Schizophrenia is a psychiatric disorder with heterogeneous clinical manifestations and complex aetiology. Notably, the triple-network model proposes an interesting framework for investigating abnormal neurocircuit activity at rest in schizophrenia. The present study on 30 chronic schizophrenia individuals and 30 controls aimed to explore the differences in EEG resting state effective connectivity within a triple-network model using source-localization-based Directed Transfer Function. Our findings revealed multiband effective connectivity disturbances within default mode (DMN), central executive (CEN), and salience (SN) networks in schizophrenia. The most significant difference was manifested in a global DMN hyperconnectivity, accompanied by low-band hyperconnectivity and high-band hypoconnectivity in CEN, along with the aberrant information flows in SN. In conclusion, our study presents novel insights into schizophrenia neuropathology, with a particular emphasis on the reversed directionality in information flows between hubs of SN, DMN, and CEN. This may be suggested as a promising biomarker of schizophrenia.

• MeSH
• Default Mode Network * physiopathology   MeSH
• Adult MeSH
• Electroencephalography MeSH
• Connectome * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Nerve Net * physiopathology   diagnostic imaging   MeSH
• Schizophrenia * physiopathology   diagnostic imaging   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity is vital for cellular function and physiological processes. The inadequate repair of DNA damage results in the genomic instability, which has been associated with the development and progression of various human diseases. Accumulation of DNA damage can lead to multiple diseases, such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and ageing. This comprehensive review delves the impact of alterations in DNA damage response genes (DDR) and tries to elucidate how and to what extent the same traits modulate diverse major human diseases, such as cancer, neurodegenerative diseases, and immunological disorders. DDR is apparently the trait connecting important complex disorders in humans. However, the pathogenesis of the above disorders and diseases are different and lead to divergent consequences. It is important to discover the switch(es) that direct further the pathogenic process either to proliferative, or degenerative diseases. Our understanding of the influence of DNA damage on diverse human disorders may enable the development of the strategies to prevent, diagnose, and treat these diseases. In our article, we analysed publicly available GWAS summary statistics from the NHGRI-EBI GWAS Catalog and identified 12 009 single-nucleotide polymorphisms (SNPs) associated with cancer. Among these, 119 SNPs were found in DDR pathways, exhibiting significant P-values. Additionally, we identified 44 SNPs linked to various cancer types and neurodegenerative diseases (NDDs), including four located in DDR-related genes: ATM, CUX2, and WNT3. Furthermore, 402 SNPs were associated with both cancer and immunological disorders, with two found in the DDR gene RAD51B. This highlights the versatility of the DDR pathway in multifactorial diseases. However, the specific mechanisms that regulate DDR to initiate distinct pathogenic processes remain to be elucidated.

• MeSH
• Genome-Wide Association Study MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Neoplasms * genetics   MeSH
• Immune System Diseases * genetics   MeSH
• Genomic Instability genetics   MeSH
• Neurodegenerative Diseases * genetics   MeSH
• DNA Repair * genetics   MeSH
• DNA Damage * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

STUDY QUESTION: Can oocyte functionality be assessed by observing changes in their intracytoplasmic lipid droplets (LDs) profiles? SUMMARY ANSWER: Lipid profile changes can reliably be detected in human oocytes; lipid changes are linked with maternal age and impaired developmental competence in a mouse model. WHAT IS KNOWN ALREADY: In all cellular components, lipid damage is the earliest manifestation of oxidative stress (OS), which leads to a cascade of negative consequences for organelles and DNA. Lipid damage is marked by the accumulation of LDs. We hypothesized that impaired oocyte functionality resulting from aging and associated OS could be assessed by changes in LDs profile, hereafter called lipid fingerprint (LF). STUDY DESIGN, SIZE, DURATION: To investigate if it is possible to detect differences in oocyte LF, we subjected human GV-stage oocytes to spectroscopic examinations. For this, a total of 48 oocytes derived from 26 young healthy women (under 33 years of age) with no history of infertility, enrolled in an oocyte donation program, were analyzed. Furthermore, 30 GV human oocytes from 12 women were analyzed by transmission electron microscopy (TEM). To evaluate the effect of oocytes' lipid profile changes on embryo development, a total of 52 C57BL/6 wild-type mice and 125 Gnpat+/- mice were also used. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human oocytes were assessed by label-free cell imaging via coherent anti-Stokes Raman spectroscopy (CARS). Further confirmation of LF changes was conducted using spontaneous Raman followed by Fourier transform infrared (FTIR) spectroscopies and TEM. Additionally, to evaluate whether LF changes are associated with developmental competence, mouse oocytes and blastocysts were evaluated using TEM and the lipid dyes BODIPY and Nile Red. Mouse embryonic exosomes were evaluated using flow cytometry, FTIR and FT-Raman spectroscopies. MAIN RESULTS AND THE ROLE OF CHANCE: Here we demonstrated progressive changes in the LF of oocytes associated with the woman's age consisting of increased LDs size, area, and number. LF variations in oocytes were detectable also within individual donors. This finding makes LF assessment a promising tool to grade oocytes of the same patient, based on their quality. We next demonstrated age-associated changes in oocytes reflected by lipid peroxidation and composition changes; the accumulation of carotenoids; and alterations of structural properties of lipid bilayers. Finally, using a mouse model, we showed that LF changes in oocytes are negatively associated with the secretion of embryonic exosomes prior to implantation. Deficient exosome secretion disrupts communication between the embryo and the uterus and thus may explain recurrent implantation failures in advanced-age patients. LIMITATIONS, REASONS FOR CAUTION: Due to differences in lipid content between different species' oocytes, the developmental impact of lipid oxidation and consequent LF changes may differ across mammalian oocytes. WIDER IMPLICATIONS OF THE FINDINGS: Our findings open the possibility to develop an innovative tool for oocyte assessment and highlight likely functional connections between oocyte LDs and embryonic exosome secretion. By recognizing the role of oocyte LF in shaping the embryo's ability to implant, our original work points to future directions of research relevant to developmental biology and reproductive medicine. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by National Science Centre of Poland, Grants: 2021/41/B/NZ3/03507 and 2019/35/B/NZ4/03547 (to G.E.P.); 2022/44/C/NZ4/00076 (to M.F.H.) and 2019/35/N/NZ3/03213 (to Ł.G.). M.F.H. is a National Agency for Academic Exchange (NAWA) fellow (GA ULM/2019/1/00097/U/00001). K.F. is a Diamond Grant fellow (Ministry of Education and Science GA 0175/DIA/2019/28). The open-access publication of this article was funded by the Priority Research Area BioS under the program "Excellence Initiative - Research University" at the Jagiellonian University in Krakow. The authors declare no competing interest. TRIAL REGISTRATION NUMBER: N/A.

• MeSH
• Adult MeSH
• Embryonic Development physiology   MeSH
• Humans MeSH
• Lipid Droplets metabolism   MeSH
• Lipid Metabolism MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Oocytes * metabolism   MeSH
• Oxidative Stress MeSH
• Spectrum Analysis, Raman MeSH
• Aging metabolism   MeSH
• Microscopy, Electron, Transmission MeSH
• Maternal Age MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Female sexual behaviors in rodents (lordosis and appetitive or "proceptive" behaviors) are induced through a genomic mechanism by the sequential actions of estradiol (E2) and progesterone (P), or E2 and testosterone (T) at their respective receptors. However, non-steroidal agents, such as gonadotropin-releasing hormone (GnRH), Prostaglandin E2 (PGE2), noradrenaline, dopamine, oxytocin, α-melanocyte stimulating hormone, nitric oxide, leptin, apelin, and others, facilitate different aspects of female sexual behavior through their cellular and intracellular effects at the membrane and genomic levels in ovariectomized rats primed with E2. These neurotransmitters often act as intermediaries of E2 and P (or T). The classical model of steroid hormone action through intracellular receptor binding has been complemented by an alternative scenario wherein the steroid functions as a transcription factor after binding the receptor protein to DNA. Another possible mechanism occurs through the activation of second messenger systems (cyclic AMP, cyclic GMP, calcium), which subsequently initiate phosphorylation events via diverse kinase systems (protein kinases A, G, or C). These kinases target the progesterone receptor (PR) or associated effector proteins that connect the PR to the trans-activation machinery. This may also happen to the androgen receptor (AR). In addition, other cellular mechanisms could be involved since the chemical structure of these non-steroidal agents causes a change in their lipophobicity that prevents them from penetrating the cell and exerting direct transcriptional effects; however, they can exert effects on different components of the cell membrane activating a cross-talk between the cell membrane and the regulation of the transcriptional mechanisms.

• MeSH
• Rodentia MeSH
• Gonadal Steroid Hormones metabolism   pharmacology   MeSH
• Progesterone pharmacology   metabolism   MeSH
• Sexual Behavior, Animal * drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Denture, Complete MeSH
• Dentistry MeSH

• Conspectus
• Stomatologie
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• zubní lékařství
• technika lékařská, zdravotnický materiál a protetika
• NML Publication type
• učebnice vysokých škol

The single-stranded RNA genome of SARS-CoV-2 is highly structured. Numerous helical stem-loop structures interrupted by mismatch motifs are present in the functionally important 5'- and 3'-UTRs. These mismatches modulate local helical geometries and feature unusual arrays of hydrogen bonding donor and acceptor groups. However, their conformational and dynamical properties cannot be directly inferred from chemical probing and are difficult to predict theoretically. A mismatch motif (SL1-motif) consisting of three consecutive U•U base pairs is located in stem-loop 1 of the 3'-UTR. We combined NMR-spectroscopy and MD-simulations to investigate its structure and dynamics. All three U•U base pairs feature two direct hydrogen bonds and are as stable as Watson-Crick A:U base pairs. Plasmodium falciparum 25S rRNA contains a triple U•U mismatch motif (Pf-motif) differing from SL1-motif only with respect to the orientation of the two closing base pairs. Interestingly, while the geometry of the outer two U•U mismatches was identical in both motifs the preferred orientation of the central U•U mismatch was different. MD simulations and potassium ion titrations revealed that the potassium ion-binding mode to the major groove is connected to the different preferred geometries of the central base pair in the two motifs.

• MeSH
• 3' Untranslated Regions * MeSH
• Base Pair Mismatch * MeSH
• COVID-19 virology   MeSH
• Genome, Viral MeSH
• Nucleic Acid Conformation MeSH
• Humans MeSH
• Nucleotide Motifs * MeSH
• Base Pairing MeSH
• Plasmodium falciparum genetics   MeSH
• RNA, Viral * chemistry   genetics   MeSH
• SARS-CoV-2 * genetics   chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Hydrogen Bonding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Alterations in the default mode network (DMN) are associated with aging. We assessed age-dependent changes of DMN interactions and correlations with a battery of neuropsychological tests, to understand the differences of DMN directed connectivity between young and older subjects. Using a novel multivariate analysis method on resting-state functional MRI data from fifty young and thirty-one healthy older subjects, we calculated intra- and inter-DMN 4-nodes directed pathways. For the old subject group, we calculated the partial correlations of inter-DMN pathways with: psychomotor speed and working memory, executive function, language, long-term memory and visuospatial function. Pathways connecting the DMN with visual and limbic regions in older subjects engaged at BOLD low frequency and involved the dorsal posterior cingulate cortex (PCC), whereas in young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) cortex and the DMN, were SM efferent in the young subjects and SM afferent in the older subjects. Most DMN efferent pathways correlated with reduced speed and working memory. We suggest that the reduced sensorimotor efferent and the increased need to control such activities, cause a higher dependency on external versus internal cues thus suggesting how physical activity might slow aging.

• MeSH
• Memory, Short-Term MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Brain Mapping * methods   MeSH
• Brain * diagnostic imaging   MeSH
• Neural Pathways MeSH
• Aged MeSH
• Aging MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

Cannabinoid CB1 receptors have been shown to regulate wide array of functions ranging from homeostasis to the cognitive functioning but recent data support the hypothesis that astrocytes also operate as a mediator of synaptic plasticity and contribute to cognition and learning. The receptor heterogeneity plays a key role in understanding the molecular mechanisms underlying these processes. Despite the fact that the majority of CB1 receptors act on neurons, studies have revealed that cannabinoids have direct control over astrocytes, including energy generation and neuroprotection. The tripartite synapse connects astrocytes to neurons and allows them to interact with one another and the astrocytes are key players in synaptic plasticity, which is associated with cognitive functions. This review focuses on our growing understanding of the intricate functions of astroglial CB1 that underpin physiological brain function, and in Alzheimer's disease.

• MeSH
• Alzheimer Disease * MeSH
• Astrocytes MeSH
• Endocannabinoids MeSH
• Cognitive Dysfunction * MeSH
• Humans MeSH
• Neurons MeSH
• Neuronal Plasticity physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Studies in the sensorimotor system of older versus young individuals have shown alterations in functional connectivity and organization. Our objective was to explore the implications of these differences in terms of local organizations, and to identify processes that correlate with neuropsychological parameters. METHODS: Using a novel multivariate analysis method on resting-state functional MRI data obtained from 50 young and 31 older healthy individuals, we identified directed 4-node functional pathways within the sensorimotor system and examined their correlations with neuropsychological assessments. RESULTS: In young individuals, the functional pathways were unidirectional, flowing from the primary motor and sensory cortices to higher motor and visual regions. In older individuals, the functional pathways were more complex. They originated either from the calcarine sulcus or the insula and passed through mutually coupled high-order motor areas before reaching the primary sensory and motor cortices. Additionally, the pathways in older individuals that resembled those found in young individuals exhibited a positive correlation with years of education. DISCUSSION: The flow pattern of young individuals suggests efficient and fast information transfer. In contrast, the mutual coupling of high-order motor regions in older individuals suggests an inefficient and slow transfer, a less segregated and a more integrated organization. The differences in the number of sensorimotor pathways and of their directionality suggests reduced efferent degenerated pathways and increased afferent compensated pathways. Furthermore, the positive effect of years of education may be associated with the Cognitive Reserve Hypothesis, implying that cognitive reserve could be maintained through specific information transfer pathways.

• Publication type
• Journal Article MeSH

• MeSH
• Biology MeSH
• Cytology MeSH
• Molecular Biology MeSH

• Conspectus
• Biochemie. Molekulární biologie. Biofyzika
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• biologie
• NML Publication type
• učebnice vysokých škol