PIWI-interacting RNAs (piRNAs) play a crucial role in safeguarding genome integrity by silencing mobile genetic elements. From flies to humans, piRNAs originate from long single-stranded precursors encoded by genomic piRNA clusters. How piRNA clusters form to adapt to genomic invaders and evolve to maintain protection remain key outstanding questions. Here, we generate a roadmap of piRNA clusters across seven species that highlights both similarities and variations. In mammals, we identify transcriptional readthrough as a mechanism to generate piRNAs from transposon insertions (piCs) downstream of genes (DoG). Together with the well-known stress-dependent DoG transcripts, our findings suggest a molecular mechanism for the formation of piRNA clusters in response to retroviral invasion. Finally, we identify a class of dynamic piRNA clusters in humans, underscoring unique features of human germ cell biology. Our results advance the understanding of conserved principles and species-specific variations in piRNA biology and provide tools for future studies.
- MeSH
- druhová specificita MeSH
- lidé MeSH
- malá interferující RNA * metabolismus genetika MeSH
- myši MeSH
- Piwi-interagující RNA MeSH
- psi MeSH
- savci * genetika MeSH
- transpozibilní elementy DNA genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
The MBT Pathfinder is an automated colony-picking robot designed for efficient sample preparation in matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. This article presents results from three key experiments evaluating the instrument's performance in conjunction with MALDI Biotyper instrument. The method comparison experiment assessed its clinical performance, demonstrating comparable results with gram-positive, gram-negative, and anaerobic bacteria (scores larger than 2.00) and superior performance over simple direct yeast transfer (score: 1.80) when compared to samples prepared manually. The repeatability experiment confirmed consistent performance over multiple days and labs (average log score: 2.12, std. deviation: 0.59). The challenge panel experiment showcased its consistent and accurate performance across various samples and settings, yielding average scores between 1.76 and 2.19. These findings underline the MBT Pathfinder as a reliable and efficient tool for MALDI-TOF mass spectrometry sample preparation in clinical and research applications.
- MeSH
- Bacteria * klasifikace izolace a purifikace MeSH
- laboratorní automatizace * metody MeSH
- lidé MeSH
- odběr biologického vzorku metody MeSH
- reprodukovatelnost výsledků MeSH
- robotika * MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
PURPOSE: Excessive tachycardia in resuscitated septic shock patients can impair hemodynamics and worsen patient outcome. We investigated whether heart rate (HR) control can be achieved without increased vasopressor requirements using the titratable highly selective, ultra-short-acting β1-blocker landiolol. METHODS: This randomized, open-label, controlled trial was conducted at 20 sites in 7 European countries from 2018 to 2022 and investigated the efficacy and safety of landiolol in adult patients with septic shock and persistent tachycardia. Patients were randomly assigned to receive either landiolol along with standard treatment (n = 99) or standard treatment alone (n = 101). The combined primary endpoint was HR response (i.e., HR within the range of 80-94 beats per minute) and its maintenance without increasing vasopressor requirements during the first 24 h after treatment start. Key secondary endpoints were 28-day mortality and adverse events. RESULTS: Out of 196 included septic shock patients, 98 received standard treatment combined with landiolol and 98 standard treatment alone. A significantly larger proportion of patients met the combined primary endpoint in the landiolol group than in the control group (39.8% [39/98] vs. 23.5% [23/98]), with a between-group difference of 16.5% (95% confidence interval [CI]: 3.4-28.8%; p = 0.013). There were no statistically significant differences between study groups in tested secondary outcomes and adverse events. CONCLUSION: The ultra-short-acting beta-blocker landiolol was effective in reducing and maintaining HR without increasing vasopressor requirements after 24 h in patients with septic shock and persistent tachycardia. There were no differences in adverse events and clinical outcomes such as 28-day mortality vs. standard of care. The results of this study, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.
- MeSH
- lidé středního věku MeSH
- lidé MeSH
- močovina * analogy a deriváty terapeutické užití farmakologie MeSH
- morfoliny * terapeutické užití farmakologie MeSH
- senioři MeSH
- septický šok * farmakoterapie komplikace patofyziologie MeSH
- srdeční frekvence * účinky léků MeSH
- tachykardie * farmakoterapie patofyziologie komplikace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Evropa MeSH
Recent advances in AI-based methods have revolutionized the field of structural biology. Concomitantly, high-throughput sequencing and functional genomics have generated genetic variants at an unprecedented scale. However, efficient tools and resources are needed to link disparate data types-to 'map' variants onto protein structures, to better understand how the variation causes disease, and thereby design therapeutics. Here we present the Genomics 2 Proteins portal ( https://g2p.broadinstitute.org/ ): a human proteome-wide resource that maps 20,076,998 genetic variants onto 42,413 protein sequences and 77,923 structures, with a comprehensive set of structural and functional features. Additionally, the Genomics 2 Proteins portal allows users to interactively upload protein residue-wise annotations (for example, variants and scores) as well as the protein structure beyond databases to establish the connection between genomics to proteins. The portal serves as an easy-to-use discovery tool for researchers and scientists to hypothesize the structure-function relationship between natural or synthetic variations and their molecular phenotypes.
Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by IgG antibodies targeting NMDAR. The prevalence is remarkably higher in women and some develop the condition during pregnancy. While immunotherapies have shown good outcomes for pregnant mothers and their infants, the impact on early neurodevelopment remains elusive. This study investigates the effects of anti-NMDAR antibody on the development of primary cortical cultures. Anti-NMDAR antibody was administered to the cultures at day in vitro 5 for the following 5 days to assess dendritic branching and arbor complexity, and at day in vitro 14 for measuring the expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. Immature cultured neurons treated with anti-NMDAR antibody exhibited impaired dendritic branching and arbor complexity. Interestingly, BDNF expression was unaffected in mature neurons. Additionally, GluN1 expression, a mandatory NMDAR subunit, was significantly reduced, while no significant alterations were observed in PSD-95, gephyrin and synaptophysin expression. These findings shed light on the structural and synaptic impacts of anti-NMDAR antibody on immature neurons, providing evidence for their consequences in early neuronal development.
- MeSH
- dendrity * účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- membránové proteiny metabolismus imunologie MeSH
- mozkový neurotrofický faktor * metabolismus MeSH
- neurony * metabolismus účinky léků MeSH
- protein PSD-95 metabolismus MeSH
- proteiny nervové tkáně imunologie metabolismus MeSH
- receptory N-methyl-D-aspartátu * imunologie MeSH
- synaptofysin metabolismus MeSH
- transportní proteiny MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We investigated neural correlates of Emotion Recognition Accuracy (ERA) using the Assessment of Contextualized Emotions (ACE). ACE infuses context by presenting emotion expressions in a naturalistic group setting and distinguishes between accurately perceiving intended emotions (signal), and bias due to perceiving additional, secondary emotions (noise). This social perception process is argued to induce perspective taking in addition to pattern matching in ERA. Thirty participants were presented with an fMRI-compatible adaptation of the ACE consisting of blocks of neutral and emotional faces in single and group-embedded settings. Participants rated the central character's expressions categorically or using scalar scales in consequent fMRI scans. Distinct brain activations were associated with the perception of emotional vs. neutral faces in the four conditions. Moreover, accuracy and bias scores from the original ACE task performed on another day were associated with brain activation during the scalar (vs. categorical) condition for emotional (vs. neutral) faces embedded in group. These findings suggest distinct cognitive mechanisms linked to each type of emotional rating and highlight the importance of considering cognitive bias in the assessment of social emotion perception.
- MeSH
- dospělí MeSH
- emoce * fyziologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mapování mozku * MeSH
- mladý dospělý MeSH
- mozek * fyziologie diagnostické zobrazování MeSH
- rozpoznání obličeje fyziologie MeSH
- sociální percepce * MeSH
- světelná stimulace metody MeSH
- výraz obličeje * MeSH
- zkreslení výsledků (epidemiologie) MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Prepregnancy optimization of cardiovascular function may reduce the risk of pre-eclampsia. We aimed to assess the feasibility and effect of preconception cardiovascular monitoring, exercise, and beetroot juice on cardiovascular parameters in women planning to conceive. DESIGN AND METHOD: Prospective single-site, open-label, randomized controlled trial. Thirty-two women, aged 18-45 years, were allocated into one of four arms (1 : 1 : 1 : 1): exercise, beetroot juice, exercise plus beetroot juice and no intervention for 12 weeks. Blood pressure (BP) was measured at home daily. Cardiac output ( CO ) and total peripheral resistance (TPR) were assessed via bio-impedance. RESULTS: Twenty-nine out of 32 (91%) participants completed the study. Adherence to daily BP and weight measurements were 81% and 78%, respectively ( n = 29). Eight out of 15 (53%) of participants did not drink all the provided beetroot juice because of forgetfulness and taste. After 12 weeks, exercise was associated with a reduction in standing TPR (-278 ± 0.272 dynes s cm -5 , P < 0.05), and an increase in standing CO (+0.88 ± 0.71 l/min, P < 0.05). Exercise and beetroot juice together was associated with a reduction in standing DBP ( 7 ± 6 mmHg, P < 0.05), and an increase in standing CO (+0.49 ± 0.66 l/min, P < 0.05). The control group showed a reduction in standing TPR ( 313 ± 387 dynes s cm -5 ) and standing DBP ( 8 ± 5mmHg). All groups gained weight. CONCLUSION: Exercise and beetroot juice in combination showed a signal towards improving cardiovascular parameters. The control group showed improvements, indicating that home measurement devices and regular recording of parameters are interventions in themselves. Nevertheless, interventions before pregnancy to improve cardiovascular parameters may alter the occurrence of hypertensive conditions during pregnancy and require further investigation in adequately powered studies.
- MeSH
- cvičení fyziologie MeSH
- dusičnany * MeSH
- dvojitá slepá metoda MeSH
- hypertenze * MeSH
- krevní tlak MeSH
- lidé MeSH
- potravní doplňky MeSH
- prospektivní studie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Non-contact injuries are highly prevalent among young athletes and occur particularly in situations that require fast decision making and divided attention. Administering relevant neurocognitive tests could help identify deficiencies in these cognitive abilities and thus potentially mitigate injury risk. However, processes such as selective attention and response inhibition might depend to some extent on the athlete's maturation stage. We aimed to examine the effect of maturation on selective visual attention and response inhibition among adolescent volleyball players. METHODS: In this cross-sectional study, 52 female adolescents (age 12.3 ± 2.1 years) performed an Eriksen Flankers task. Participants were divided into subgroups based on their estimated adult stature, using the Khamis & Roche method: Pre-pubertal (PRE; n = 13, age: 9.9 ± 1.3), early-puberty (EPUB; n = 7, age: 10.5 ± 0.6), mid-puberty (MPUB; n = 8, age: 12.6 ± 0.8) and late puberty (LPUB; n = 24, age: 14.1 ± 0.9). Analyses of covariance (ANCOVA) were performed on congruent and incongruent reaction times (RT), with corresponding success rates (% correct responses) as covariate. Flanker interference effect was tested using ANOVA. Correlations were further examined between the dependent variables and participants' chronological age. RESULTS: There was a significant group effect, with PRE demonstrating longer RT compared with LPUB (P < 0.001) for both congruent and incongruent RT. Moderate negative correlations were observed between age and RT (Rp = -0.695, Rp = -0.614 for congruent and incongruent RT, respectively) and low positive correlations between age and incongruent success rate (Rs = 0.318). Low to moderate correlations were also observed within the LPUB group for RT (Rp = -0.431--0.532) and success rate (negative Rs = -574 for congruent and positive Rs = 0.417 for incongruent). There were no group differences nor age associations with interference effect. CONCLUSIONS: Our findings indicate that information processing and selective visual attention are superior at late maturation compared with early maturation among female adolescents. The same cannot be said for response inhibition, which did not differ between maturation groups. Similar tendencies were observed with regards to chronological age, but not entirely explained by it. Maturation level, rather than chronological age, should guide practitioners during sport participation and injury prevention programs for young athletes, whose neurocognitive abilities are not yet fully developed, placing them at risk for non-contact injuries.
- Publikační typ
- časopisecké články MeSH
The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARCA5 as a key chromatin remodeler in B cells. While the naive B cell compartment remained unaffected following conditional depletion of Smarca5, effective proliferation during B cell activation, immunoglobulin class switching, and as a result GC formation and ASC differentiation were impaired. Single-cell multiomic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell activation and differentiation. These findings offer novel insights into the functions of SMARCA5, which can be targeted in various human pathologies.
- MeSH
- adenosintrifosfatasy MeSH
- aktivace lymfocytů imunologie MeSH
- B-lymfocyty * metabolismus imunologie MeSH
- buněčná diferenciace * MeSH
- chromozomální proteiny, nehistonové * metabolismus genetika MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- přesmyk imunoglobulinových tříd genetika MeSH
- restrukturace chromatinu * MeSH
- zárodečné centrum lymfatické uzliny * imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: The significance of dental status and oral hygiene on a range of medical conditions is well-recognised. However, the correlation between periodontitis, oral bacterial dysbiosis and visceral surgical outcomes is less well established. To this end, we study sought to determine the influence of dental health and oral hygiene on the rates of postoperative complications following major visceral and transplant surgery in an exploratory, single-center, retrospective, non-interventional study. METHODS: Our retrospective non-interventional study was conducted at the Department of General, Visceral, and Transplant Surgery, University Hospital Heidelberg, Germany. Patients operated on between January 2018 and December 2019 were retrospectively enrolled in the study based on inclusion (minimum age of 18 years, surgery at our Department, intensive care / IMC treatment after major surgery, availability of patient-specific preoperative dental status assessment, documentation of postoperative complications) and exclusion criteria (minor patients or legally incapacitated patients, lack of intensive care or intermediate care (IMC) monitoring, incomplete documentation of preoperative dental status, intestinal surgery with potential intraoperative contamination of the site by intestinal microbes, pre-existing preoperative infection, absence of data regarding the primary endpoints of the study). The primary study endpoint was the incidence of postoperative complications. Secondary study endpoints were: 30-day mortality, length of hospital stay, duration of intensive care stay, Incidence of infectious complications, the microbial spectrum of infectious complication. A bacteriology examination was added whenever possible (if and only if the examination was safe for the patient)for infectious complications. RESULTS: The final patient cohort consisted of 417 patients. While dental status did not show an influence (p = 0.73) on postoperative complications, BMI (p = 0.035), age (p = 0.049) and quick (p = 0.033) were shown to be significant prognostic factors. There was significant association between oral health and the rate of infectious complications for all surgical procedures (p = 0.034), excluding transplant surgery. However, this did not result in increased 30-day mortality rates, prolonged intensive care unit treatment or an increase in the length of hospital stay (LOS) for the cohort as a whole. In contrast there was a significant correlation between the presence of oral pathogens and postoperative complications for a group as a whole (p < 0.001) and the visceral surgery subgroup (p < 0.001). Whilst this was not the case in the cohort who underwent transplant surgery, there was a correlation between oral health and LOS in this subgroup (p = 0.040). Bacterial swabs supports the link between poor oral health and infectious morbidity. CONCLUSIONS: Dental status was a significant predictor of postoperative infectious complications in this visceral surgery cohort. This study highlights the importance preoperative dental assessment and treatment prior to major surgery, particularly in the case of elective surgical procedures. Further research is required to determine the effect of oral health on surgical outcomes in order to inform future practice. TRIAL REGISTRATION: Trial registered under the ethics-number S-082/2022 (Ethic Committee of the University Heidelberg).
- MeSH
- délka pobytu statistika a číselné údaje MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- orální hygiena MeSH
- orální zdraví MeSH
- pooperační komplikace * epidemiologie etiologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- transplantace orgánů škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Německo MeSH
