Maximum Level Research Articles

Platelet-fibrin clot strength and platelet reactivity predicting cardiovascular events after percutaneous coronary interventions.

Platelet-fibrin clot strength (PFCS) is linked to major adverse cardiovascular event (MACE) risk. However, the association between PFCS and platelet reactivity and their prognostic implication remains uncertain in patients undergoing percutaneous coronary intervention (PCI). In PCI-treated patients (n = 2512) from registry data from January 2010 to November 2018 in South Korea, PFCS using thromboelastography and platelet reactivity using VerifyNow were measured. High PFCS (PFCSHigh) was defined as thromboelastography maximal amplitude ≥ 68 mm, and high platelet reactivity (HPR) was defined as >208 P2Y12 reaction units. Patients were stratified into four groups according to maximal amplitude and P2Y12 reaction unit levels: (i) normal platelet reactivity (NPR)-PFCSNormal (31.8%), (ii) HPR-PFCSNormal (29.0%), (iii) NPR-PFCSHigh (18.1%), and (iv) HPR-PFCSHigh (21.1%). Major adverse cardiovascular event (all-cause death, myocardial infarction, or stroke) and major bleeding were followed up to 4 years. High platelet reactivity and PFCSHigh showed an additive effect for clinical outcomes (log-rank test, P < .001). Individuals with NPR-PFCSNormal, NPR-PFCSHigh, HPR-PFCSNormal, and HPR-PFCSHigh demonstrated MACE incidences of 7.5%, 12.6%, 13.4%, and 19.3%, respectively. The HPR-PFCSHigh group showed significantly higher risks of MACE compared with the NPR-PFCSNormal group [adjusted hazard ratio (HRadj) 1.89; 95% confidence interval (CI) 1.23-2.91; P = .004] and the HPR-PFCSNormal group (HRadj 1.60; 95% CI 1.12-2.27; P = .009). Similar results were observed for all-cause death. Compared with HPR-PFCSNormal phenotype, NPR-PFCSNormal phenotype was associated with a higher risk of major bleeding (HRadj 3.12; 95% CI 1.30-7.69; P = .010). In PCI patients, PFCS and platelet reactivity demonstrated important relationships in predicting clinical prognosis. Their combined assessment may enhance post-PCI risk stratification for personalized antithrombotic therapy.

Biochemical markers of neuro-myocardial damage after pulmonary vein isolation: the effect of different energy sources

Abstract Background Pulmonary vein isolation (PVI) by thermal energy, both radiofrequency (RF) and cryoenergy(Cryo), is associated with a significant release of myocardial and collateral neural injury markers. Damage to periatrial ganglionated plexi also results in a substantial change in cardiac autonomic regulations. On the contrary, pulsed electric field (PEF) energy tends to spare cardiac neural tissue. Purpose To quantify the impact of different ablation energy sources that are used for PVI on neuro-myocardial damage by the assessment of specific biomarkers. Methods A study enrolled 85 patients with paroxysmal atrial fibrillation who underwent PVI (age: 61 ± 12 years, 74% males). In 23 patients, RF energy was delivered by the irrigated-tip catheter, while 30 patients were ablated using a second-generation cryoballoon catheter. In 32 patients, PVI was performed using a multipolar pentaspline catheter and PEF energy. Peripheral venous blood samples for assessing the plasmatic levels of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), high-sensitivity troponin I and T (hsTnI and hsTnT) were obtained before, immediately after the PVI, and the next day (usually 18-24 hours after the procedure). Study groups were compared regarding absolute biomarker levels and hsTnT/S100B ratio (a surrogate of cardioselectivity). Results Following successful PVI, a significant increase in plasma levels of all biomarkers was observed: DhsTnT = 1040±434 ng/L, 1731±830 ng/L and 1010±397 ng/L; DhsTnI = 1504±918 ng/L, 16464±11911 ng/L and 10789±7589 ng/L; DS100B: 0.04±0.02 mg/L, 0.03±0.04 mg/L and 0.14±0.08 mg/L; DNSE: 34±72 ng/mL, 27±53 ng/mL and 45±52 ng/mL (all with P &amp;lt;0.001) for RF, PEF and Cryo groups, respectively. A direct comparison of maximal biomarker levels between study groups is depicted in the Figure. The hsTnT/S100B ratio was 23±14, 12±6, and 6±3 in PEF, RF, and Cryo groups, respectively (ANOVA P &amp;lt;0.01), indicating that PEF was 1.9-times and 3.8-times more cardioselective than RF and Cryo, respectively. Following the PVI, the heart rate accelerated by 2±8, 13±14, and 9±11 bpm in the PEF, RF, and Cryo groups, respectively. No correlation was observed between S100B release and HR acceleration (R = 0.07, P = 0.55). Conclusion Compared to thermal energy sources, PEF energy induces more specific damage to cardiomyocytes than cardiac nerves. There was no correlation between S100B release and HR acceleration.

Multiband multiple‐input multiple‐output antenna design with high‐resolution circularly polarized wireless communication

SummaryA design problem of multiband multi‐input, multi‐output (MIMO) antenna arrays for maximal side lobe level lessening with constraint of a fixed beam width is dealt with. Multiband MIMO antenna is the most promising solution in a communication system, due to its maximal speed, higher data rate, and short‐range communication. Conversely, MIMO faces several complications including designing a proper antenna for a specific bandwidth and lesser antenna efficacy. In this manuscript, a high‐resolution CP multiband MIMO (HS‐CPMB‐MIMO) antenna design for wireless communication is proposed. MIMO antenna plays a vital part in the present wireless technology at MSA. A multiband microstrip line‐fed two‐port hybrid CPMIMO antenna is intended and fabricated. The proposed microstrip feed antenna contains a tapering structure, and the inverted L‐shaped slots in the radiating element are opened on both sides to present notches in sub‐6‐GHz frequencies. The inverted L‐shaped slots is positioned in the middle of asymmetric Z‐shaped radiating elements for enhancing the isolation among the two ports. The invention of a multiband MIMO antenna with four CP bands has an efficient ECC value because of a large L‐shaped slot in the ground as well as a protruding Z‐shape ground stub embedded with circular rings to have highly isolated cells. Finally, the proposed HS‐CPMB‐MIMO antenna design is implemented by utilizing simulation software CST Microwave Studio, and it is evaluated with the performance metrics. The simulation outcomes of the proposed HS‐CPMB‐MIMO antenna provide 36.34%, 57.36%, and 25.33% higher BW, 24.13%, 15.96%, and 21.22% higher gain compared with existing methods.

Abstract RF02-02: BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism

Abstract PI3Kα is the most mutated kinase and the second most mutated oncogene in human cancer. Activation of PI3Ka can be achieved by receptor tyrosine kinases such as insulin receptor and insulin-like growth factor receptor 1 and/or by directly interacting with RAS family members. Previous elegant preclinical studies have established that RAS-driven PI3Ka activation is important in tumor cells but may not be involved in cell types controlling glucose metabolism. Alpelisib, a small molecule inhibitor of the kinase activity of PI3Ka, has been approved for the treatment of ER+ PIK3CA mutant breast cancer in combination with fulvestrant after endocrine therapy in advanced or metastatic breast cancer based on an improvement in PFS versus fulvestrant alone. Inhibition of PI3Ka activity by alpelisib in normal tissues resulted in a severe (G3/4) hyperglycemia rate of 37% with frequent dose interruptions and discontinuations. Additionally, preclinical studies have demonstrated that the dysregulation of glucose homeostasis resulting from PI3Ka kinase inhibition leads to hyperinsulinemia that increases pathway flux, rendering kinase inhibitors less effective. Here, we report on a novel covalent small molecule designed to inhibit RAS-mediated activation of the AKT pathway via PI3Ka without the resultant hyperglycemia associated with direct inhibition of PI3Ka kinase activity. BBO-10203 disrupts the physical interaction between RAS and PI3Ka in tumor cells resulting in potent signaling pathway inhibition. This agent selectively binds to PI3Ka and disrupts its interaction with K-,H-, and N-RAS with low single digit nanomolar potency (~5 nM). Breaking the interaction between these two oncogenes inhibits basal pAKT cellular levels (BT-474/KYSE-410 IC50: ~5 nM) in HER2 amplified (HER2amp) and wild-type or mutant PI3Ka cell lines. Even though BBO-10203 does not inhibit the kinase activity of PI3Ka, its effects on cancer cell signaling inhibition and transcriptional regulation highly resemble those of alpelisib. BBO-10203 displays excellent drug-like properties and oral bioavailability. Single dose treatment of KYSE-410 (HER2amp/KRASG12C) tumor bearing mice with increasing doses (1-100 mg/kg, PO) of BBO-10203 results in dose and time dependent inhibition of pAKT in vivo. Maximal inhibition (~80%) is achieved at 30 mg/kg and lasts for 24 hours. Repeated dose treatment of tumor bearing mice with BBO-10203 is well tolerated and results in significant efficacy in PIK3CA mutant as well as HER2amp human xenograft models. In the KYSE-410 xenograft model, BBO-10203 daily oral dosing of 30 mg/kg results in significant tumor regressions. Importantly, treatment with BBO-10203 does not affect insulin signaling in differentiated adipocytes in vitro, nor does it impact glucose metabolism in vivo at 3-times the maximal efficacious dose level in xenograft studies. In conclusion, we have identified a novel approach to inhibit the PI3Ka signaling pathway by blocking its interaction with, and activation by RAS. This approach can achieve strong pAKT inhibition in tumor cells without changes in glucose metabolism. Clinical investigation of BBO-10203 for the treatment of both ER+/PIK3CA mutant and HER2amp breast cancer is warranted. Citation Format: Pedro Beltran, Simanshu Dhirendra, Rui Xu, Ming Chen, Daniel Czyzyk, Sofia Donovan, Siyu Feng, Cindy Feng, Lijuan Fu, Felice Lightstone, Ken Lin, Anna Maciag, Dwight Nissley, Erin Riegler, Kerstin Sinkevicius, Andrew Stephen, James Stice, David Turner, Bin Wang, Keshi Wang, Yue Yang, Cathy Zhang, Frank McCormick, Eli Wallace. BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-02.

Abstract RF01-01: SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer

Abstract Background Camizestrant, a next-generation oral selective estrogen receptor (ER) degrader (SERD) and pure ER antagonist, has demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit over fulvestrant at both 75 and 150 mg once-daily doses in the Phase 2 SERENA-2 (NCT04214288) study in post-menopausal women with ER+ HER2- advanced breast cancer. SERENA-3 (NCT04588298) was established to explore the biological effects of three camizestrant dose levels in post-menopausal women with ER+ HER2- primary breast cancer. Methods Post-menopausal women with ER+ HER2- primary breast cancer scheduled to undergo curative intent surgery were randomly assigned in Stages 1 and 2 to pre-surgical treatment with camizestrant at 75, 150 or 300 mg once daily for 5 to 7 days or, in a sequential Stage 3, randomly assigned to camizestrant at 75 or 150 mg once daily for 12 to 15 days. Image-guided tumor biopsies were accessed as pre-treatment samples, while on-treatment ultrasound-guided tumor biopsies were obtained on the last day of camizestrant treatment. The primary objective was to explore the effect of camizestrant on ER expression by comparison of pre-treatment and on-treatment biopsies as assessed by immunohistochemistry (IHC) H-score. Secondary objectives included assessment of Ki67 and progesterone receptor (PgR) expression, and also of safety and tolerability, with exploratory pharmacodynamic (PD) assessment using other transcriptomic and proteomic technologies. The study was undertaken in 17 centers across 3 countries (Georgia, Mexico and the United Kingdom). Results 135 patients were randomized and received treatment. 76 patients received camizestrant for 5 to 7 days at doses of 75 mg (n=30), 150 mg (n=33), and 300 mg (n=13); 59 received camizestrant for 12 to 15 days at doses of 75 mg (n=30) and 150 mg (n=29). Baseline disease characteristics, and ER, Ki67 and PgR levels were well balanced across arms and stages. Pharmacokinetic (PK) observations in all stages were commensurate with steady-state predictions derived from previous studies. PD data for ER and Ki67 are shown in Table 1. Camizestrant reduced ER H-score by approximately 65% irrespective of dose or duration. While the 75 mg dose reduced Ki67 score to a lesser degree than 150 mg and 300mg after 5–7 days exposure, after 12–15 days exposure 75 and 150 mg reduced Ki76 score to a similar substantial degree (82% reduction). PD results assessed by additional transcriptomics and proteomics assays were concordant with the IHC analyses. No serious adverse events were reported. All treatment-emergent adverse events were grade 1, apart from one patient with a grade 2 visual impairment, and one patient with grade 3 diarrhea. Conclusions SERENA-3 is the first study investigating the effect of multiple dose levels of camizestrant with different treatment durations on ER, Ki67 and PgR expression in post-menopausal women with primary ER+ HER2˗ breast cancer. SERENA-3 demonstrated that the 75 mg dose of camizestrant achieves maximal levels of ER degradation and Ki67 suppression. Together with SERENA-2, this provides strong evidence supporting 75 mg as the optimal dose of camizestrant, including for the early disease setting, and highlights the additive value of a specifically designed multi-dose pre-surgical PD study for optimal dose selection. Table 1 Citation Format: John Robertson, Teimuraz Gogitidze, Zaza Katashvili, Juan Enrique Bargallo Rocha, Ekaterine Arkania, Iain Moppett, Kwok-Leung Cheung, Gia Nemsadze, Maxine Ajimi, Itziar Irurzun-Arana, Justin Lindemann, Teresa Klinowska, Alastair Mathewson, Christopher Morrow, Myria Nikolaou, Giorgi Dzagnidze. SERENA-3: A randomized pre-surgical window of opportunity study assessing dose and duration of camizestrant treatment in post-menopausal women with ER-positive, HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-01.

A Nonstationary Stochastic Rainfall Generator Conditioned on Global Climate Models for Design Flood Analyses in the Mississippi and Other Large River Basins

AbstractExisting stochastic rainfall generators (SRGs) are typically limited to relatively small domains due to spatial stationarity assumptions, hindering their usefulness for flood studies in large basins. This study proposes StormLab, an SRG that simulates precipitation events at 6‐hr and 0.03° resolution in the Mississippi River Basin (MRB). The model focuses on winter and spring storms caused by water vapor transport from the Gulf of Mexico—the key flood‐generating storm type in the basin. The model generates anisotropic spatiotemporal noise fields that replicate local precipitation structures from observed data. The noise is transformed into precipitation through parametric distributions conditioned on large‐scale atmospheric fields from a climate model, reflecting spatial and temporal nonstationarity. StormLab can produce multiple realizations that reflect the uncertainty in fine‐scale precipitation arising from a specific large‐scale atmospheric environment. Model parameters were fitted monthly from December–May, based on storms identified from 1979 to 2021 ERA5 reanalysis data and Analysis of Record for Calibration (AORC) precipitation. StormLab then generated 1,000 synthetic years of precipitation events based on 10 CESM2 ensemble simulations. Empirical return levels of simulated annual maxima agree well with AORC data and show an overall increase in 1‐ to 500‐year events in the future period (2022–2050). To our knowledge, this is the first SRG simulating nonstationary, anisotropic high‐resolution precipitation over continental‐scale river basins, demonstrating the value of conditioning such stochastic models on large‐scale atmospheric variables. StormLab provides a wide range of extreme precipitation scenarios for design floods in the MRB and can be further extended to other large river basins.

Universal bounds for spreading on networks.

Spreading (diffusion) of innovations is a stochastic process on social networks. When the key driving mechanism is the peer effect (word of mouth), the rate at which the aggregate adoption level increases with time depends strongly on the network structure. In many applications, however, the network structure is unknown. To estimate the aggregate adoption level as a function of time for such innovations, we show that the minimal and maximal adoption levels are attained on a homogeneous two-node network and on a homogeneous infinite complete network, respectively. Solving the Bass model on these two networks yields explicit lower and upper bounds for the expected adoption level on any network. These bounds are tight, and they also hold for the individual adoption probabilities of nodes. The gap between the lower and upper bounds increases monotonically with the ratio of the rates of internal and external influences.

Effect of Warm-Up Exercise on Functional Regulation of Motor Unit Activation during Isometric Torque Production.

In this study, we tested several hypotheses related to changes in motor unit activation patterns after warm-up exercise. Fifteen healthy young men participated in the experiment and the main task was to produce voluntary torque through the elbow joint under the isometric condition. The experimental conditions consisted of two directions of torque, including flexion and extension, at two joint angles, 10° and 90°. Participants were asked to increase the joint torque to the maximal level at a rate of 10% of the maximum voluntary torque. The warm-up protocol followed the ACSM guidelines, which increased body temperature by approximately 1.5°C. Decomposition electromyography electrodes, capable of extracting multiple motor unit action potentials from surface signals, were placed on the biceps and triceps brachii muscles, and joint torque was measured on the dynamometer. The mean firing rate and the recruitment threshold of the decomposed motor units were quantified. In addition, a single motor unit activity from the spike train was quantified for each of five selected motor units. The magnitude of joint torque increased with the warm-up exercise for all the experimental conditions. The results of the motor unit analyses showed a positive and beneficial effect of the warm-up exercise, with an increase in both the mean firing rate and the recruitment threshold by about 56% and 33%, respectively, particularly in the agonist muscle. Power spectral density in the gamma band, which is thought to be the dominant voluntary activity, was also increased by the warm-up exercise only in the high threshold motor units.

A triple cysteine motif as major determinant of the modulation of neuronal KV7 channels by the paracetamol metabolite N-acetyl-p-benzo quinone imine.

The analgesic action of paracetamol involves KV7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H2O2, or nitric oxide has been found to modulate currents through KV7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal KV7 channels might be responsible for the effects of NAPQI. To address this question, we used a combination of perforated patch-clamp recordings, site-directed mutagenesis, and mass spectrometry applied to recombinant KV7.1 to KV7.5 channels. Currents through the cardiac subtype KV7.1 were reduced by NAPQI. Currents through all other subtypes were increased, either by an isolated shift of the channel voltage dependence to more negative values (KV7.3) or by such a shift combined with increased maximal current levels (KV7.2, KV7.4, KV7.5). A stretch of three cysteine residues in the S2-S3 linker region of KV7.2 was necessary and sufficient to mediate these effects. The paracetamol metabolite N-acetyl-p-benzo quinone imine (NAPQI) modifies cysteine residues of KV7 subunits and reinforces channel gating in homomeric and heteromeric KV7.2 to KV7.5, but not in KV7.1 channels. In KV7.2, a triple cysteine motif located within the S2-S3 linker region mediates this reinforcement that can be expected to reduce the excitability of nociceptors and to mediate antinociceptive actions of paracetamol.

The concurrent validity and test-retest reliability of a submaximal exercise test in adolescents with autism

Purpose There is a need for valid and reliable clinical assessment tools to assess cardiorespiratory fitness (CRF) levels in adolescents with autism. Therefore, this study aimed to examine the concurrent validity and test-retest reliability of the Astrand-Rhyming Test (ART) in this population. Materials and methods 45 adolescents with autism aged 12–18 years (n = 32 males, 14.47 ± 1.79 years) performed the ART twice (test-retest reliability) and completed a maximal cardiopulmonary exercise test (CPET) (concurrent validity). Reliability parameters included Pearson correlations, intraclass correlation coefficients (ICCs), standard error of measurements (SEM), minimal detectable changes (MDC), coefficients of variation, paired sample t-tests, linear regressions and Bland-Altman plots. The concurrent validity was evaluated with Pearson correlations, ICCs, paired sample t-tests, linear regressions and Bland-Altman plots. Results Strong test-retest reliability (r = 0.84–0.85, ICC = 0.84–0.85) was found for the ART, but the wide limits of agreement intervals suggest the presence of substantial variability. The large SEM (4.73–5.08 mL/kg/min) and MDC (13.20-14.07 mL/kg/min) values suggest lower absolute reliability. Moderate to strong levels of association (r = 0.74–0.75) and agreement (ICC = 0.59–0.66) were found between estimated (ART1) and measured (CPET) VO2 max levels, but significant systematic differences (5.71–8.82 mL/kg/min) were observed. Conclusion The ART is an accessible and promising method to monitor submaximal CRF levels over time but is less appropriate to estimate maximal CRF levels in this population.

Investigation of a haze-to-dust and dust swing process at a coastal city in northern China part II: A study on the solubility of iron and manganese across aerosol sources and secondary processes

The soluble fractions of iron (FeS) and manganese (MnS) in atmospheric aerosols potentially impact human health and ocean ecosystems. This study investigated a persistent haze-to-dust process observed in winter Qingdao, a coastal city in Northern China, focusing on the aerosol sources and acidification process affecting the dissolution of Fe and Mn. It was found that FeS in PM2.5 peaked during the intermingling of dust plumes with local haze, while other species of Fe and Mn reached their maximal levels coinciding with PM10. Positive Matrix Factorization (PMF) analysis determined that aged dust was the main source of FeS in PM2.5, accounting for 44.0%, while fresh dust contributed just 1.9%. Conversely, fresh dust played a more significant role in PM10, contributing 8.9% to FeS. Similar trends were observed in the initial dust and dust swing periods, aged dust was the dominant contributor to FeS, but fresh dust accounted for a higher fraction in PM10 (11.5%) than in PM2.5 (4.9%). In contrast, MnS levels, with high solubility (%MnS), were mainly from fresh dust (27.9% and 63.2% in PM2.5 and PM10, respectively). The PMF estimated %MnS in fresh dust at 17.0% for PM2.5 and 19.4% for PM10, considerably higher than Fe solubility (%FeS) at 0.3% and 0.1% in the corresponding particulate sizes. Additionally, %FeS correlated more strongly with sulfate and nitrate per unit Fe mass (R2 = 0.68 and 0.79 in PM2.5 and PM10) than %MnS (R2 = 0.49 and 0.50), suggesting a more profound impact of acidification on Fe dissolution. Further analysis suggests liquid water content rather than pH played a more critical role during the acidification process within fine particles. This study successfully estimated the solubility of Fe and Mn within various aerosols, providing valuable information and advancing our understanding of their dissolution and potential health and ecosystem impacts.

Exceptionally high levels of total mercury in deep-sea sharks of the Southeastern Mediterranean sea over the last ∼ 40 years

Deep-sea habitats are currently recognized as a hot spot for mercury (Hg) accumulation from anthropogenic sources, resulting in elevated concentrations of total mercury (THg) in deep-sea megafauna. Among them, deep-sea sharks (Class Chondrichthyes) are characterized by high trophic position and extended longevity and are, therefore, at high risk for mercury contamination. Despite this, sharks are overexploited by fishing activity in increasingly deeper water, worldwide, imposing health risks to human consumption. While it is imperative to better understand long-term mercury contamination in deep-sea megafauna, few historical data sets exist to capture this process. Here we explore four decades (1985–2022) of THg accumulation in five species of deep-sea sharks (G. melastomus, E. spinax, S. rostratus, C. granulosus, and D. licha) of the ultra-oligotrophic Southeastern Mediterranean Sea (SEMS) sampled during 19 research cruises. We exhibited exceptionally high THg levels (per length/weight), the highest as 16.6 μg g−1 (wet wt.), almost entirely (98.9 %; n = 298 specimens) exceeding the limit for safe consumption (0.3–0.5 μg THg g−1 wet wt.). The maximal THg levels of the long-lived species D. licha and C. granulosus in the SEMS were enriched by a factor of ∼ 7 and >10 compared to counterpart species from other oceanic areas, respectively. We attribute this to the ultra-oligotrophic conditions of the SEMS, which cause slower growth rates and dwarfism in deep-sea sharks, resulting in an extended exposure time to mercury contamination. In the long-lived species, C. granulosus and D. licha, a temporal increase of average THg levels of ∼ 80 % was recorded between 1987–1999 and 2021–2022. This likely reflects the long-term accumulation of historical anthropogenic Hg in deep-sea environments, which is further amplified in marginal seas such as the Mediterranean, impacted by global air pollution crossroads and surrounded by land-based pollution sources. Future consumption of products from deep-sea sharks is potentially high risk to human health.

BIOMARKER «PEAK HEIGHT VELOCITY» AS THE INDICATOR OF SECULAR DYNAMICS OF PHYSICAL STATUS IN INTERGROUP STUDIES/COMPARISONS

Introduction. The goal of study is the estimation of «peak height velocity» (PHV) as the marker of secular trends in addition to secular dynamics of height (H). Material and methods. The study embraces the block of samples of scholars (6/7-17 years) from Russia and former USSR, examined through the vast historical period from 1920th till nowadays, literary data and personal archives of the authors. The main attention is paid to three urban agglomerations - Moscow, Nizhniy Novgorod, Minsk. The following number of parameters is determined for each sample: the age of maximal velocity of growth dynamics of average levels of H during adolescence (APHV), determined according to the empirical patterns of annual changes of average H levels and consequent smoothing by least square method - differentially for boys and girls; and delta between parameters of boys and girls; maximal quantitative level of growth changes in cm (IPHV), different for boys and girls as well, and delta between the parameters. Results. The difference of APHV between boys and girls for each population under study is about two years - boys have delayed PHV as compared to girls in any ecological niche. Secular dynamics of APHV has nonlinear character, doesn’t decrease progressively through the whole historical interval from 1920th to 2000th, despite of permanent increase of the level of anthropogenic stress in cities under analysis, the lowest APHV is fixed in 1980th. Correlations of APHV with absolute annual H values through the age interval 6/7-17 years is systematic and high enough for boys (correlation about 0,5, determination coefficient about 0,25) and accidental for girls, being revealed for only one annual age group among 12 analyzed. Correlations of IPHV with absolute values of H are maximal at 7 years and minimal at 17 years, the level of correlations is less for girls as compared to boys. Conclusion. PHV really marks the secular somatic dynamics along with H itself as genetic marker. Correlation of APHV with absolute annual levels of H through the interval 6/7-17 years is systematic and significant for boys and accidental for girls, which witness to genetic determination of growth tempo of boys. Correlation of IPHV with absolute values of H, having highest levels at 7 years, points to the fact that height at 7 years is a real trigger of PHV parameters.

Anticancer, antioxidant, and antibacterial activity of chemically fingerprinted extract from Cyclamen persicum Mill.

In the last few decades, researchers have thoroughly studied the use of plants in Palestine, one of them is Cyclamen persicum Mill. (C. persicum). Cyclamen persicum has been historically cultivated since the 1700s due to its tuber. The tuber is known to stimulate the nasal receptors, thus triggering the sensory neurons. Cyclamen persicum has anti-inflammatory effects, reduces cholesterol levels, treats diabetes, and inhibits tumor growth. In this respect, in-vitro examination of antibacterial and anticancer activities and antioxidative potency of C. persicum ethanolic extract were evaluated. The antioxidative potency of the extracted plant material was determined spectrophotometrically using the DPPH free radical scavenging method and the HPLC–PDA method to evaluate its total phenolic content (TPC) and total flavonoid content (TFC). The experimental results revealed weak antibacterial activity of C. persicum extract against both gram negative (E. coli) and gram positive (Streptococcus aureus and S. aureus) bacterial strains, with the zones of inhibition found to be less than 8 mm. On the other hand, powerful activity against MCF7 breast cancer as well as HT29 colon cancer cell lines was obtained. The findings also revealed potent inhibition of free radicals and the presence of maximal levels of natural products such as phenolic compounds and flavonoids, which supportits biological activities and powerful ability to scavenge free radicals. HPLC results showed the presence of numerous flavonoid and phenolic compounds such as rutin, chlorogenic acid, kaempferol, trans-cinnamic acid, quercetin, sinapic acid, and p-coumaric acid.

Pesticides and Polychlorinated Biphenyls in Milk and Dairy Products in Croatia: A Health Risk Assessment.

The aim of this study was to evaluate contamination levels and the frequency of detection of organochlorine (OCPs) and organophosphate pesticides (OPPs), pyrethroids, carbamates and polychlorinated biphenyls (seven PCB congeners) in a total of 534 samples of cow's, sheep's and goat's milk and dairy products from Croatia. Concentrations above the limit of quantification (LOQ) were measured for fourteen OCPs, nine OPPs, six pyrethroids, one carbamate and PCBs with a total of 172 results, and no concentrations exceeded the maximal residue levels defined by the European Union. The mean concentrations of pesticides and the sum of seven PCBs were determined in the ranges 0.92-17.4 μg/kg and 1.38-2.74 μg/kg. Pesticides were quantified in 27% of samples, and seven PCBs were quantified in 5.23% of samples. Among the three pesticide groups, the highest numbers of quantified results were found for OCPs (12.1-20.8%). The highest frequencies of detection were found for the sum of 4,4'-dichlorodiphenyltrichloroethane and its isomers (DDTs), hexachlorobenzene and seven PCBs. The sum of seven PCBs was quantified within the range of 3.3-6.67% of samples per milk type and dairy products. Among the OPPs, the highest frequency of detection was found for chlorpyrifos in cow's milk. Based on the estimated daily intakes, chronic risk characterisation showed no risk for adults or ten-year-old children for the consumption of cow's milk and dairy products.

Influence of salinity, nitrogen and phosphorus concentrations on the physiological and biochemical characteristics of two Chlorophyceae isolated from Fez freshwater, Morocco

Microalgae are widely exploited for numerous biotechnology applications, including biofuels. In this context, Chlamydomonas debaryana and Chlorococcum sp. were isolated from Fez freshwater (Morocco), and their growth and lipid and carbohydrate production were assessed at different concentrations of NaCl, NaNO3, and K2HPO4. The results indicate a small positive variation in growth parameters linked to nutrient enrichment, with no considerable variation in carbohydrate and lipid levels in both algae. Moreover, a negative variation was recorded at increased salinity and nutrient limitation, accompanied by lipid and carbohydrate accumulation. Chlorococcum sp. showed better adaptation to salt stress below 200 mM NaCl. Furthermore, its growth and biomass productivity were strongly reduced by nitrogen depletion, and its lipid production reached 47.64% DW at 3.52 mM NaNO3. As for Chlamydomonas debaryana, a substantial reduction in growth was induced by nutrient depletion, a maximal carbohydrate level was produced at less than 8.82 mM NaNO3 (40.59% DW). The effect of phosphorus was less significant. However, a concentration of 0.115 mM K2HPO4 increased lipid and carbohydrate content without compromising biomass productivity. The results suggest that growing the two Chlorophyceae under these conditions seems interesting for biofuel production, but the loss of biomass requires a more efficient strategy to maximize lipid and carbohydrate accumulation without loss of productivity.

Diagnostic capabilities of PET/CT with &lt;sup&gt;18&lt;/sup&gt;F-DOPA in biochemical recurrence of medullary thyroid carcinoma: a retrospective study

INTRODUCTION: Medullary thyroid carcinoma (MTС) is a rare neuroendocrine malignant neoplasm of the thyroid gland. In most cases, sporadic MTС is diagnosed at late stages due to the absence of specific symptoms. The main method of treatment of MTС is surgical — thyroidectomy and in most cases cervical lymphodissection. Current international guidelines suggest the use of basal calcitonin levels and cancer embryonic antigen (CEA) as markers of biochemical recurrence. In biochemical recurrence of the disease, it is advisable to search for tumor foci regardless of the level of cancer markers. Positron emission tomography combined with computed tomography (PET/CT) has the highest sensitivity and specificity for searching for local recurrence and distant metastases. Anatomical imaging methods (computed tomography (CT), magnetic resonance imaging (MRI)) have suboptimal sensitivity and specificity in detection of a recurrent tumor.OBJECTIVE: To explore the diagnostic capabilities of PET/CT with 18F-DOPA in patients with biochemical recurrence of medullary thyroid carcinoma, depending on the concentration of calcitonin in blood plasma.MATERIALS AND METHODS: To evaluate the diagnostic capabilities of PET/CT with 18F-DOPA in patients with biochemical recurrence of medullary thyroid carcinoma, 81 PET/CT studies were analyzed in patients after thyroidectomy. In most cases (76/81), at the time of the study, patients had elevated basal calcitonin levels (&gt;10 pg/ml, including in 52/81 cases &gt;150 pg/ml), which corresponded to a biochemical recurrence of the disease. In 6 cases, the calcitonin level was &lt;10 pg/ml. PET/CT results were processed by visual image analysis, measurement of a semi-quantitative indicator of the maximal standardized level of radiopharmaceutical accumulation normalized to lean body mass (SUVlbm max) and the total volume of PET-positive tumor tissue (metabolic tumor volume).RESULTS: In 41 studies, foci of pathological accumulation of 18F-DOPA were identified, corresponding to recurrent tumor foci. DOPA-negative results in patients with elevated calcitonin levels were regarded as false negative. The highest sensitivity of the method was achieved at calcitonin levels &gt;150 pg/ml. A noticeable positive correlation was found between the concentration of basal serum calcitonin, the number of pathological foci of 18F-DOPA hyperaccumulation and the total metabolic volume of tumor tissue. In most cases of biochemical recurrence, the PET method was superior to the CT method in detecting recurrent tumor foci.CONCLUSION: PET/CT with 18F-DOPA is the most informative method for molecular and structural imaging in patients with biochemical recurrence of medullary thyroid carcinoma. The results of the study directly correlate with the level of basal calcitonin in the blood.

Differential expression of neuropeptide F in the digestive organs of female freshwater prawn, Macrobrachium rosenbergii, during the ovarian cycle.

Neuropeptide F is a key hormone that controls feeding in invertebrates, including decapod crustaceans. We investigated the differential expression of Macrobrachium rosenbergii neuropeptide F (MrNPF) in the digestive organs of female prawns, M. rosenbergii, during the ovarian cycle. By using RT-qPCR, the expression of MrNPF mRNA in the esophagus (ESO), cardia (CD), and pylorus (PY) of the foregut (FG) gradually increased from stage II and peaked at stage III. In the midgut (MG), hindgut (HG), and hepatopancreas (HP), MrNPF mRNA increased from stage I, reaching a maximal level at stage II, and declined by about half at stages III and IV (P < 0.05). In the ESO, CD, and PY, strong MrNPF-immunoreactivities were seen in the epithelium, muscle, and lamina propria. Intense MrNPF-ir was found in the MG cells and the muscular layer. In the HG, MrNPF-ir was detected in the epithelium of the villi and gland regions, while MrNPF-ir was also more intense in the F-, R-, and B-cells in the HP. However, we found little colocalization between the MrNPF and PGP9.5/ChAT in digestive tissues, implying that most of the positive cells might not be neurons but could be digestive tract-associated endocrine cells that produce and secrete MrNPF to control digestive organ functions in feeding and utilizing feed. Taken together, our first findings indicated that MrNPF was differentially expressed in digestive organs in correlation with the ovarian cycle, suggesting an important link between MrNPF, the physiology of various digestive organs in feeding, and possibly ovarian maturation in female M. rosenbergii.

Stronger together: towards constructive conversations about strength differences, gender, and sex

ABSTRACT The differences in strength development processes and maximum strength levels between cisgender men and women – i.e. the ‘strength gap’ – are considerably fraught topics, with significant implications for our broader understandings of sex and gender. The polarization of exercise science and sociocultural research about the relationships between strength, gender, and sex adds further challenges. As a result of their highly diverging conclusions on the strength gap as well as the general absence of communication between the two fields, it becomes nearly impossible to have meaningful discussions that acknowledge the not-just-biological, not-just-cultural complexities of strength development and maximal strength levels. To aid in connecting these seemingly disparate academic fields, this paper engages a biocultural reading of research on the strength training body. By framing the body as the ever-developing result of inextricably intertwined biological and cultural influences, this critical reading outlines the limitations of our current understandings of strength, illuminates areas of complexity and contradiction, demonstrates shared concepts, and suggests possible topics for boundary-crossing inquiry.

On the detection, modeling, and mitigation of anomalous QoT fluctuations in optical networks

Monitoring data from deployed backbone networks shows that many lightpaths present large fluctuations of their quality of transmission (QoT), beyond 1 dB in range. In this paper, we investigate the hypothesis that the evidenced fluctuations stem from anomalies in polarization-dependent loss (PDL), equivalent to one large PDL element. We eventually propose and experimentally test a closed-loop automation designed to stabilize the QoT at a maximal level for lightpaths impaired by such a PDL anomaly.