CssRS is a two-component system that plays a pivotal role in mediating the secretion stress response in Bacillus subtilis. This system upregulates the synthesis of membrane-bound HtrA family proteases that cope with misfolded proteins that accumulate within the cell envelope as a result of overexpression or heat shock. Recent studies have shown the induction of CssRS-regulated genes in response to cell envelope stress. We investigated the induction of the CssRS-regulated htrA promoter in the presence of different cell wall- and membrane-active substances and observed induction of the CssRS-controlled genes by glycopeptides (vancomycin and teicoplanin), polymyxins B and E, certain β-lactams, and detergents. Teicoplanin was shown to elicit remarkably stronger induction than vancomycin and polymyxin B. Teicoplanin and polymyxin B induced the spxO gene expression in a CssRS-dependent fashion, resulting in increased activity of Spx, a master regulator of disulfide stress in Bacillus subtilis. The CssRS signaling pathway and Spx activity were demonstrated to be involved in Bacillus subtilis resistance to teicoplanin and polymyxin B.

• MeSH
• antibakteriální látky * farmakologie   MeSH
• Bacillus subtilis * genetika   účinky léků   metabolismus   MeSH
• bakteriální proteiny * genetika   metabolismus   MeSH
• polymyxin B * farmakologie   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u bakterií * účinky léků   MeSH
• signální transdukce MeSH
• teikoplanin * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH

Syncytin-1 and Syncytin-2 are envelope glycoproteins encoded by human endogenous retroviruses that have been exapted for the fusion of cytotrophoblast cells into syncytiotrophoblasts during placental development. Pregnancy complications like preeclampsia are associated with altered expression of interferon-stimulated genes, including guanylate-binding protein 5 (GBP5). Here, we show that misdirected antiviral activity of GBP5 impairs processing and activation of Syncytin-1. In contrast, the proteolytic activation of Syncytin-2 is not affected by GBP5, and its fusogenic activity is only modestly reduced. Mechanistic analyses revealed that Syncytin-1 is mainly cleaved by the GBP5 target furin, whereas Syncytin-2 is also efficiently processed by the proprotein convertase subtilisin/kexin type 7 (PCSK7) and thus resistant to GBP5-mediated restriction. Mutational analyses mapped PCSK7 processing of Syncytin-2 to a leucine residue upstream of the polybasic cleavage site. In summary, we identified an innate immune mechanism that impairs the activity of a co-opted endogenous retroviral envelope protein during pregnancy and may potentially contribute to the pathogenesis of pregnancy disorders.

• MeSH
• furin metabolismus   MeSH
• fúze buněk MeSH
• genové produkty env metabolismus   genetika   MeSH
• lidé MeSH
• placenta * metabolismus   cytologie   MeSH
• proteiny vázající GTP * metabolismus   genetika   MeSH
• těhotenské proteiny * metabolismus   genetika   MeSH
• těhotenství MeSH
• trofoblasty * metabolismus   cytologie   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f1 and f2 > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f2 - f1|. OBJECTIVE: The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD). METHODS: DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f1 = 9.00 kHz; f2 = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target. RESULTS: The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients. CONCLUSIONS: TIS has the potential to effectively modulate the STN and reduce the beta oscillatory activity in a completely noninvasive manner, as is traditionally possible only with intracranial DBS. Future studies should confirm the clinical effectiveness of TIS and determine whether TIS could be used to identify optimal DBS candidates and individualize DBS targets. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• MeSH
• beta rytmus EEG * fyziologie   MeSH
• hluboká mozková stimulace * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nucleus subthalamicus * patofyziologie   MeSH
• Parkinsonova nemoc * terapie   patofyziologie   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes which allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not yet been well addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation. Teaser Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.

• Publikační typ
• časopisecké články MeSH

Tick-borne encephalitis virus (TBEV) infection can manifest as disease of variable severity, ranging from subclinical infection to severe disease with neurological involvement and potentially fatal outcome. Although TBE is recognized as a major public health problem in Europe, the true burden of disease is potentially underestimated. Here, we investigated TBEV-specific antibody prevalence, infection incidence, and seroreversion and antibody decline rates in a prospective Swiss healthcare worker (HCW) cohort. We screened serum samples from 1444 HCWs between June and October 2020, and from a subset again between August and September 2021, using a TBEV envelope (E) protein IgG ELISA. Positive samples underwent further analysis with a TBEV non-structural protein 1 (NS1) IgG ELISA, and seroconversions in unvaccinated individuals were confirmed by seroneutralization testing. Questionnaire data were used to determine vaccination status and risk factors. TBEV E protein-specific IgG prevalence was 72.1% (95% CI 68.2-75.7%) in TBEV-vaccinated and 6% (95% CI 4.4-7.8%) in unvaccinated individuals. The estimated annual incidence of infection was 735/100,000. Age was the only factor significantly associated with seroprevalence. The seroreversion rate in unvaccinated individuals was 30.3% within one year, which is almost ten times higher than in vaccinated individuals (3.4%, annual decline rate 8.0%). NS1-specific IgG antibodies were six times more common in vaccinated than unvaccinated HCWs. In conclusion, undetected TBEV infections are common, and infection incidence is much higher than reported clinical cases. Individuals with abortive infections have high antibody decline and seroreversion rates. Whether lifelong protection is conferred and by which immune subsets remain unclear.

• MeSH
• dospělí MeSH
• imunoglobulin G krev   MeSH
• incidence MeSH
• klíšťová encefalitida * epidemiologie   imunologie   krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• protilátky virové * krev   MeSH
• senioři MeSH
• séroepidemiologické studie MeSH
• viry klíšťové encefalitidy * imunologie   MeSH
• zdravotnický personál statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Švýcarsko MeSH

Dystonia is a movement disorder characterized by genetic and clinical heterogeneity. A recurring p.(Glu303del)-deletion in TOR1A is a well-established cause for DYT-TOR1A (DYT1), an autosomal dominant early-onset isolated dystonia. TOR1A encodes TorsinA, an AAA + ATPase located in the nuclear envelope. By whole exome analyses of a family with a novel dystonia-hemichorea-/hemiballism phenotype, we identified a TOR1AIP2 NM_001199260.2 c.1234A > G p.(Arg412Gly) variant. The variant is very rare in databases and was absent from whole exome data from >1000 dystonia patients. TOR1AIP2 encodes LULL1, a transmembrane protein that activates TorsinA, and correct interaction between TorsinA and LULL1 is essential for proper nuclear envelope architecture. The p.(Arg412Gly) variant disrupts the binding interface between TorsinA and LULL1 around p.Arg412; this same interface is also impaired in DYT1. Functional analyses via a co-purification assay revealed that interaction between TorsinA-LULL1Arg412Gly is weaker than the wild-type interaction, and that it resembles the situation in DYT1 (TorsinAΔE303-LULL1). A second family with milder dystonia, hemichorea, and stereotypic leg flexion during gait and a TOR1AIP2 p.(Gln338His) variant was identified. The clinical phenotype of both families shared proximal arm movements, and flutter in facial musculature. Expressivity of the movement disorder symptoms was variable. Several proteins in the nuclear envelope have been implicated in various forms of neurodevelopmental disorders with dystonia. Taken together, our findings suggest TOR1AIP2 as a new candidate gene implicated in a complex hereditary movement disorder with dystonia and hemichorea/hemiballism.

• MeSH
• chorea * genetika   MeSH
• dospělí MeSH
• dyskineze * genetika   MeSH
• dystonické poruchy * genetika   MeSH
• dystonie * genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární chaperony * genetika   MeSH
• rodokmen MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Perivascular adipose tissue (PVAT) envelops the majority of systemic vessels, providing crucial mechanical support and vessel protection. In physiological conditions, PVAT releases various bioactive molecules, contributing to the anti-inflammatory environment around neighboring vessels. However, in conditions like obesity, PVAT can exacerbate cardiovascular issues such as atherosclerosis. Communication between PVAT and nearby vessels is bidirectional, with PVAT responding dynamically to signals from the vasculature. This responsiveness positions PVAT as a promising indicator of vascular inflammation. Recently, the role of PVAT in the CVD risk prediction is also greatly discussed. The objective of this review is to summarize the current state of knowledge about the PVAT function, its role in physiologic and pathophysiologic processes and its potential in CVD risk prediction. Keywords: Perivascular adipose tissue, inflammation, atherogenesis, Fat attenuation index.

• MeSH
• ateroskleróza * metabolismus   patologie   patofyziologie   MeSH
• lidé MeSH
• obezita metabolismus   patofyziologie   patologie   MeSH
• tuková tkáň * metabolismus   patologie   patofyziologie   MeSH
• zánět * metabolismus   patologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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
• elektrická stimulace MeSH
• mozek * MeSH
• počítačová simulace MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of the research is to determine the technical efficiency of legendary hockey players in the National Hockey League (NHL), to create a ranking of these players and to reveal the best NHL players of all time. The research uses statistical data on 379 players from the 1944/45 season to the 2023/24 season. The methodology is based on multi-criteria analysis, specifically the concept of data envelopment analysis (DEA). The DEA provides an objective measure of the overall playing profile of hockey players and can help supplement the information in rankings provided by sports journalists. Andersen and Petersen's model is used to evaluate the data collected, providing super efficiency scores by aggregating NHL statistics related to various aspects of the game to produce a final ranking of hockey legends. The concept of data envelopment analysis works with multiple variables and allows for greater objectivity to be incorporated into the rankings. The number of games played is chosen as one of the model's input variables. The output variables include: number of goals scored, number of assists, plus/minus, inverse of penalty minutes, points per game, number of shots, number of individual awards, and number of Stanley Cups won. The research named Wayne Gretzky, Butch Goring and Serge Savard as the best players in the NHL historically in terms of technical efficiency. Among other things, the ranking of legendary hockey players revealed that players with a high number of games played or points scored are not necessarily technically efficient.

PURPOSE: The optimal motion management strategy for patients receiving stereotactic arrhythmia radioablation (STAR) for the treatment of ventricular tachycardia (VT) is not fully known. We developed a framework using a digital phantom to simulate cardiorespiratory motion in combination with different motion management strategies to gain insight into the effect of cardiorespiratory motion on STAR. METHODS AND MATERIALS: The 4-dimensional (4D) extended cardiac-torso (XCAT) phantom was expanded with the 17-segment left ventricular (LV) model, which allowed placement of STAR targets in standardized ventricular regions. Cardiac- and respiratory-binned 4D computed tomography (CT) scans were simulated for free-breathing, reduced free-breathing, respiratory-gating, and breath-hold scenarios. Respiratory motion of the heart was set to population-averaged values of patients with VT: 6, 2, and 1 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction was adjusted by reducing LV ejection fraction to 35%. Target displacement was evaluated for all segments using envelopes encompassing the cardiorespiratory motion. Envelopes incorporating only the diastole plus respiratory motion were created to simulate the scenario where cardiac motion is not fully captured on 4D respiratory CT scans used for radiation therapy planning. RESULTS: The average volume of the 17 segments was 6 cm3 (1-9 cm3). Cardiac contraction-relaxation resulted in maximum segment (centroid) motion of 4, 6, and 3.5 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction-relaxation resulted in a motion envelope increase of 49% (24%-79%) compared with individual segment volumes, whereas envelopes increased by 126% (79%-167%) if respiratory motion also was considered. Envelopes incorporating only the diastole and respiration motion covered on average 68% to 75% of the motion envelope. CONCLUSIONS: The developed LV-segmental XCAT framework showed that free-wall regions display the most cardiorespiratory displacement. Our framework supports the optimization of STAR by evaluating the effect of (cardio)respiratory motion and motion management strategies for patients with VT.

• MeSH
• čtyřrozměrná počítačová tomografie MeSH
• dýchání * MeSH
• fantomy radiodiagnostické MeSH
• lidé MeSH
• pohyb těles MeSH
• srdce * diagnostické zobrazování   účinky záření   MeSH
• srdeční arytmie MeSH
• srdeční komory diagnostické zobrazování   účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH