Search Results (357)

In this paper, we investigate the Malliavin differentiability and density smoothness of solutions to stochastic differential equations (SDEs) with non-Lipschitz coefficients. Specifically, we consider equations of the form $d{X}_t= b\left(X_t\right)dt + \sigma \left(X_t\right)d{W}_t, X_0= x_0$ where the drift b(·) and diffusion σ(·) may violate the global Lipschitz condition but satisfy weaker assumptions such as Hölder continuity, linear growth, and non-degeneracy. By employing Malliavin calculus theory, large deviation principles, and Fokker–Planck equations, we establish comprehensive results concerning the existence and uniqueness of solutions, their Malliavin differentiability, and the smoothness properties of density functions. Our main contributions include (1) proving the Malliavin differentiability of solutions under the standard linear growth condition combined with Hölder continuity; (2) establishing the existence and smoothness of density functions using Norris lemma and the Bismut–Elworthy–Li formula; and (3) providing optimal estimates for density functions through large deviation theory. These results have significant applications in financial mathematics (e.g., CIR, CEV, and Heston models), biological system modeling (e.g., stochastic population dynamics and neuronal and epidemiological models), and other scientific domains. Full article

Background: Cryocompression, an emerging therapy combining cryotherapy and compression therapy, has limited evidence regarding its effects on recovery from exercise-induced muscle damage. Methods: This study aimed to compare the effects of cryotherapy (CT), normothermic water compression (NWC), and cryocompression (CC) on muscle damage, proprioception, and performance following eccentric exercise. Forty healthy male participants performed 30 sets of 10 maximal isokinetic eccentric contractions (30°/s) of the quadriceps of the non-dominant leg. Muscle damage indicators [thigh circumference (CIR), muscle soreness measured by visual analog scale (VAS)], proprioception [position sense (PS), force sense (FS)], and performance parameters [range of motion (ROM), maximal voluntary isometric contraction (MVIC)] were assessed before and on days 1–5 following eccentric exercise. Two-way repeated-measures ANOVA with Tukey’s post hoc tests was used to evaluate group × time interactions. Results: Significant interactions were observed for CIR between the CT, NWC and CC groups compared to the control group, as well as for VAS scores between the CC and CON groups (p < 0.05). No other outcome measures showed significant interactions (p > 0.05). The control group showed a peak CIR increase of ~6.6 mm (day 3) versus 2.4 mm (CT), 3.6 mm (NWC), and 2.1 mm (CC). By day 5, the control group remained elevated at 5.2 mm, while CT returned to baseline by day 4. NWC and CC groups showed no significant changes on days 1–5. VAS scores in the CON group peaked at ~77 mm on day 2, not returning by day 5, whereas the CC group reached 48 mm and returned to baseline by day 3. Conclusion: Cryocompression reduced limb swelling and muscle soreness, as well as post-exercise-induced muscle damage, and NWC mitigated limb swelling, but none significantly affected proprioception or performance parameters. Full article

Orthogonal Frequency Division Multiplexing (OFDM) modulation currently dominates the physical layer design in modern transmission systems. Its primary advantage is the simple reconstruction of channel frequency response (CFR). However, the Least Squares (LS) algorithm commonly used here is prone to significant estimation errors due to noise interference. A promising and relatively simple alternative is a DFT-based strategy that uses a pre-computed refinement/correction matrix to improve estimation performance. This paper investigates two implementation approaches for CFR reconstruction with pre-computed matrices. Focusing on multiplication operations, a threshold number of active subcarriers was identified at which these two implementations exhibit comparable numerical complexity. A numerical performance factor was defined and a detailed performance analysis was carried out for different guard interval (GI) lengths and the number of active subcarriers in the OFDM signal. Additionally, to maintain channel estimation quality irrespective of GI length, a channel impulse response (CIR) energy detection procedure was introduced. This procedure refines the results of the symbol synchronization process and, by using the circular shift property, preserves constant values of the precomputed matrix coefficients without system performance loss, as measured by Bit Error Rate (BER) and Mean Square Error (MSE) metrics. Full article

Background/Objectives: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an urgent public health threat due to its rapid dissemination and resistance to last-line antibiotics. Cefiderocol (FDC), a novel siderophore cephalosporin, targets resistant Gram-negative pathogens by exploiting bacterial iron uptake mechanisms. However, resistance to FDC is emerging among Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains. This study characterizes a spontaneous FDC-resistant subpopulation (IHC216) derived from a KPC-producing strain (KPNMA216) using comprehensive genomic, transcriptional, and phenotypic analyses. Methods: Given the whole-genome sequencing results, where mutations were identified in genes involved in transcriptional regulation and membrane permeability (ompC) among others, in the present work we further explore their potential implications and conduct a more detailed analysis of the IHC216 genome. A qRT-PCR analysis highlighted significant downregulation of classical siderophore-mediated iron acquisition systems (fepA, cirA, iroN) and upregulation of alternative iron uptake pathways (iucA, fiU), reflecting a switch in iron acquisition strategies. Results: A notable downregulation of bla_KPC-163 correlated with restored susceptibility to carbapenems, indicating collateral susceptibility. Altered expressions of pbp2 and pbp3 implicated adaptive changes in cell wall synthesis, potentially affecting FDC resistance mechanisms. Furthermore, enhanced oxidative stress responses via upregulated sodC expression and increased capsule production were observed. Conclusions: These findings underscore the complex interplay of genetic and transcriptional adaptations underlying FDC resistance, highlighting potential therapeutic vulnerabilities. Full article

Oxidative stress significantly contributes to the exacerbation of brain damage during cerebral ischemia-reperfusion injury (CIR/I). In our previous study, purified cornel iridoid glycoside (PCIG), consisting of morroniside (MOR) and loganin (LOG), showed neuroprotective effects against CIR/I. To further explore the antioxidative effects and underlying molecular mechanisms, we applied PCIG, MOR, and LOG to rats injured by middle cerebral artery occlusion/reperfusion (MCAO/R) as well as H₂O₂-stimulated PC12 cells. Additionally, the molecular docking analysis was performed to assess the interaction between the PCIG constituents and Kelch-like ECH-associated protein 1 (Keap1). The results showed that the treated rats experienced fewer neurological deficits, reduced lesion volumes, and lower cell death accompanied by decreased levels of malondialdehyde (MDA) and protein carbonyl, as well as increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In H₂O₂-stimulated PC12 cells, the treatments decreased reactive oxygen species (ROS) production, mitigated mitochondrial dysfunction, and inhibited mitochondrial-dependent apoptosis. Moreover, the treatments facilitated Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation into the nucleus and selectively increased the expression of NAD(P)H quinone oxidoreductase 1 (NQO-1) and heme oxygenase 1 (HO-1) through MOR and LOG, respectively. Both MOR and LOG demonstrated strong binding affinity to Keap1. These findings suggested that PCIG, rather than any individual components, might serve as a valuable treatment for ischemic stroke by activating the Nrf2/NQO-1 and Nrf2/HO-1 signaling pathway. Full article

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling. Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions. While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases. This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency in the host, with the bone marrow (BM) CD34+ cells serving as a key reservoir. To investigate tissue-specific immune responses to CMV, we analysed paired peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMNCs) from HCMV-seropositive donors using multiparametric flow cytometry and cytokine FluroSpot assays. We assessed immune cell composition, memory T cell subsets, cytokine production, cytotoxic potential, activation marker expression, and checkpoint inhibitory receptor (CIR) profiles, both ex vivo and following stimulation with lytic and latent HCMV antigens. BMMNCs were enriched in CD34+ progenitor cells and exhibited distinct T cell memory subset distributions. HCMV-specific responses were compartmentalised: IFN-γ responses predominated in PBMCs following lytic antigen stimulation, while IL-10 and TNF-α responses were more prominent in BMMNCs, particularly in response to latent antigens. US28-specific T cells in the BM showed elevated expression of CD39, PD-1, BTLA, CTLA-4, ICOS, and LAG-3 on CD4+ T cells and increased expression of PD-1, CD39, BTLA, TIGIT, LAG-3, and ICOS on CD8+ T cell populations, suggesting a more immunoregulatory phenotype. These findings highlight functional and phenotypic differences in HCMV-specific T cell responses between blood and bone marrow, underscoring the role of the BM niche in shaping antiviral immunity and maintaining viral latency. Full article

The cold recycling (CR) technique is gaining traction, with an increasing demand for sustainable pavement construction practices. Cold in-place recycling (CIR) and cold central plant recycling (CCPR) are two strategies under the umbrella of cold recycling. These techniques use reclaimed asphalt pavement (RAP) to rehabilitate pavement, and CCPR offers the added advantage of utilizing stockpiled RAP. While many agencies have expertise in cold recycling techniques including CCPR, the lack of pavement performance data prevented the largescale implementation of these technologies. Recent studies in high-traffic volume applications demonstrate that CCPR technology can be implemented on the entire road network across all traffic levels. This reignited interest in the widespread implementation of CCPR. Therefore, the purpose of this study is to provide agencies with the most up-to-date information on CCPR to help them make informed decisions. To this end, this paper comprehensively reviews the mix-design for CCPR, the structural design of pavements containing CCPR layers, best construction practices, and the agency experience in using this technology on high-traffic volume roads to provide in-depth information on the steps to follow from project selection to field implementation. The findings specify the suitable laboratory curing conditions to achieve the optimum mix design and specimen preparation procedures to accurately capture the material properties. Additionally, this review synthesizes existing quantitative data from previous studies, providing context for the comparison of findings, where applicable. The empirical and mechanistic–empirical design inputs, along with the limitations of AASHTOWare Pavement ME software for analyzing this non-conventional material, are also presented. Full article

Background/Objectives: Cefiderocol is a novel siderophore cephalosporin with potent in vitro activity against a broad spectrum of Gram-negative bacteria, including carbapenemase-producing Enterobacterales (CPE). However, the recent emergence of resistance in clinical settings raises important concerns regarding its long-term effectiveness. This study aims to investigate the genomic determinants associated with cefiderocol resistance in CPE isolates of human origin. Methods: Comparative genomic analyses were conducted between cefiderocol-susceptible and -resistant CPE isolates recovered from human clinical and epidemiological samples at a tertiary care hospital. Whole-genome sequencing, variant annotation, structural modelling, and pangenome analysis were performed to characterize resistance mechanisms. Results: A total of 59 isolates (29 resistant and 30 susceptible) were analyzed, predominantly comprising Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. The most frequent carbapenemase gene among the resistant isolates was bla_NDM, which was also present in a subset of susceptible strains. The resistant isolates exhibited a significantly higher burden of non-synonymous mutations in their siderophore receptor genes, notably within fecR, fecA, fiu, and cirA. Structural modelling predicted deleterious effects for mutations such as fecR:G104S and fecA:A190T. Additionally, porin loss and loop 3 insertions (e.g., GD/TD) in OmpK36, as well as OmpK35 truncations, were more frequent in the resistant isolates, particularly in high-risk clones such as ST395 and ST512. Genes associated with toxin–antitoxin systems (chpB2, pemI) and a hypothetical metalloprotease (group_2577) were uniquely found in the resistant group. Conclusions: Cefiderocol resistance in CPE appears to be multifactorial. NDM-type metallo-β-lactamases and missense mutations in siderophore uptake systems—especially in those encoded by fec, fhu, and cir operons—play a central role. These may be further potentiated by alterations in membrane permeability, such as porin disruption and efflux deregulation. The integration of genomic and structural approaches provides valuable insights into emerging resistance mechanisms and may support the development of diagnostic tools and therapeutic strategies. Full article

This study aimed to compare the contents of copper (Cu), zinc (Zn), magnesium (Mg), and iron (Fe) in healthy liver tissue from deceased liver donors (DGs), in cirrhotic tissue from patients without (CIR) or with hepatocellular carcinoma (CIR-HCC) and in HCC tissue from the latter patients. Liver tissue samples were obtained from cirrhotic liver transplant recipients, with (n = 14) and without HCC (n = 14), and from DGs (n = 18). In patients with HCC, both cirrhotic and tumor tissue was collected. The tissue metal content was measured using atomic absorption spectrometry. The Cu content of DG tissue was significantly lower than that of CIR-HCC and HCC tissue but not CIR tissue. The tissue Zn and Mg contents were significantly higher in DG tissue than in CIR, CIR-HCC, and HCC tissues. No difference was observed for Fe. The Cu/Zn ratio progressively increased in DG, CIR, CIR-HCC, and HCC tissues. The increased Cu content in cirrhotic and tumor tissue of HCC patients and the fact that the latter had the highest value for the Cu/Zn ratio indirectly suggest the potential role of these metals in hepatocarcinogenesis. These findings support a pathophysiological basis for further experimental studies to investigate the potential therapeutic implications of pharmacological agents targeting metal homeostasis in this malignancy. Full article

Background/Objectives: The role of KDM6A gene mutations in acute myeloid leukemia (AML) remains poorly understood. This study aimed to evaluate the impact of KDM6A mutations on relapse risk, cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) in adult AML patients, with a particular focus on those with RUNX1::RUNX1T1 fusion. Methods: the retrospective analysis was conducted on 1970 adult AML patients treated at Peking University People’s Hospital. Of these, 1676 patients who achieved complete remission (CR) were included. Among them, 27 harbored KDM6A mutations. Propensity score matching (PSM) was used (1:10 ratio) to compare outcomes between patients with and without KDM6A mutations. Further analysis focused on 207 patients with RUNX1::RUNX1T1 fusion, among whom 13 had KDM6A mutations (PSM 1:5). Results: In the overall cohort, KDM6A variants (n = 27) had a higher 2-year CIR (45.7% vs. 28.6%, p = 0.04). Fine–Gray analysis showed KDM6A variants independently increased relapse risk (HR = 1.98 [1.08–3.63], p = 0.03). KDM6A mutations were associated with inferior 2-year RFS (36.3% vs. 60.9%, p = 0.044). Multivariable analysis confirmed KDM6A mutations as independent predictors of poor RFS (HR = 3.08 [1.56–6.08], p = 0.001). Among RUNX1::RUNX1T1 patients, KDM6A mutations significantly increased relapse risk (75.0% vs. 21.7%, p < 0.001), raised 2-year CIR (46.9% vs. 24.0%, p = 0.05), worsened 2-year RFS (31.3% vs. 71.9%, p < 0.001), and lowered 2-year OS (63.3% vs. 86.4%, p = 0.002). They were also independent predictors of CIR (HR = 2.46 [1.11–5.47], p = 0.03), RFS (HR = 5.1, [2.5–10.5], p < 0.001) and OS (HR = 12.9, [4.3–38.7], p < 0.001). Conclusions: KDM6A mutations are significantly associated with increased relapse risk and poor prognosis in AML, especially in patients with RUNX1::RUNX1T1 fusion, and may serve as a valuable prognostic biomarker. Full article

Background and Objectives: Due to the progress made in all areas of research, pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) now have an average overall survival rate of 90%. There are still discrepancies between high-income countries and limited-resource centers. The aim of this study was to analyze prognostic factors and outcome parameters in a 223-patient cohort from a single center in Romania, treated with two adapted BFM protocols. Materials and Methods: The patients diagnosed with ALL in our center were enrolled in this study from January 2016 to December 2022 and subsequently followed up until December 2024. The patients were treated first according to the ALL IC BFM 2009 protocol until June 2019 and afterwards with the ALL AIEOP BFM 2017 protocol starting with July 2019. The prognostic factors were analyzed in both subgroups and the outcomes were measured: event-free survival (EFS), overall survival (OS), cumulative incidence of relapse (CIR), relapse-free survival (RFS) and non-relapse mortality (NRM). Results: The comparison between the two subgroups revealed that every parameter improved over time: complete remission after induction (87.75% vs. 80.7%), early deaths (3.92% vs. 5.78%), deaths in remission (4.08% vs. 5.26%), 5-year EFS (73.79% vs. 70.22%), 5-year CIR (18.36% vs. 19.04%), 5-year RFS (81.76% vs. 80.97%), 5-year NRM (7.85% vs. 10.77%), and 5-year OS (88.18% vs. 82.54%). Whereas for the standard-risk group, events such as relapse or death were isolated, for intermediate-risk patients, the events were limited to a small number and did not significantly influence the overall results, and for high-risk children, the results improved significantly between the two subgroups. The worst outcomes were observed in patients with the BCR::ABL1 fusion gene, T-cell phenotype, and in teenagers, compared to the ETV6::RUNX1 fusion gene, B precursor ALL, and in smaller children, respectively. Conclusions: The 5-year OS increased in our center from 82.54% to almost 90%, with the most substantial finding being the survival rate for high-risk patients, now reaching up to 80%. The prognostic factors were age at diagnosis, genetic characteristics, and response to treatment, especially prednisone sensibility. Full article

The current paper is devoted to the dynamical property of the stochastic Cox–Ingersoll–Ross (CIR) model with pure jump noise, which is an extension of the CIR model. Firstly, we characterize the existence and 2-moment of the CIR process with a pure jump process. Consequently, we provide sufficient conditions for the compensated Poisson random measure under which the CIR process with a pure jump process is ergodic. Moreover, the stationary solution can be constructed from the invariant measure. Some numerical simulations are provided to visualize the theoretical results. Full article

Conventional Global Navigation Satellite System (GNSS) time transfer algorithms typically model receiver clock offsets as white noise for estimation, neglecting the physical characteristics of atomic clocks, which consequently limits the performance of GNSS time transfer. To overcome this limitation, this study proposes an undifferenced GPS/Galileo combined Precise Point Positioning (PPP) time transfer model, incorporating both one-state (only clock offset parameter) and two-state (both clock offset and frequency offset parameters) refined clock models with clock instantaneous re-initialization (CIR) strategy at the day boundary epoch. Using observations from International GNSS Service (IGS) Multi-GNSS Experiment (MGEX) stations equipped with external hydrogen masers, precise time transfer performance under refined clock models was evaluated based on undifferenced GPS/Galileo combined PPP float solutions and PPP ambiguity resolutions. Experimental results demonstrate that, compared to traditional models, the refined clock models improve time transfer accuracy and frequency stability by an average of 6.7% and 25.8%, respectively. The improvement is most significant for short term frequency stability, with a maximum enhancement exceeding 85%. As the averaging time increases, the improvement in long term frequency stability gradually diminishes. Notably, the two-state refined clock model slightly outperforms the one-state model in time transfer performance, with the two-state refined clock model improving short-, medium-, and long term frequency stability by 11.5%, 8.0%, and 0.2%, respectively, compared to the one-state refined clock model. These findings strongly advocate adopting the two-state refined clock model to optimize both time transfer precision and short term stability in high-accuracy applications. Full article

The popular Wishart (WI) processes, first introduced by Bru in 1991, exhibit convenient analytical properties for modeling asset prices, particularly a closed-form characteristic function, and the ability to jointly model stochastic volatility and correlation. These features tend to increase substantially during crisis periods, more than predicted by a Wishart dynamic. Moreover, the variance processes implied by the Wishart, similar to CIR models, have no buffer away from zero. In this paper, we introduced the Markov-Modulated Shifted Wishart processes (MMSW) and the embedded Shifted Wishart processes (SW) to address these shortcomings in the modeling of asset prices. We obtain analytical representations for several characteristic functions. We also estimate the parameters and evaluate the price of Spread options via the Fourier transform under the two new models compared to the standard Wishart. Our analyses demonstrate a significant impact of the MMSW process compared to the standard Wishart process of up to $7\%$ in Spread option prices. Full article