Search Results (30)

This study intends to portray how varying degrees of environmental policy stringency and the growing pressure of global competition reflect on high-tech (HT) sectors’ cost rationalization strategies and lead to environmental consequences in 15 G20 countries (1992–2019). Moreover, we center the pattern of cost rationalization management regarding the opportunity cost of ecosystem service consumption and propose to test the fundamental hypothesis stating the possible transmission of competition-induced technological innovations to green economic transformation. Our new methodology estimates quantile-specific effects with MM-QR, while identifying the main interaction effects between regulatory pressure and trade competition uses an extended STIRPAT model. The results reveal a paradoxical finding: despite higher environmental policy stringency and opportunity costs of ecosystem services, HT sectors persistently adopt environmentally detrimental cost-reduction approaches. These findings carry important policy implications: (1) environmental regulations for HT sectors require complementary innovation subsidies, (2) trade agreements should incorporate clean technology transfer clauses, and (3) governments must monitor sectoral emission leakage risks. Our dual machine learning–econometric approach provides policymakers with targeted insights for different emission scenarios, highlighting the need for differentiated strategies across clean and polluting HT subsectors. Full article

Background: The isolated rectus femoris tendon (RT) is a less commonly used autograft for anterior cruciate ligament (ACL) reconstruction. Graft selection is a critical part of ACL reconstruction, especially in revision surgery. Hypothesis: This study compares patient-reported outcome measurements (PROMs) between revision ACL reconstruction with an RT autograft and a hamstring tendon (HT) autograft. We hypothesized that the RT autograft will yield comparable functional results and high patient satisfaction. Study Design: This was a cohort study; the level of evidence is III. Methods: Fifty-five patients (RT n = 28; HT n = 27) who underwent revision ACL reconstruction were included in this study, with a mean follow-up time of 40.3 months (range, 16.4–64.8) for RT and 61.2 months (range, 34.6–86.3) for HT. Apart from the harvesting technique, the surgical technique was the same for both groups. Clinical and intraoperative data were collected for our postoperative registry. In addition, funcinal outcome was measured using the International Knee Documentation Committee score (IKDC), the Lysholm score, Tegner activity scale, and numeric rating scale (NRS). The type and frequency of postoperative complications were documented. Results: At the final follow-up, no significant differences were observed between the RT and HT groups in the IKDC (mean ± SD: 74.7 ± 10.9 vs. 74.9 ± 12.9), Lysholm score (90.9 ± 15.0 vs. 89.0 ± 14.6), or Tegner activity scale (median [IQR]: 5 [4–6] vs. 5 [4–6]). The mean femoral tunnel diameter was 9.0 mm (range, 7.5–10 mm) for the RT and 8.2 mm (range 7.0–9.5 mm) for the HT. The use of the RT reduced the need for a two-stage procedure by 50% compared to HT (n = 5 vs. n = 10), although this difference was not statistically significant (p = 0.11). Stability measured by the Lachman test improved significantly in both groups from the pre- to postoperative period. Retear of the ACL graft was observed in two patients in both groups (7.1% RT and 7.4% HT). Conclusions: The RT and HT autografts achieved similar outcomes in PROMs for revision ACL reconstruction. Good tendon quality with parallel fibers and adjustable thickness characterize the RT. A tendency for a reduced rate of two-stage surgery with RT was noticed. Clinical Relevance: The incidence of revision ACL reconstruction is rising. Surgeons should be aware of all the available graft options. The isolated RT expands the range of autografts available for ACL reconstruction. Full article

Agmatine is a naturally occurring biogenic amine that acts primarily as an inhibitor of neuronal nitric oxide synthase (nNOS). Previous studies have shown that both acute and chronic agmatine administration induced anxiolytic and antidepressant-like effects in rodents. In the dorsal raphe nucleus (DRN), nitric oxide (NO) donors inhibit serotonergic (5-HT) neuronal activity, with the nNOS-expressing 5-HT neurons showing lower baseline firing rates than the non-nNOS expressing neurons. Our study aimed to test the hypothesis that the psychoactive effects of agmatine are mediated, at least in part, via a mechanism involving the stimulation of the DRN 5-HT neurons, as well as to assess the molecular pathway allowing agmatine to modulate the excitability of 5-HT neurons. Using extracellular in vivo electrophysiology, we demonstrated that both acute (1–3 mg/kg, i.v.) and chronic (40 mg/kg/day, i.p., 14 days) agmatine administration significantly increased the firing rate of DRN 5-HT neurons. Quantitative PCR (qPCR) analysis revealed that chronic agmatine treatment selectively upregulated the expression of serotonin-1B (5-HT_1B) and serotonin-2A (5-HT_2A) receptor mRNA in the DRN. Previous studies have shown that DRN 5-HT_2A receptor activation stimulates 5-HT neurons and produces antidepressant-like effects; our findings suggest that agmatine’s excitatory effect on DRN 5-HT neurons may be partially 5-HT_2A receptor-dependent. Given that modulation of the 5-HT neuronal firing activity is critical for the proper antidepressant efficacy, nNOS inhibitors can be potential antidepressants by their own and/or effective adjuncts to other antidepressant drugs. Full article

Accumulation of evidence highlighted the crosstalk between DNA damage repair and the immune system. Herein, we tested the hypothesis that in head and neck squamous cell carcinoma (HNSCC), the DNA repair capacity of patients’ PBMCs correlates with therapeutic response to immune checkpoint blockade. Following in vitro UVC irradiation, oxidative stress, apurinic/apyrimidinic (AP) lesions, endogenous/baseline DNA damage, and DNA damage repair efficiency were evaluated in three HNSCC (UM-SCC-11A, Cal-33, BB49) and two normal cell lines (RPMI-1788, 1BR-3h-T), as well as in peripheral blood mononuclear cells (PBMCs) from 15 healthy controls (HC) and 49 recurrent/metastatic HNSCC patients at baseline (8 responders, 41 non-responders to subsequent nivolumab therapy). HNSCC cell lines showed lower DNA repair efficiency, increased oxidative stress, and higher AP sites than normal ones (all p < 0.001). Moreover, patients’ PBMCs exhibited increased endogenous/baseline DNA damage, decreased DNA repair capacity, augmented oxidative stress, and higher AP sites than PBMCs from HC (all p < 0.001). Importantly, PBMCs from responders to nivolumab therapy showed lower endogenous/baseline DNA damage, higher DNA repair capacities, decreased oxidative stress, and reduced AP sites than non-responders (all p < 0.05). Together, we demonstrated that oxidative stress status and DNA repair efficiency in PBMCs from HNSCC patients are correlated with the response to immune checkpoint blockade. Full article

Background/Objectives: After anterior cruciate ligament reconstruction (ACLR), a 6-month composite test is recommended during rehabilitation before the return to sport, and the influence of a meniscal tear is not known. The hypothesis was that the location and treatment of meniscus injuries could influence the results of the composite test. Methods: A retrospective single-center study was carried out of prospectively collected data involving 504 patients who performed a composite test 6 months after ACLR. Isolated ACLR was compared to ACLR with medial meniscus injuries (MM), lateral meniscus injuries (LM), and bimeniscal injuries (BM) using a composite test including a single-leg squat (SLS), a single-leg landing (SLL), a single hop for distance (SHD), a triple hop for distance (THD) and a side-hop test (Side-HT), isokinetic strength tests, and an assessment of the anterior cruciate ligament—return to sport after injury (ACL-RSI). Results: Compared with isolated ACLR, MM injury was associated with a quadricipital deficit at a velocity of 240°/s (14% ± 14% vs. 18% ± 18%, p = 0.02), hamstring deficit at 30°/s (14% ± 18% vs. 18% ± 18%, p = 0.02) and an increase in the hamstring/quadricipital ratio at 240°/s (68% ± 27% vs. 80% ± 67% p = 0.02). Furthermore, ACLR + MM or ML injuries in the operated knee generated an increase in the dynamic valgus frequency detected by the SLS, respectively (40% ± 49% vs. 51% ± 50%, p = 0. 05) and (40% ± 49% vs. 54% ± 50%, p = 0.02). Meniscal repair and meniscectomies showed no differences. Conclusions: These results show that meniscal injuries lead to muscle imbalance for MM injuries and impaired neuromuscular control for MM and LM injuries and suggest that meniscal repairs should be done. Moreover, rehabilitation must be adapted to meniscus injuries. Full article

Toxigenic fungi are among the most significant disease-causing agents in wheat. DON is the most common Fusarium mycotoxin, and for a long time, it was the only toxin researched. However, multitoxin data from wheat samples have drawn attention to the fact that much more toxins can be involved in the wheat toxin story than we supposed earlier. For resistance breeding, we need a more detailed approach to identify toxins that occur above the limit and identify the source of the fungal species that produces them. This study analyzed local wheat varieties for fungal infections and natural multitoxin contamination. Eighteen winter wheat genotypes were tested for fungal contaminations across three different locations in 2021 and 2022. Fourteen different mycotoxins—deoxynivalenol, aflatoxins (B1, B2, G1, and G2), fumonisins (B1 and B2), sterigmatocystin, ochratoxin A, zearalenone, T-2, HT-2, and diacetoxyscirpenol—were analyzed using HPLC/triple-quad MS. Toxigenic species such as Fusarium, Aspergillus, and Penicillium had low rates of occurrence, but the toxin contamination was often surprisingly high. Many samples without corresponding fungal infections were also identified as containing mycotoxins. Therefore, the identified fungal infection is less useful for forecasting toxin level. In conclusion, mycotoxin contamination is decisive. Most samples were contaminated by one or more mycotoxins. Although the mycotoxin concentrations typically remained below EU limits, some samples exhibited higher levels, particularly aflatoxins and Ht-2 toxin. Significant variations were observed across year, location, and genotype. For several toxins, significant genotype differences were identified, supporting the hypothesis that resistance may be a useful and suitable control measure. Stability of toxin contamination across years and locations is a very valuable trait; genotypes were identified with low toxin levels and stability (low variance) to all mycotoxins tested. It seems that, in addition to DON, more attention should be given to aflatoxin B1, B2, and G1, which provided similar concentrations. The HT-2 toxin was present in many samples surpassing EU limits. This is the first report on the dangerous occurrence of preharvest-origin aflatoxins and the HT-2 toxin of wheat in Hungary. Full article

Tegaserod (1-{[(5-methoxy-1H-indol-3-yl)methyliden]amino}-3-pentylguanidine) is a potent agonist at human recombinant 5-HT₄ serotonin receptors. Consequently, tegaserod is utilized in the treatment of bowel diseases. The objective of this study was to test the hypothesis that tegaserod stimulates human cardiac atrial 5-HT₄-receptors via cyclic adenosine monophosphate (cAMP)-dependent pathways. Tegaserod exerted positive inotropic effects (PIEs) and positive chronotropic effects (PCEs) in isolated left and right atrial preparations, respectively, from mice with cardiac-specific overexpression of the human 5-HT₄ serotonin receptor (5-HT₄-TG) in a concentration- and time-dependent manner. However, no effect was observed in the hearts of littermates of wild-type mice (WT). Western blot analysis revealed that the expression of 5-HT₄ receptors was significantly higher in 5-HT₄-TG mice compared to WT mice. The specificity of the signal for the 5-HT₄ receptor was confirmed by the absence of the signal in the hearts of 5-HT₄ receptor knockout mice. Furthermore, tegaserod increased the force of contraction (at concentrations as low as 10 nM), reduced the time of tension relaxation, and increased the rate of tension development in isolated electrically stimulated (at a rate of 60 beats per minute) human right atrial preparations (HAPs, obtained during open-heart surgery) when administered alone. The potency and efficacy of tegaserod to raise the force of contraction were enhanced in the presence of cilostamide, a phosphodiesterase III inhibitor. The positive inotropic effect of tegaserod in HAPs was found to be attenuated by the 5-HT₄ serotonin receptor antagonist GR 125487 (0.1 µM). The efficacy of tegaserod (10 µM) in raising the force of contraction in HAPs was less pronounced than that of serotonin (10 µM) or isoprenaline (1 µM). Tegaserod shifted the concentration–response curve of the force of contraction to serotonin to the right in HAPs, indicating that it is a partial agonist at 5-HT₄ serotonin receptors in this model. We propose that the mechanism of action of tegaserod in HAPs involves cAMP-dependent phosphorylation of cardiac regulatory proteins. Full article

A central challenge in hypothesis testing (HT) lies in determining the optimal balance between Type I (false positive) and Type II (non-detection or false negative) error probabilities. Analyzing these errors’ exponential rate of convergence, known as error exponents, provides crucial insights into system performance. Error exponents offer a lens through which we can understand how operational restrictions, such as resource constraints and impairments in communications, affect the accuracy of distributed inference in networked systems. This survey presents a comprehensive review of key results in HT, from the foundational Stein’s Lemma to recent advancements in distributed HT, all unified through the framework of error exponents. We explore asymptotic and non-asymptotic results, highlighting their implications for designing robust and efficient networked systems, such as event detection through lossy wireless sensor monitoring networks, collective perception-based object detection in vehicular environments, and clock synchronization in distributed environments, among others. We show that understanding the role of error exponents provides a valuable tool for optimizing decision-making and improving the reliability of networked systems. Full article

The No Free Lunch Theorem tells us that no algorithm can beat other algorithms on all types of problems. The algorithm selection structure is proposed to select the most suitable algorithm from a set of algorithms for an unknown optimization problem. This paper introduces an innovative algorithm selection approach called the CNN-HT, which is a two-stage algorithm selection framework. In the first stage, a Convolutional Neural Network (CNN) is employed to classify problems. In the second stage, the Hypothesis Testing (HT) technique is used to suggest the best-performing algorithm based on the statistical analysis of the performance metric of algorithms that address various problem categories. The two-stage approach can adapt to different algorithm combinations without the need to retrain the entire model, and modifications can be made in the second stage only, which is an improvement of one-stage approaches. To provide a more general structure for the classification model, we adopt Exploratory Landscape Analysis (ELA) features of the problem as input and utilize feature selection techniques to reduce the redundant ones. In problem classification, the average accuracy of classifying problems using CNN is 96%, which demonstrates the advantages of CNN compared to Random Forest and Support Vector Machines. After feature selection, the accuracy increases to 98.8%, further improving the classification performance while reducing the computational cost. This demonstrates the effectiveness of the first stage of the CNN-HT method, which provides a basis for algorithm selection. In the experiments, CNN-HT shows the advantages of the second stage algorithm as well as good performance with better average rankings in different algorithm combinations compared to the individual algorithms and another algorithm combination approach. Full article

Increasing dietary fiber consumption is linked to lower colon cancer incidence, and this anticancer effect is tied to elevated levels of short-chain fatty acids (e.g., butyrate) because of the fermentation of fiber by colonic bacteria. While butyrate inhibits cancer cell proliferation, the impact on cancer cell type remains largely unknown. To test the hypothesis that butyrate displays different inhibitory potentials due to cancer cell type, we determined half-maximal inhibitory concentrations (IC₅₀) of butyrate in HCT116, HT-29, and Caco-2 human colon cancer cell proliferation at 24, 48, and 72 h. The IC₅₀ (mM) butyrate concentrations of HCT116, HT-29, and Caco-2 cells were [24 h, 1.14; 48 h, 0.83; 72 h, 0.86], [24 h, N/D; 48 h, 2.42; 72 h, 2.15], and [24 h, N/D; 48 h, N/D; 72 h, 2.15], respectively. At the molecular level, phosphorylated ERK1/2 and c-Myc survival signals were decreased by (>30%) in HCT116, HT-29, and Caco-2 cells treated with 4 mM butyrate. Conversely, butyrate displayed a stronger potential (>1-fold) for inducing apoptosis and nuclear p21 tumor suppressor in HCT116 cells compared to HT-29 and Caco-2 cells. Moreover, survival analysis demonstrated that a cohort with high p21 gene expression in their colon tissue significantly increased survival time compared to a low-p21-expression cohort of colon cancer patients. Collectively, the inhibitory efficacy of butyrate is cell type-specific and apoptosis-dependent. Full article

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT_2A receptor (5-HT_2AR) in mice. In that regard, we used male and female, 5-HT_2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT_2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT_2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT_2AR blunted noribo-mediated responses to NMDA synaptic transmission. Full article

Quaternary ammonium surfactants, due to their diverse chemical structure and their biological properties, can be used in medicine as DNA carriers, disinfectants, and antimicrobial and antitumor agents. In this study, using melanoma A375, colon adenocarcinoma HT-29 and normal human dermal fibroblast (NHDF) cells, we tested the hypothesis that the quaternary ammonium surfactants 2-dodecanoyloxyethyl)trimethylammonium bromide (DMM-11), 2-dodecanoyloxypropyl)trimethylammonium bromide (DMPM-11) and 2-pentadecanoyloxymethyl)trimethylammonium bromide (DMGM-14) act selectively against cancer cells. The results showed that these compounds led to the initiation of the apoptotic process of programmed cell death, as evidenced by the ratio of the relative expression of Bax protein to Bcl-2. The encapsulation of surfactants in liposomes allowed lower concentrations to be used. Moreover, encapsulation reduced their toxicity towards non-cancerous cells. The anticancer efficiency and apoptotic effect of the liposomal formulations with surfactants (DMM-11, DMPM-11 and DMGM-14) were higher than those of surfactant-free liposomes. Therefore, quaternary ammonium surfactant-loaded liposomes show significant potential as delivery vehicles for the treatment of melanoma and colon cancers. The use of nano-formulations offers the advantage of optimizing quaternary ammonium surfactant delivery for improved anticancer therapy. Full article

Serotonin 1A (5-HT1A) autoreceptors located on serotonin neurons inhibit their activity, and their upregulation has been implicated in depression, suicide and resistance to antidepressant treatment. Conversely, post-synaptic 5-HT1A heteroreceptors are important for antidepressant response. The transcription factor deformed epidermal autoregulatory factor 1 (Deaf1) acts as a presynaptic repressor and postsynaptic enhancer of 5-HT1A transcription, but the mechanism is unclear. Because Deaf1 interacts with and is phosphorylated by glycogen synthase kinase 3β (GSK3β)—a constitutively active protein kinase that is inhibited by the mood stabilizer lithium at therapeutic concentrations—we investigated the role of GSK3β in Deaf1 regulation of human 5-HT1A transcription. In 5-HT1A promoter-reporter assays, human HEK293 kidney and 5-HT1A-expressing SKN-SH neuroblastoma cells, transfection of Deaf1 reduced 5-HT1A promoter activity by ~45%. To identify potential GSK3β site(s) on Deaf1, point mutations of known and predicted phosphorylation sites on Deaf1 were tested. Deaf1 repressor function was not affected by any of the mutants tested except the Y300F mutant, which augmented Deaf1 repression. Both lithium and the selective GSK3 inhibitors CHIR-99021 and AR-014418 attenuated and reversed Deaf1 repression compared to vector. This inhibition was at concentrations that maximally inhibit GSK3β activity as detected by the GSK3β-sensitive TCF/LEF reporter construct. Our results support the hypothesis that GSK3β regulates the activity of Deaf1 to repress 5-HT1A transcription and provide a potential mechanism for actions of GSK3 inhibitors on behavior. Full article

Breast cancer is a frequent disease for which the discovery of markers that enable early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops that are produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated co-transcriptionally, and backsplicing and linear splicing compete against each other. As mRNAs are key players in tumorigenesis, we hypothesize that a disruption of the balance between circRNAs and mRNAs could promote breast cancer. Hence, we developed an assay for a simultaneous study of circRNAs and mRNAs, which we have called splice and expression analyses by exon ligation and high-throughput sequencing (SEALigHTS). Following SEALigHTS validation for BRCA1 and BRCA2, our hypothesis was tested using an independent research set of 95 pairs from tumor and adjacent normal breast tissues. In this research set, ratios of BRCA1 and BRCA2 circRNAs/mRNAs were significantly lower in the tumor breast tissue compared to normal tissue (p = 1.6 × 10⁻⁹ and p = 4.4 × 10⁻⁵ for BRCA1 and BRCA2, respectively). Overall, we developed an innovative method to study linear splicing and backsplicing, described the repertoire of BRCA1 and BRCA2 circRNAs, including 15 novel ones, and showed for the first time that a disequilibrium between BRCA1 and BRCA2 circRNAs and mRNAs plays a role in breast cancer. Full article

During mouse pregnancy placental lactogens stimulate prolactin receptors on pancreatic islet beta cells to induce expression of the tryptophan hydroxylase Tph1, resulting in the synthesis and secretion of serotonin. Presently, the functional relevance of this phenomenon is unclear. One hypothesis is that serotonin-induced activation of 5-HT_2B receptors on beta cells stimulates beta cell proliferation during pregnancy. We tested this hypothesis via three different mouse models: (i) total Tph1KO mice, (ii) 129P2/OlaHsd mice, which are incompetent to upregulate islet Tph1 during pregnancy, whereas Tph1 is normally expressed in the intestine, mammary glands, and placenta, and (iii) Htr2b-deficient mice. We observed normal pregnancy-induced levels of beta cell proliferation in total Tph1KO mice, 129P2/OlaHsd mice, and in Htr2b^−/− mice. The three studied mouse models indicate that islet serotonin production and its signaling via 5-HT_2B receptors are not required for the wave of beta cell proliferation that occurs during normal mouse pregnancy. Full article