhibitor. Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor. In conclusion, our data report on several shared mechanisms of lymphoma cell adaptation to long-term hypoxia including: 1. Upregulation of proteins responsible for glucose utilization, 2. Degradation of mitochondrial proteins for potential mitochondrial recycling (by mitophagy), and 3. Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells.
- Publication type
- Journal Article MeSH
Microbial diversity plays a crucial role in litter decomposition. However, the relationships between microbial diversity and substrate successional stage are the drivers of this decomposition. In this study, we experimentally manipulated microbial diversity and succession in post-mining soil. We used leaf litter samples from two forests of a post-mining site near Sokolov, Czech Republic: one alder plantation and one mixed forest with birch aspen and willow. Litter from each site was decomposed in the field for 3 and 12 months. The litter was X-ray sterilized and part of the litter was kept unsterilized to produce inoculum. Leaf litter samples of two different ages (3 and 12 months) from each site were each inoculated with litter of two different ages (3 and 12 months), using less and more diluted inoculum, producing two levels of microbial diversity. In each of these eight treatments, the bacterial community was then characterized by amplicon sequencing of the 16S rRNA gene and microbial respiration was used to assess the rate of decomposition. A significantly higher respiration (p < 0.05) was found for the litter inoculated with the higher level of microbial diversity. Higher respiration was also found for the younger litter compared to the older litter and both litter origins. This shows a reduction in microbial respiration with substrate age and inoculation diversity, suggesting that microbial diversity supports the decomposition of soil organic matter.
- Publication type
- Journal Article MeSH
Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.
- Publication type
- Journal Article MeSH
Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipids caused by nonalcoholic factors, where histone lactylation is lately discovered as a modification driving disease progression. This research aimed to explore the role of histone 3 lysine 18 lactylation (H3K18lac) in NAFLD progression using a high-fat diet (HFD)-treated mouse model and free fatty acids (FFA)-treated L-02 cell lines. Lipids accumulation was screened via Oil Red O staining, real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and commercially available kits. Similarly, molecular mechanism was analyzed using immunoprecipitation (IP), dual-luciferase reporter assay, and RNA decay assay. Results indicated that FFA upregulated lactate dehydrogenase A (LDHA) and H3K18lac levels in L-02 cells. Besides, LDHA-mediated H3K18lac was enriched on the proximal promoter of methyltransferase 3 (METTL3), translating into an increased expression. Moreover, METTL3 or LDHA knockdown relieved lipid accumulation, decreased total cholesterol (TC) and triglyceride (TG) levels, and downregulated lipogenesis-related proteins in FFA-treated L-02 cell lines, in addition to enhancing the m6A and mRNA levels of stearoyl-coenzyme A desaturase 1 (SCD1). The m6A modification of SCD1 was recognized by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), resulting in enhanced mRNA stability. LDHA was found to be highly expressed in HFD-treated mice, where knocking down LDHA attenuated HFD-induced hepatic steatosis. These findings demonstrated that LDHA-induced H3K18lac promoted NAFLD progression, where LDHA-induced H3K18lac in METTL3 promoter elevated METTL3 expression, thereby promoting m6A methylation and stabilizing SCD1 via a YTHDF1-dependent manner. Keywords: Nonalcoholic fatty liver disease, LDHA, METTL3, YTHDF1, Histone lactylation.
- MeSH
- Adenosine * metabolism analogs & derivatives MeSH
- Diet, High-Fat adverse effects MeSH
- Histones * metabolism MeSH
- L-Lactate Dehydrogenase metabolism MeSH
- Humans MeSH
- Methyltransferases * metabolism genetics MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Non-alcoholic Fatty Liver Disease * metabolism pathology MeSH
- Disease Progression * MeSH
- RNA-Binding Proteins * metabolism genetics MeSH
- Stearoyl-CoA Desaturase * metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Eyeglasses MeSH
- Humans MeSH
- Myopia MeSH
- Night Vision MeSH
- Glare MeSH
- Automobile Driving * MeSH
- Vision, Ocular MeSH
- Check Tag
- Humans MeSH
- Publication type
- Interview MeSH
BACKGROUND: Electrical stimulation involving temporal interference of two different kHz frequency sinusoidal electric fields (temporal interference (TI)) enables non-invasive deep brain stimulation, by creating an electric field that is amplitude modulated at the slow difference frequency (within the neural range), at the target brain region. OBJECTIVE: Here, we investigate temporal interference neural stimulation using square, rather than sinusoidal, electric fields that create an electric field that is pulse-width, but not amplitude, modulated at the difference frequency (pulse-width modulated temporal interference, (PWM-TI)). METHODS/RESULTS: We show, using ex-vivo single-cell recordings and in-vivo calcium imaging, that PWM-TI effectively stimulates neural activity at the difference frequency at a similar efficiency to traditional TI. We then demonstrate, using computational modelling, that the PWM stimulation waveform induces amplitude-modulated membrane potential depolarization due to the membrane's intrinsic low-pass filtering property. CONCLUSIONS: PWM-TI can effectively drive neural activity at the difference frequency. The PWM-TI mechanism involves converting an envelope amplitude-fixed PWM field to an amplitude-modulated membrane potential via the low-pass filtering of the passive neural membrane. Unveiling the biophysics underpinning the neural response to complex electric fields may facilitate the development of new brain stimulation strategies with improved precision and efficiency.
- MeSH
- Electric Stimulation MeSH
- Brain * MeSH
- Computer Simulation MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
