Weak coupling of neurons enables very high-frequency and ultra-fast oscillations through the interplay of synchronized phase shifts.

Recently, in the past decade, high-frequency oscillations (HFOs), very high-frequency oscillations (VHFOs), and ultra-fast oscillations (UFOs) were reported in epileptic patients with drug-resistant epilepsy. However, to this day, the physiological origin of these events has yet to be understood. Our study establishes a mathematical framework based on bifurcation theory for investigating the occurrence of VHFOs and UFOs in depth EEG signals of patients with focal epilepsy, focusing on the potential role of reduced connection strength between neurons in an epileptic focus. We demonstrate that synchronization of a weakly coupled network can generate very and ultra high-frequency signals detectable by nearby microelectrodes. In particular, we show that a bistability region enables the persistence of phase-shift synchronized clusters of neurons. This phenomenon is observed for different hippocampal neuron models, including Morris-Lecar, Destexhe-Paré, and an interneuron model. The mechanism seems to be robust for small coupling, and it also persists with random noise affecting the external current. Our findings suggest that weakened neuronal connections could contribute to the production of oscillations with frequencies above 1000 Hz, which could advance our understanding of epilepsy pathology and potentially improve treatment strategies. However, further exploration of various coupling types and complex network models is needed.

We have built a mathematical framework to examine how a reduced neuronal coupling within an epileptic focus could lead to very high-frequency (VHFOs) and ultra-fast oscillations (UFOs) in depth EEG signals. By analyzing weakly coupled neurons, we found a bistability synchronization region where in-phase and anti-phase synchrony persist. These dynamics can be detected as very high-frequency EEG signals. The principle of weak coupling aligns with the disturbances in neuronal connections often observed in epilepsy; moreover, VHFOs are important markers of epileptogenicity. Our findings point to the potential significance of weakened neuronal connections in producing VHFOs and UFOs related to focal epilepsy. This could enhance our understanding of brain disorders. We emphasize the need for further investigations of weakly coupled neurons.

Revisiting ab initio carcinoembryonic antigen and CA19-9 tumor markers in colorectal carcinoma in association with anatomotopographic location and staging of disease.

OBJECTIVE: This study purposed to evaluate preoperative two tumor markers, namely, carcinoembryonic antigen and carbohydrate antigen (CA)19-9, in colorectal cancer for anatomotopographic location with disease stage and to assess their utility for diagnostic staging purposes. METHODS: The study retrospectively incorporated patients who had undergone surgery for colorectal cancer at our department in 2015-2018 and in whom carcinoembryonic antigen and CA19-9 tumor markers had been preoperatively analyzed. The obtained data were then statistically processed using R-project. RESULTS: A total of 155 patients had been incorporated, of whom 96 (62%) were men and 59 (38%) were women. Rectum was the most common location (74 patients, 48%), and the least represented stage was IV (18, 12%). The marker carcinoembryonic antigen was obtained in all 155 cases, while CA19-9 was in 105. The median carcinoembryonic antigen was 3 (0.34-1104.25), and the median CA19-9 was 12 (0.18-840.00). A significance was recognized between median carcinoembryonic antigen and disease stage (p-value=0.016), with stages I, II, and III (medians 2, 3, and 2) different from stage IV (median 13), while no significance for CA19-9 was recognized (p-value=0.343). No significance between either marker and location (carcinoembryonic antigen: p=0.276; CA19-9: p=0.505) was detected. The testing was performed at a significance level of alpha=0.05. CONCLUSION: This study revealed a significance between the marker carcinoembryonic antigen, but not CA19-9, and the disease stage, while no relationship of either of these markers with tumor location was found. Herewith, the study confirmed that higher carcinoembryonic antigen values may suggest the finding of more advanced forms of colorectal cancer and thus a worse prognosis of this malignant phenomenon.

Using real-time ascertainment rate estimate from infection and hospitalization dataset for modeling the spread of infectious disease: COVID-19 case study in the Czech Republic.

We present a novel approach to estimate the time-varying ascertainment rate in almost real-time, based on the surveillance of positively tested infectious and hospital admission data. We also address the age dependence of the estimate. The ascertainment rate estimation is based on the Bayes theorem. It can be easily calculated and used (i) as part of a mechanistic model of the disease spread or (ii) to estimate the unreported infections or changes in their proportion in almost real-time as one of the early-warning signals in case of undetected outbreak emergence. The paper also contains a case study of the COVID-19 epidemic in the Czech Republic. The case study demonstrates the usage of the ascertainment rate estimate in retrospective analysis, epidemic monitoring, explanations of differences between waves, usage in the national Anti-epidemic system, and monitoring of the effectiveness of non-pharmaceutical interventions on Czech nationwide surveillance datasets. The Czech data reveal that the probability of hospitalization due to SARS-CoV-2 infection for the senior population was 12 times higher than for the non-senior population in the monitored period from the beginning of March 2020 to the end of May 2021. In a mechanistic model of COVID-19 spread in the Czech Republic, the ascertainment rate enables us to explain the links between all basic compartments, including new cases, hospitalizations, and deaths.

Protection provided by vaccination, booster doses and previous infection against covid-19 infection, hospitalisation or death over time in Czechia.

Studies demonstrating the waning of post-vaccination and post-infection immunity against covid-19 generally analyzed a limited range of vaccines or subsets of populations. Using Czech national health data from the beginning of the covid-19 pandemic till November 20, 2021 we estimated the risks of reinfection, breakthrough infection, hospitalization and death by a Cox regression adjusted for sex, age, vaccine type and vaccination status. Vaccine effectiveness against infection declined from 87% at 0-2 months after the second dose to 53% at 7-8 months for BNT162b2 vaccine, from 90% at 0-2 months to 65% at 7-8 months for mRNA-1273, and from 83% at 0-2 months to 55% at 5-6 months for the ChAdOx1-S. Effectiveness against hospitalization and deaths declined by about 15% and 10%, respectively, during the first 6-8 months. Boosters (third dose) returned the protection to the levels observed shortly after dose 2. In unvaccinated, previously infected individuals the protection against infection declined from 97% after 2 months to 72% at 18 months. Our results confirm the waning of vaccination-induced immunity against infection and a smaller decline in the protection against hospitalization and death. Boosting restores the original vaccine effectiveness. Post-infection immunity also decreases over time.

Protection by Vaccines and Previous Infection Against the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evades immunity conferred by vaccines and previous infections. METHODS: We used a Cox proportional hazards model and a logistic regression on individual-level population-wide data from the Czech Republic to estimate risks of infection and hospitalization, including severe states. RESULTS: A recent (≤2 months) full vaccination reached vaccine effectiveness (VE) of 43% (95% confidence interval [CI], 42%-44%) against infection by Omicron compared to 73% (95% CI, 72%-74%) against Delta. A recent booster increased VE to 56% (95% CI, 55%-56%) against Omicron infection compared to 90% (95% CI, 90%-91%) for Delta. The VE against Omicron hospitalization of a recent full vaccination was 45% (95% 95% CI, 29%-57%), with a recent booster 87% (95% CI, 84%-88%). The VE against the need for oxygen therapy due to Omicron was 57% (95% CI, 32%-72%) for recent vaccination, 90% (95% CI, 87%-92%) for a recent booster. Postinfection protection against Omicron hospitalization declined from 68% (95% CI, 68%-69%) at ≤6 months to 13% (95% CI, 11%-14%) at >6 months after a previous infection. The odds ratios for Omicron relative to Delta were 0.36 (95% CI, .34-.38) for hospitalization, 0.24 (95% CI, .22-.26) for oxygen, and 0.24 (95% CI, .21-.28) for intensive care unit admission. CONCLUSIONS: Recent vaccination still brings substantial protection against severe outcome for Omicron.

Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents.

BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.

Intraoperative fluorescence angiography and risk factors of anastomotic leakage in mini-invasive low rectal resections.

BACKGROUND: One of the prerequisites for proper healing of the anastomosis after a colorectal resection is adequate blood supply to the connected intestinal segments. It has been proposed that adequate visualization of the blood flow using indocyanine green (ICG) could lead to the reduction in the incidence of anastomotic leakage (AL). The aim of this study was to assess the effectiveness of intraoperative fluorescence angiography (FA) in decreasing the incidence of AL after minimally invasive low anterior resection (LAR) with total mesorectal excision (TME) in rectal cancer patients and to determine predictors of anastomotic leak. METHODS: From August 2015 to January 2019, data from 100 patients who underwent mini-invasive TME for rectal cancer using FA with indocyanine green (ICG) were prospectively collected and analyzed. They were compared with retrospectively analyzed data from a historical control group operated by one team of surgeons before the introduction of FA from November 2012 to August 2015 (100 patients). All patients from both groups were operated sequentially in one oncological center in Nový Jicín. RESULTS: The incidence of AL was significantly lower in the ICG group (19% vs. 9%, p = 0.042, χ2 test). In fifteen patients in the ICG group (15%), the resection line was moved due to insufficient perfusion. Using Pearson's χ2 test, diabetes (p = 0.036) and application of a transanal drain (NoCoil) (p = 0.032) were identified as other risk factors (RFs) for AL. CONCLUSION: The use of ICG to visualize tissue perfusion in low rectal resections for cancer can lead to a reduction of AL.

Bifurcation manifolds in predator-prey models computed by Gröbner basis method.

Many natural processes studied in population biology, systems biology, biochemistry, chemistry or physics are modeled by dynamical systems with polynomial or rational right-hand sides in state and parameter variables. The problem of finding bifurcation manifolds of such discrete or continuous dynamical systems leads to a problem of finding solutions to a system of non-linear algebraic equations. This approach often fails since it is not possible to express equilibria explicitly. Here we describe an algebraic procedure based on the Gröbner basis computation that finds bifurcation manifolds without computing equilibria. Our method provides formulas for bifurcation manifolds in commonly studied cases in applied research - for the fold, transcritical, cusp, Hopf and Bogdanov-Takens bifurcations. The method returns bifurcation manifolds as implicitly defined functions or parametric functions in full parameter space. The approach can be implemented in any computer algebra system; therefore it can be used in applied research as a supporting autonomous computation even by non-experts in bifurcation theory. This paper demonstrates our new approach on the recently published Rosenzweig-MacArthur predator-prey model generalizations in order to highlight the simplicity of our method compared to the published analysis.

Two-parameter bifurcations in LPA model.

The structured population LPA model is studied. The model describes flour beetle (Tribolium) population dynamics of four stage populations: eggs, larvae, pupae and adults with cannibalism between these stages. We concentrate on the case of non-zero cannibalistic rates of adults on eggs and adults on pupae and no cannibalism of larvae on eggs, but the results can be numerically continued to non-zero cannibalism of larvae on eggs. In this article two-parameter bifurcations in LPA model are analysed. Various stable and unstable invariant sets are found, different types of hysteresis are presented and abrupt changes in dynamics are simulated to explain the complicated way the system behaves near two-parameter bifurcation manifolds. The connections between strong 1:2 resonance and Chenciner bifurcations are presented as well as their very significant consequences to the dynamics of the Tribolium population. The hysteresis phenomena described is a generic phenomenon nearby the Chenciner bifurcation or the cusp bifurcation of the loop.

De novo cost-utility analysis of oral paliperidone in the treatment of schizoaffective disorder.

OBJECTIVES: The aim of this analysis is to compare costs and effectiveness of paliperidone ER vs. placebo in the treatment of schizoaffective disorder (SAD) in the Czech Republic based on pooled clinical trial data. METHODS: A de novo micro-simulation model was developed to assess the cost-utility analysis of paliperidone vs. placebo as there is lack of clinical data comparing paliperidone to other interventions. There are no studies primarily evaluating the efficacy of treatment of SAD with other antipsychotics. The model estimated effectiveness and costs of patients with SAD every week during 24-week time horizon. The effectiveness was defined as improvement of a patient's PANSS score where utilities were assigned to each modelled PANSS score. Based on the patient level data a linear mixed-effects model was used to estimate the regression equations of percentage decrease of PANSS score from the baseline. Utilities were computed using a regression function of patients' age, sex and PANSS score, which was adapted from a clinical study of patients with schizophrenia as there are no QoL data on SAD patients. Among relevant costs, reflecting the payer's perspective, costs of pharmacotherapy, concomitant medications and outpatient care were considered. RESULTS: The average ICER of paliperidone compared to placebo reached 28,935 EUR/QALY. The probability of paliperidone being cost-effective compared to placebo was 99.5%. CONCLUSIONS: Treatment of SAD with paliperidone results in acceptable ICER and high probability of being cost-effective compared to placebo. Thus, it can be considered as a cost-effective treatment of patients with SAD in the Czech Republic.

Predator interference and stability of predator-prey dynamics.

Predator interference, that is, a decline in the per predator consumption rate as predator density increases, is generally thought to promote predator-prey stability. Indeed, this has been demonstrated in many theoretical studies on predator-prey dynamics. In virtually all of these studies, the stabilization role is demonstrated as a weakening of the paradox of enrichment. With predator interference, stable limit cycles that appear as a result of environmental enrichment occur for higher values of the environmental carrying capacity of prey, and even a complete absence of the limit cycles can happen. Here we study predator-prey dynamics using the Rosenzweig-MacArthur-like model in which the Holling type II functional response has been replaced by a predator-dependent family which generalizes many of the commonly used descriptions of predator interference. By means of a bifurcation analysis we show that sufficiently strong predator interference may bring about another stabilizing mechanism. In particular, hysteresis combined with (dis)appearance of stable limit cycles imply abrupt increases in both the prey and predator densities and enhanced persistence and resilience of the predator-prey system. We encourage refitting the previously collected data on predator consumption rates as well as for conducting further predation experiments to see what functional response from the explored family is the most appropriate.

Comparative genomics of protoploid Saccharomycetaceae.

Our knowledge of yeast genomes remains largely dominated by the extensive studies on Saccharomyces cerevisiae and the consequences of its ancestral duplication, leaving the evolution of the entire class of hemiascomycetes only partly explored. We concentrate here on five species of Saccharomycetaceae, a large subdivision of hemiascomycetes, that we call "protoploid" because they diverged from the S. cerevisiae lineage prior to its genome duplication. We determined the complete genome sequences of three of these species: Kluyveromyces (Lachancea) thermotolerans and Saccharomyces (Lachancea) kluyveri (two members of the newly described Lachancea clade), and Zygosaccharomyces rouxii. We included in our comparisons the previously available sequences of Kluyveromyces lactis and Ashbya (Eremothecium) gossypii. Despite their broad evolutionary range and significant individual variations in each lineage, the five protoploid Saccharomycetaceae share a core repertoire of approximately 3300 protein families and a high degree of conserved synteny. Synteny blocks were used to define gene orthology and to infer ancestors. Far from representing minimal genomes without redundancy, the five protoploid yeasts contain numerous copies of paralogous genes, either dispersed or in tandem arrays, that, altogether, constitute a third of each genome. Ancient, conserved paralogs as well as novel, lineage-specific paralogs were identified.

Gas chromatography/mass spectrometry analysis of components of pyridine temperature-programmed desorption spectra from surface of copper-supported catalysts.

The method of pyridine temperature-programmed desorption (TPD) was applied for the measurement of acid properties of in situ reduced copper catalysts on silicate support. A thermal-conductivity detector (TCD) was used for the detection of TPD spectra of pyridine. The combination of flame-ionization detector and thermal conductivity detector shows that the region of TPD spectrum with the peak maxima T(MAX1)=350 degrees C is a superposition of the TCD response on spectra of desorbed pyridine, water and carbon dioxide, desorbing simultaneously from the catalyst surface. The method for the elimination of H(2)O and CO(2) on the layer of NaOH was tested and the pure TPD spectrum of pyridine was obtained. The exact determination of pyridine concentration allows to estimate the amount of weak and medium acid centers of the catalyst. The gas chromatography with the mass spectroscopy (GC-MS) analyses was used for the interpretation of high temperature region of the pyridine TPD spectra (T(MAX2)=620 degrees C). It was found that pyridine bonded on the strong acid centers is decomposed to N(2) and CO under very high temperature. The available chromatographic method for the separation of components present in pyridine TPD spectrum in the high-temperature region was suggested. The method for the quantification of strong acidity of copper-supported catalyst was found.

The salt tolerant yeast Zygosaccharomyces rouxii possesses two plasma-membrane Na+/H+-antiporters (ZrNha1p and ZrSod2-22p) playing different roles in cation homeostasis and cell physiology.

Antiporters exporting Na(+) and K(+) in exchange for protons are conserved among yeast species. The only exception so far has been Zygosaccharomyces rouxii, an osmotolerant species closely related to Saccharomyces cerevisiae. Z. rouxii was described as possessing one plasma-membrane antiporter transporting only Na(+) (ZrSod2-22p in the CBS 732(T) type strain). We report the characterization of a second gene, ZrNHA1, encoding a new K(+)(Na(+))/H(+)-antiporter capable of both K(+) and Na(+) export. Synteny analyses suggested that ZrSOD2-22 originated by single duplication of the ZrNHA1 gene. Substrate specificities and transport properties of ZrNha1p and ZrSod2-22p were compared upon heterologous expression in S. cerevisiae, and then directly in Z. rouxii. Deletion mutants and phenotype analyses revealed that ZrSod2-22 antiporter is important for Na(+) detoxification, probably together with ZrEna1 ATPase; ZrNha1p is indispensable to maintain potassium homeostasis and ZrEna1p is not, in contrast to the situation in S. cerevisiae, involved in this function.

Tools for the genetic manipulation of Zygosaccharomyces rouxii.

A set of tools for the genetic manipulation of the osmotolerant yeast Zygosaccharomyces rouxii was developed. Auxotrophic mutants (ura3 leu2, ura3 ade2, ura3 leu2 ade2) derived from the CBS 732 type strain were prepared. Centromeric and episomal Z. rouxii/Escherichia coli shuttle plasmids with different marker genes (ScURA3, ZrLEU2, ZrADE2) and with multiple cloning sites were constructed, together with a plasmid enabling green fluorescent protein-tagging. A system for repeatable targeted gene deletion in Z. rouxii was established, involving first the integration of a PCR-generated loxP-kanMX-loxP cassette and second the removal of kanMX from the genome using a Z. rouxii plasmid harbouring cre recombinase.

Characterisation of Zygosaccharomyces rouxii centromeres and construction of first Z. rouxii centromeric vectors.

Zygosaccharomyces rouxii is a hemiascomycetous yeast known for its high osmotolerance, the basis of which still remains unknown. By exploring the Génolevures I database, four Z. rouxii fragments homologous to Saccharomyces cerevisiae centromeres were identified. Two of them were subjected to further analysis. Their function as centromeres in Z. rouxii was proved, and they were localized to Z. rouxii chromosomes II and VII, respectively. The species-specificity of centromeres was observed; plasmids with a Z. rouxii centromere were not recognized as centromeric in S. cerevisiae, and a S. cerevisiae centromere did not function as a centromere in Z. rouxii. Constructed plasmids bearing Z. rouxii centromeres serve as the first specific centromeric plasmids, and thus contribute to the so-far limited set of genetic tools needed to study the Z. rouxii specific features.

Osmoresistant yeast Zygosaccharomyces rouxii: the two most studied wild-type strains (ATCC 2623 and ATCC 42981) differ in osmotolerance and glycerol metabolism.

The yeast Zygosaccharomyces rouxii is known for its high tolerance to osmotic stress, which is thought to be caused by sets of specific genes. Relatively few Z. rouxii genes have been identified so far, all of them having homologues in Saccharomyces cerevisiae; none of them was Z. rouxii-specific. Most of the known Z. rouxii genes were isolated from two wild-type strains, ATCC 2623 and ATCC 42981. In this study, we compared these two strains with regard to some of their morphological, physiological and genomic properties. Important differences were found in their salt tolerance and assimilation of glycerol and karyotype; slight differences were also present in their cell morphology. The ATCC 42981 strain showed a higher resistance to salts, higher glycerol production and, unlike ATCC 2623, was able to assimilate glycerol. Under conditions of osmotic stress, the glycerol production in both Z. rouxii strains was much lower than in a S. cerevisiae S288c culture, which suggested the presence of a system that efficiently retains glycerol inside Z. rouxii cells. The karyotype analysis revealed that ATCC 42981 cells contain more chromosomes and have a bigger genome size than those of ATCC 2623.

Efficient transformation of the osmotolerant yeast Zygosaccharomyces rouxii by electroporation.

A rapid and simple electroporation method to transform osmotolerant yeast Zygosaccharomyces rouxii has been developed and conditions for efficient transformation of mutants derived from different Z. rouxii wild-type strains optimized.