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Abstract The ability of serum biomarkers to predict the prognosis and response to deep-brain stimulation (DBS) therapy in Parkinson’s disease (PD) patients is promising. Here, we showed that NfL differed between healthy individuals and PD patients and that changes in NfL, GFAP, and BDNF occurred only transiently after DBS surgery. Therefore, subthalamic stimulation does not promote neurodegeneration, and these biomarkers do not serve as clinical improvement endpoints in PD DBS patients.

Abstract The incorporation of digital pathology in clinical practice will require the training of pathologists in digital skills. Our study aimed to assess the reliability among pathologists in determining tumor percentage in whole slide images (WSI) of non-small cell lung cancer (NSCLC) using digital image analysis, and study how the results correlate with the molecular findings. Pathologists from nine centers were trained to quantify epithelial tumor cells, tumor-associated stromal cells, and non-neoplastic cells from NSCLC WSI using QuPath. Then, we conducted two consecutive ring trials. In the first trial, analyzing four WSI, reliability between pathologists in the assessment of tumor cell percentage was poor (intraclass correlation coefficient (ICC) 0.09). After performing the first ring trial pathologists received feedback. The second trial, comprising 10 WSI with paired next-generation sequencing results, also showed poor reliability (ICC 0.24). Cases near the recommended 20% visual threshold for molecular techniques exhibited higher values with digital analysis. In the second ring trial reliability slightly improved and human errors were reduced from 5.6% to 1.25%. Most discrepancies arose from subjective tasks, such as the annotation process, suggesting potential improvement with future artificial intelligence solutions.

Abstract Chronic liver disease is closely linked to dietary intake factors, such as high consumption of simple carbohydrates including sucrose. In this study, the influence of sucrose on the development of hepatocellular carcinoma (HCC), the most common primary liver malignancy, was explored. Using the hepatocarcinogen diethylnitrosamine (DEN) to induce HCC in the rat, we co-administered sucrose with DEN. The co-administration significantly modified body, liver and pancreas weight, as well as, serum fatty acids and triglycerides. DEN caused liver structural alteration, fibrosis, and tumor formation; surprisingly, co-administration with sucrose restored hepatic lipids, improved liver architecture, and reduced fibrosis and tumor development. Sucrose intake negatively regulated tumor markers and cell proliferation, and reduced the expression of genes associated with lipid metabolism and oxidative stress response. These findings highlight a hepatoprotective effect of sucrose during DEN-induced hepatocarcinogenesis, underlining an intriguing role of high sucrose consumption during HCC development and providing new insights as well as possible pathways of cellular protection under sucrose intake on hepatocarcinogenesis.

Abstract Background A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. Methods Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. Results Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. Conclusions This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

This study sought to examine the impact of negative photoperiod on the incidence of multiple ovulations and pregnancies in dairy cattle. The study population consisted of 5,373 pregnant cows in their third or greater lactation that experienced their first post-partum pregnancy after spontaneous estrus. The positive photoperiod (increasing day-length) extends from December 22 to June 21, whereas the negative photoperiod (decreasing day-length) extends from June 22 to December 21. The odds ratios (ORs) for multiple ovulations and pregnancies in cows that became pregnant during the negative photoperiod and the remaining cows that became pregnant during the positive photoperiod were 1.4 and 1.3 (P < 0.0001), respectively. The ORs for cows that became pregnant ≥ 90 days in milk and the remaining cows that became pregnant < 90 days in milk were 4.3 and 4.1 (P < 0.0001), respectively. No significant differences were detected in the monthly rates of multiple ovulations or pregnancies during positive and negative photoperiods. Thus, the present study demonstrates that the ovarian function in cows is related to changes in day-length, with decreasing day-length being associated with greater multiple ovulation and pregnancy rates. The present study also shows that positive and negative photoperiods exhibit different trends. The results of this study are consistent with a growing body of work demonstrating the effects of photoperiod patterns on the reproductive physiology of cows, with clear implications for twin pregnancy prevention.

Dairy cattle have played an important role in economic development since the beginning of agriculture [...]

Persistent HGF/Met signaling drives tumor growth and dissemination. Proteoglycans within the tumor microenvironment might control HGF availability and signaling by affecting its accessibility to Met (HGF receptor), likely defining whether acute or sustained HGF/Met signaling cues take place. Given that betaglycan (BG, also known as type III TGFβ receptor or TGFBR3), a multi-faceted proteoglycan TGFβ co-receptor, can be found within the tumor microenvironment, we addressed its hypothetical role in oncogenic HGF signaling. We found that HGF/Met promotes lung cancer and endothelial cells migration via PI3K and mTOR. This effect was enhanced by recombinant soluble betaglycan (solBG) via a mechanism attributable to its glycosaminoglycan chains, as a mutant without them did not modulate HGF effects. Moreover, soluble betaglycan extended the effect of HGF-induced phosphorylation of Met, Akt, and Erk, and membrane recruitment of the RhoGEF P-Rex1. Data-mining analysis of lung cancer patient datasets revealed a significant correlation between high MET receptor, HGF, and PREX1 expression and reduced patient survival. Soluble betaglycan showed biochemical interaction with HGF and, together, they increased tumor growth in immunocompetent mice. In conclusion, the oncogenic properties of the HGF/Met pathway are enhanced and sustained by GAG-containing soluble betaglycan.

Objective:. To evaluate the feasibility, safety, and effectiveness of gastric conditioning using preoperative arterial embolization (PAE) before McKeown esophagectomy at a tertiary university hospital. Background:. Cervical anastomotic leakage (AL) is a common complication of esophagectomy. Limited clinical evidence suggests that gastric conditioning mitigates this risk. Methods:. This pilot randomized clinical trial was conducted between April 2016 and October 2021 at a single-center tertiary hospital. Eligible patients with resectable malignant esophageal tumors, suitable for cervical esophagogastrostomy, were randomized into 2 groups: one receiving PAE and the other standard treatment. The primary endpoints were PAE-related complications and incidence of cervical AL. Results:. The study enrolled 40 eligible patients. PAE-related morbidity was 10%, with no Clavien-Dindo grade III complications. Cervical AL rates were similar between the groups (35% vs 25%, P = 0.49), even when conduit necrosis was included (35% vs 35%, P = 1). However, AL severity, including conduit necrosis, was higher in the control group according to the Clavien-Dindo ≥IIIb (5% vs 30%, P = 0.029) and Comprehensive Complication Index (20.9 vs 33.7, P = 0.01). No significant differences were found in other postoperative complications, such as pneumonia or postoperative mortality. Conclusions:. PAE is a feasible and safe method for gastric conditioning before McKeown minimally invasive esophagectomy and shows promise for preventing severe AL. However, further studies are required to confirm its efficacy.

Abstract This study aimed to estimate the prevalence of alterations in self-perceived mental health during the COVID-19 pandemic and their associated factors in four Latin American countries. This is a cross-sectional study based on data collected from adults in 2021 through the Collaborative Response COVID-19 Survey by the MacDonnell Academy at Washington University in St. Louis (United States). The sample was composed of 8,125 individuals from Brazil, Colombia, Mexico, and Chile. A generalized linear model for a binary outcome variable with a logistic link and fixed country effects was used. There were 2,336 (28.75%) individuals who considered having suffered alterations in self-perceived mental health. Unemployed individuals (OR = 1.40; 95%CI: 1.24-1.58), those with bad/regular quality of life (OR = 5.03; 95%CI: 4.01-6.31), and those with high socioeconomic status (OR = 1.66; 95%CI: 1.41-1.96) had a higher risk of self-perceived mental health alterations than those with full-time employment, excellent quality, and low socioeconomic status. According to the fixed-effects model, Brazilians living in the country during the pandemic, who disagreed with their government’s decisions (OR = 2.05; 95%CI: 1.74-2.42) and lacked trust in their government (OR = 2.10; 95%CI: 1.74-2.42) had a higher risk of having self-perceived mental health alterations. Nearly 30% of respondents indicated that the COVID-19 pandemic altered their self-perceived mental health. This outcome was associated with political, sociodemographic, and health risk factors. These findings should help policymakers develop post-pandemic community interventions.

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [Au(dpta)Cl2, Au(dpta)(mrdtc), and Au(dpta)(dedtc)] or thiophosphonamide [Au(bpta)(dedtc)] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity.

This study aims to understand and simulate the mechanical properties of concrete, focusing specifically on the mesoscopic scale and its relation to the macro scale. Investigating concrete at this level involves examining its composition as a heterogeneous amalgamation of mortar, aggregates, and the Interfacial Transition Zone (ITZ). Numerical models, utilizing the finite element method (FEM), are employed to thoroughly examine the structural behavior of concrete. The study uses MATLAB (2023a) programming to develop three-dimensional models, which are then subjected to FEM analysis. Various mesoscopic Representative Volume Elements (RVEs) are formulated, considering spherical aggregates with different locations and dimensions to capture the complex nature of concrete. MATLAB is used to generate files containing comprehensive information about the RVEs, which are then processed with FEM to simulate compression strength tests. As the complexity increases with the inclusion of the ITZ, prismatic RVEs are developed to better represent real-world conditions. The proposed mesoscopic model establishes a foundational framework for a numerical simulation methodology tailored to laboratory compression tests, bridging the gap between mesoscopic and macroscopic scales. This approach provides detailed insights into concrete behavior, elucidating deformation and fracture mechanisms. Although not a complete substitute for experimental methods, these models offer a cost-effective and efficient alternative, identifying vulnerable areas and exploring the effects of additional materials on concrete behavior. The progressive replacement of laboratory tests with numerical simulations using RVEs of specific compositions will make the study of concrete behavior at the mesoscopic scale increasingly sustainable, paving the way for more efficient and environmentally friendly research practices in the field.

Context: Marine organisms are sources of compounds with anti-inflammatory activity, many of them derived from the secondary metabolites produced by microorganisms. Aims: To evaluate the possible anti-inflammatory effect of M116, an extract obtained by fermentation from the CBM-116 strain of the marine bacterium Bacillus amyloliquefaciens, which was isolated from sediments of the southern coast of the Cuban shelf. Methods: The oral single and repeated different doses of the CBM-116 were evaluated for their ability to ameliorate edema using two in vivo experimental inflammation models: croton oil-induced atrial acute edema and cotton pellets-induced chronic granuloma, both in male Balb/c mice. The systemic production of redox biomarkers after repeated doses in the chronic inflammation model was also tested. Results: A single application of M116 (50-200 mg/kg, 10 mL/kg, p.o.) decreases croton oil-induced acute inflammation in a dose-dependent manner. Single and repeated doses of extract (100-400 mg/kg, p.o.) also were able to inhibit chronic inflammation during both, transudative and proliferative phases of the inflammatory process. This effect was associated with the systemic reduction of oxidative stress. Conclusions: M116 showed anti-inflammatory activity in the context of acute and chronic inflammation associated with its antioxidant mechanisms, which suggest the potential of the marine bacterium Bacillus amyloliquefaciens as a source of new products with biomedical application.

Abstract Biocatalysis is a key technology enabling plastic recycling. However, despite advances done in the development of plastic-degrading enzymes, the molecular mechanisms that govern their catalytic performance are poorly understood, hampering the engineering of more efficient enzyme-based technologies. In this work, we study the hydrolysis of PET-derived diesters and PET trimers catalyzed by the highly promiscuous lipase B from Candida antarctica (CALB) through QM/MM molecular dynamics simulations supported by experimental Michaelis–Menten kinetics. The computational studies reveal the role of the pH on the CALB regioselectivity toward the hydrolysis of bis-(hydroxyethyl) terephthalate (BHET). We exploit this insight to perform a pH-controlled biotransformation that selectively hydrolyzes BHET to either its corresponding diacid or monoesters using both soluble and immobilized CALB. The discoveries presented here can be exploited for the valorization of BHET resulting from the organocatalytic depolymerization of PET.

El objetivo fue identificar las cepas, la cantidad y la diversidad de hongos presente en tortillas de 14 razas de maíz. Se determinó el peso del complejo de hongos (PCH) y la identificación de los hongos del mismo, así como características del grano (índice de flotación), nixtamal (humedad de nixtamal y humedad de masa) y tortilla (humedad de tortillo a las 24 y 48 h). A los datos se les realizó un análisis de varianza. Todas las variables presentaron diferencias significativas (p ≤ 0.05). Para el PCH los mayores promedios estadísticamente diferente fueron las razas Naltel de altura (0.69 g) y Arrocillos amarillo (0.68 g) por tortilla. La raza Chalqueño tuvo el mayor número de hongos en el complejo (Aspergillus flavus, Mucor sp., Penicillium sp., Rhizopus oryzae, Acremonium sp. y Alternaria sp.); con diferencia del hongo Penicillium sp., la raza Cónico fue la segunda mejor, y en Pepitilla solo se identificó el hongo Acremonium sp. Para la humedad de nixtamal y de masa la raza Pepitilla obtuvo los mejores valores, con un 49.7 y 60.9%, respectivamente. Se tuvieron diferencias del 65.2% en el PCH entre las razas evaluadas, presentando el mayor y menor peso las razas Naltel de altura y Chalqueño, respectivamente.

En este artículo se aborda la importancia del pequeño riego que radica en la eficiencia en el manejo y la administración del sistema de riego por medio de la autogestión de los usuarios. Se analiza la estructura de autoridad de las instituciones comunitarias, así como el sistema físico del pequeño riego de acuerdo con los niveles organizativos. Se encontró que las tareas siempre presentes como eje central de estudio, expresan la fortaleza organizativa y el valor del trabajo colectivo direccionado a un fin común, asimismo, la efectividad institucional comunitario con relación al manejo del agua presentó un comportamiento en función de la escasez del líquido y las necesidades comunitarias. Se concluye que la organización social para el pequeño riego representa un impulso directo a la producción agrícola y permite fortalecer la cohesión social de los usuarios en condiciones de escasez y abundancia del líquido vital.

Abstract Multi-enzymatic cascades with enzymes arranged in close-proximity through a protein scaffold can trigger a substrate channeling effect, allowing for efficient cofactor reuse with industrial potential. However, precise nanometric organization of enzymes challenges the design of scaffolds. In this study, we create a nanometrically organized multi-enzymatic system exploiting engineered Tetrapeptide Repeat Affinity Proteins (TRAPs) as scaffolding for biocatalysis. We genetically fuse TRAP domains and program them to selectively and orthogonally recognize peptide-tags fused to enzymes, which upon binding form spatially organized metabolomes. In addition, the scaffold encodes binding sites to selectively and reversibly sequester reaction intermediates like cofactors via electrostatic interactions, increasing their local concentration and, consequently, the catalytic efficiency. This concept is demonstrated for the biosynthesis of amino acids and amines using up to three enzymes. Scaffolded multi-enzyme systems present up to 5-fold higher specific productivity than the non-scaffolded ones. In-depth analysis suggests that channeling of NADH cofactor between the assembled enzymes enhances the overall cascade throughput and the product yield. Moreover, we immobilize this biomolecular scaffold on solid supports, creating reusable heterogeneous multi-functional biocatalysts for consecutive operational batch cycles. Our results demonstrate the potential of TRAP-scaffolding systems as spatial-organizing tools to increase the efficiency of cell-free biosynthetic pathways.

Review of the book Kevin G. Grove, "Augustine on Memory, Oxford Studies in Historical Theology", New York 2021.

This study evaluated a commercial pregnancy-associated glycoproteins (PAGs)-based pregnancy test using whole blood or plasma samples during early pregnancy (28–55 days of gestation) in high-producing dairy cows. Transrectal ultrasonography was used as the gold standard method. The study population constituted of 284 cows. False positive diagnoses were recorded from Day 60 to 89 and from Day 60 to 99 postpartum in blood and plasma samples, respectively. In early pregnancy screening, correct positive diagnoses were recorded in 75% and 100% of blood and plasma samples, respectively. High milk production was associated with negative results in blood samples and with the lowest test line intensity in plasma samples. False positive or negative diagnoses were recorded in 0% of both types of samples in cows previously diagnosed as pregnant and showing signs of estrus. In conclusion, the use of plasma was more effective than the use of blood in early pregnancy diagnosis. In cows previously diagnosed as pregnant and showing signs of estrus, both types of samples showed the same results. Because of large individual variations, normal single pregnancies could not be differentiated from twin pregnancies, from pregnancies with a recently dead conceptus, or from pregnancies that experienced subsequent pregnancy loss.

Background and objectivesIntermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson’s disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity.MethodsA total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.DiscussionThe findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Background: Acute fetal distress (AFD) is a condition that requires timely diagnosis because it generates hypoxia, acidosis, and even intrauterine death. This study aimed to determine lactate and pH values in the umbilical cord in full-term newborns (NBs) with a history of AFD. Methods: We conducted a cross-sectional study in full-term NBs of mothers with at least one perinatal, neonatal, or gasometric AFD antecedent. Neonatal morbidity was considered: if 1-min Apgar ≤ 6, or advanced neonatal maneuvers, or neonatal intensive care unit (NICU) admissions were necessary. The cutoff points were lactate > 4mmol/L and pH < 7.2. Results: Of 66 NBs, 33.3% of mothers presented at least one antecedent for developing AFD; 22.7% presented hypertensive pregnancy disease, 13.6% oligohydramnios, and 63.6% other factors. Perinatally, 28.7% required advanced neonatal resuscitation maneuvers and 7.5% admission to the NICU. In the gasometry, the lactate and pH values for the neonatal morbidity of the NBs’ group were 4.726 ± 1.401 and 7.293 ± 0.056, respectively, versus 2.240 ± 0.318 and 7.359 ± 0.022 (p < 0.05) for the group without associated neonatal morbidity. Conclusions: Lactate values in the umbilical cord increased by 25%, and pH decreased by one percent in NBs with a history of AFD and associated morbidity.

BackgroundSquamous cell carcinoma (SCC) arising in a sacrococcygeal pilonidal sinus is rare, with cases of metastatic disease being even rarer. Among published cases, almost none have reported on systemic treatment.ObjectiveThis disease has a poorer prognosis than other forms of cutaneous SCC; therefore, our objective is to shed some light on the treatment of metastatic disease.MethodsWe present a series of nine cases treated at a single center, four of whom received systemic treatment. Additionally, other previously reported cases of metastatic disease are included in an attempt to draw stronger conclusions.ResultsFour patients were treated under several treatment regimens, with a median progression-free survival of only 2 months and two instances of partial response (18%). The best result was achieved with cemiplimab. Across all the cases, there was a trend toward a benefit of the use of systemic treatment (HR 0.41, 95% CI 0.15–1.12, p = 0.083; median overall survival 13 vs. 8 months).LimitationsLimitations include the significant lack of information on previously published cases and the extremely heterogeneous nature of the existing information.ConclusionThe initial systemic treatment should be an anti-PD-1, as with other SCCs. After progression on anti-PD-1, there is no strong evidence to support the recommendation of a specific treatment or sequence: options include cetuximab and/or chemotherapy (platinum, paclitaxel, 5-fluorouracyl).

Abstract Background Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. Specific and thorough identification of cancer cell subsets with higher tumorigenicity and chemoresistance, such as cancer stem cells (CSCs), could lead to the development of new and promising therapeutic targets. For better CSC identification, a complete or extended surface marker phenotype is needed to provide increased specificity for new cell targeting approaches. Our goal is to identify and characterize a putative extended phenotype for CSCs derived from patients with GC before treatment, as well as to evaluate its clinical value. In addition, we aim to ensure that cells with this phenotype have stemness and self-renewal capabilities. Methods This is a cohort study including 127 treatment-naïve patients with GC who attended the Instituto Nacional de Cancerología. Multiparametric flow cytometry analysis was performed to determine the extended phenotype of cells derived from gastric biopsies. The tumorigenic capability of cells identified in patients was assessed in a zebrafish model. Results CD24+CD44+CD54+EpCAM+ cells were present in all treatment-naïve patients included, with a median abundance of 1.16% (0.57–1.89%). The percentage of CD24+CD44+CD54+EpCAM+ cells was categorized as high or low using 1.19% as the cutoff for the CD24+CD44+CD54+EpCAM+ cell subset. Additionally, a higher TNM stage correlated with a higher percentage of CD24+CD44+CD54+EpCAM+ cells (Rho coefficient 0.369; p

Abstract The effect of acylglycerols on the thermal inactivation of lactic acid bacteria used in the production of fermented products was studied. The starting point was the observation of an increase in thermal sensitivity in the presence of an emulsifier based on mono- and diacylglycerols in the culture medium. Analysis of the emulsifier showed that monoacylglycerols were the compounds responsible for this effect, with monopalmitin being the main contributor. Monostearin, on the other hand, showed significantly less potentiating effect. Interestingly, monoacylglycerols showed a greater bactericidal effect when used individually than when used in combination. On the other hand, the rate of thermal inactivation observed in reconstituted skim milk emulsions was lower than in peptone water emulsions, showing that the presence of proteins and colloidal particles increased the resistance of bacteria to heat treatment. With respect to pH values, a reduction in pH from 6.6 to 5.5 promoted an increase in the rate of thermal death. However, at pH = 5.5, the enhancing bactericidal effect was only detectable when the heat treatment was performed at low temperatures but not at high temperatures. This finding is of interest, since it will allow the design of moderate heat treatments, combining the use of temperature with the addition of acylglycerols, to prolong the shelf life of products fermented with lactic acid bacteria, and minimizing the destruction of desirable compounds that were obtained by the fermentation process.

IntroductionAntimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate.Methods and resultsThe Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity.DiscussionOverall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action.

For decades there have been controversies related to the changes generated by oil palm plantations in the physicochemical properties of the soil, soil biota, and ecological interactions. Therefore, the present investigation evaluated root diameter and biomass at three ages of oil palm cultivation. Besides, we evaluated the effect of the ages on the physicochemical parameters of the soil in comparison with pasture plots. To know the diameter, fresh, and dry biomass of roots, soil sampling was carried out around the oil palm (3-, 5-, and 15-years-old) at distances of 1, 2, and 3 m from the trunk plant. Also, to know the changes in the properties of the soil, the sampling was carried out randomly in the same plots and the pasture plot (control). The results showed that both the diameter and the fresh and dry root biomass increased in 15-year-old plantations compared with 3- and 5-year-old. In addition, correlation analysis and principal component analysis indicated that the parameters evaluated are associated with the adult age of the oil palm. Also, the results of soil physicochemical showed that low soil fertility was associated with an increase in the age of the palm.

Mycobacterium tuberculosis is the main causal agent of pulmonary tuberculosis (TB); the treatment of this disease is long and involves a mix of at least four different antibiotics that frequently lead to abandonment, favoring the surge of drug-resistant mycobacteria (MDR-TB), whose treatment becomes more aggressive, being longer and more toxic. Thus, the search for novel strategies for treatment that improves time or efficiency is of relevance. In this work, we used a murine model of pulmonary TB produced by the MDR-TB strain to test the efficiency of gene therapy with adenoviral vectors codifying TNF (AdTNF), a pro-inflammatory cytokine that has protective functions in TB by inducing apoptosis, granuloma formation and expression of other Th1-like cytokines. When compared to the control group that received an adenoviral vector that codifies for the green fluorescent protein (AdGFP), a single dose of AdTNF at the chronic active stage of the disease produced total survival, decreasing bacterial load and tissue damage (pneumonia), which correlated with an increase in cells expressing IFN-γ, iNOS and TNF in pneumonic areas and larger granulomas that efficiently contain and eliminate mycobacteria. Second-line antibiotic treatment against MDR-TB plus AdTNF gene therapy reduced bacterial load faster within a week of treatment compared to empty vector plus antibiotics or antibiotics alone, suggesting that AdTNF is a new potential type of treatment against MDR-TB that can shorten second-line chemotherapy but which requires further experimentation in other animal models (non-human primates) that develop a more similar disease to human pulmonary TB.

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor that displays a variable histology with admixtures of epithelial, mesenchymal, neuroendocrine and germ cell elements. Facing a very poor prognosis, patients with TCS are in need of new options for treatment. Recently identified recurrent mutations in SMARCA4 may serve as target for modern therapies with EZH1/2 and CDK4/6 inhibitors. Here, we present the first in vitro cell line TCS627, established from a previously untreated primary TCS originating in the ethmoid sinus with invasion into the brain. The cultured cells expressed immunohistochemical markers, indicating differentiation of epithelial, neuroepithelial, sarcomatous and teratomatous components. Whole-exome sequencing revealed 99 somatic mutations including SMARCA4, ARID2, TET2, CDKN2A, WNT7A, NOTCH3 and STAG2, all present both in the primary tumor and in the cell line. Focusing on mutated SMARCA4 as the therapeutic target, growth inhibition assays showed a strong response to the CDK4/6 inhibitor palbociclib, but much less to the EZH1/2 inhibitor valemetostat. In conclusion, cell line TCS627 carries both histologic and genetic features characteristic of TCS and is a valuable model for both basic research and preclinical testing of new therapeutic options for treatment of TCS patients.

Abstract Background Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. Methods ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients

Online learning is quickly becoming a popular choice instead of traditional education. One of its key advantages lies in the flexibility it offers, allowing individuals to tailor their learning experiences to their unique schedules and commitments. Moreover, online learning enhances accessibility to education, breaking down geographical and economical boundaries. In this study, we propose the use of advanced natural language processing techniques to design and implement a recommender that supports e-learning students by tailoring materials and reinforcement activities to students’ needs. When a student posts a query in the course forum, our recommender system provides links to other discussion threads where related questions have been raised and additional activities to reinforce the study of topics that have been challenging. We have developed a content-based recommender that utilizes an algorithm capable of extracting key phrases, terms, and embeddings that describe the concepts in the student query and those present in other conversations and reinforcement activities with high precision. The recommender considers the similarity of the concepts extracted from the query and those covered in the course discussion forum and the exercise database to recommend the most relevant content for the student. Our results indicate that we can recommend both posts and activities with high precision (above 80%) using key phrases to represent the textual content. The primary contributions of this research are three. Firstly, it centers on a remarkably specialized and novel domain; secondly, it introduces an effective recommendation approach exclusively guided by the student’s query. Thirdly, the recommendations not only provide answers to immediate questions, but also encourage further learning through the recommendation of supplementary activities.

La situación acontecida por el COVID-19 ha ocasionado diversas transformaciones en la gestión de los centros educativos, donde los equipos directivos han tenido que liderar esta circunstancia. El objetivo de esta investigación es indagar sobre la opinión de los directores y directoras de 43 centros educativos de Sevilla capital (España), acerca de la gestión de sus centros durante el periodo de confinamiento. Concretamente, se persigue examinar esta situación desde la dirección de los centros, atendiendo a una perspectiva de género. La metodología de investigación es cuantitativa, de corte descriptivo, ex post facto, transversal y correlacional. Para la recogida de información se ha utilizado un cuestionario compuesto por cuatro dimensiones de estudio que indagan acerca de la organización y la gestión del equipo directivo en el centro educativo, la labor académica desarrollada en la modalidad no presencial y el vínculo establecido con las familias durante el periodo de cese de actividades lectivas presenciales. Los resultados indican que existe una diferencia significativa en la opinión expresada en el estudio, en función del género de los líderes de esos equipos directivos, que anima a reflexionar sobre la importancia de atender la gestión y organización de equipos educativos desde una perspectiva de género.

Background/Objective: Stroke knowledge is variable within and between countries. It is determined by school grade, geographical location, and language barriers. This study aims to evaluate the knowledge of stroke symptoms, risk factors, and treatment in a specific population in Mexico. Methods: We surveyed volunteer participants among the inhabitants of a medium- income condominium complex and employees of a pharmaceutical company located in Mexico City between 2016 and 2018. We collected information regarding knowledge of stroke definitions, symptoms, risk factor identification, and treatment. Results: We surveyed 499 participants at both sites, with a median age of 44 years (interquartile range 31-70) and mean years of education of 16.09 years (SD 3.67). The recognition of different definitions regarding stroke was highly heterogeneous, with “brain hemorrhage” and “stroke” being the most known. Among participants, 70% knew at least one stroke symptom. Out of four risk factors, a mean of 3 are identified when prompted, with dyslipidemia being the least acknowledged. While 70% of participants recognize stroke as treatable, only 12-25% know about intravenous thrombolysis. There was no significant difference in overall stroke knowledge between surveyed sites. Conclusions: Knowledge about stroke remains highly heterogeneous in our population. While the knowledge of the general presentation of stroke is higher than in other studies, probably due to the higher mean school education, the awareness of treatment options is low. New public education programs should consider including this information, because it may improve the proportion of cases treated promptly.

Prostaglandin F2α (PGF2α) and its analogs are used to induce luteolysis in estrus synchronization programs to terminate unwanted pregnancies or to promote ovulation in certain cow subpopulations. In the past few decades, the luteolytic dose of PGF2α has remained unchanged. This review explores the clinical implications of increasing the standard dose for these applications in high-producing dairy cows. Ultrasonography may assist in selecting the most appropriate PGF2α dose and improve the results. A reference has been used for PGF2α for promoting ovulation in herds showing poor reproductive performance.

Chlorosphaerolactylate B, a newly discovered antimicrobial halometabolite from the cyanobacterium Sphaerospermopsis sp. LEGE 00249 has been synthesized in three steps by using 12-bromododecanoic acid as starting material. A total of 0.5 g was produced for in vitro and in vivo antimicrobial efficacy testing. In vitro, the minimal inhibitory concentration (MIC) was estimated to be 256 mg/L for Staphylococcus aureus, while the minimal biofilm inhibitory concentration (MBIC) was estimated to be 74 mg/L. The in vivo study utilized a porcine model of implant-associated osteomyelitis. In total, 12 female pigs were allocated into 3 groups based on inoculum (n = 4 in each group). An implant cavity (IC) was drilled in the right tibia and followed by inoculation and insertion of a steel implant. All pigs were inoculated with 10 μL containing either: 11.79 mg synthetic Chlorosphaerolactylate B + 104 CFU of S. aureus (Group A), 104 CFU of S. aureus (Group B), or pure saline (Group C), respectively. Pigs were euthanized five days after inoculation. All Group B animals showed macroscopic and microscopic signs of bone infection and both tissue and implant harbored S. aureus bacteria (mean CFU on implants = 1.9 × 105). In contrast, S. aureus could not be isolated from animals inoculated with saline. In Group A, two animals had a low number of S. aureus (CFU = 6.7 × 101 and 3.8 × 101, respectively) on the implants, otherwise all Group A animals were similar to Group C animals. In conclusion, synthetic Chlorosphaerolactylate B holds potential to be a novel antimicrobial and antibiofilm compound.

In simulating Quantum Computing by using the circuit model the size of the matrices to deal with, together with the number of products and additions required to apply every quantum gate becomes a really hard computational restriction. This paper presents a data structure, called Functional Matrices, which is the most representative feature of QSimov quantum computing simulator which is also provided and tested. A comparative study of the performance of Functional Matrices with respect to the other two most commonly used matrix data structures, dense and sparse ones, is also performed and summarized within this work.

Carotid artery disease has traditionally been assessed based on the degree of luminal narrowing. However, this approach, which solely relies on carotid stenosis, is currently being questioned with regard to modern risk stratification approaches. Recent guidelines have introduced the concept of the “vulnerable plaque,” emphasizing specific features such as thin fibrous caps, large lipid cores, intraplaque hemorrhage, plaque rupture, macrophage infiltration, and neovascularization. In this context, imaging-based biomarkers have emerged as valuable tools for identifying higher-risk patients. Non-invasive imaging modalities and intravascular techniques, including ultrasound, computed tomography, magnetic resonance imaging, intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy, have played pivotal roles in characterizing and detecting unstable carotid plaques. The aim of this review is to provide an overview of the evolving understanding of carotid artery disease and highlight the significance of imaging techniques in assessing plaque vulnerability and informing clinical decision-making.

Background: The management of cT3 laryngeal cancers remains controversial, with studies recommending surgical or non-surgical approaches. Despite the many papers that have been published on the subject, there is a lack of studies showing which treatment has better results in terms of survival. Objective: To determine the difference in survival outcomes following total laryngectomy (TL), concurrent chemoradiation (CRT) or radiation therapy (RT) alone in T3 laryngeal cancers. Methods: Search of PubMed, Scopus, and Google Scholar databases from 1995 to 2023 employing specific keywords and Boolean operators to retrieve relevant articles. Statistical analysis was conducted using a random-effects model, and heterogeneity was evaluated using the Q-test and I2 statistic. Funnel plot asymmetry was assessed using rank correlation and regression tests. Results: The qualitative data synthesis comprised 10,940 patients from 16 included studies. TL was performed in 2149 (19.4%), CRT in 6723 (61.5%), RT in 295 (2.7%), while non-surgical treatment was not specified in 1773 (16.2%) patients. The pooled 2-year overall survival (OS) rates were TL = 73%, CRT = 74.7%, RT = 57.9%, 3-year OS rates were TL = 64.3%, CRT = 62.9%, RT = 52.4%, and 5-year OS rates were TL = 54.2%, CRT = 52.7%, RT = 40.8%. There was a significant heterogeneity in the included studies. There was no statistically significant difference in 2-year OS (logOR= −0.88 (95% confidence interval (CI): −1.99 to 0.23), p = 0.12), 3-year OS (logOR = −0.6 (95% CI: −1.34 to 0.15), p = 0.11), and 5-year OS (logOR = −0.54 (95% CI: −1.29 to 0.21), p = 0.16) between TL and CRT. Instead, there was significant difference in 2-year OS (logOR= −1.2383 (95% CI: −2.1679 to −0.3087), p = 0.009), 3-year OS (−1.1262 (95% CI: −1.6166 to −0.6358), p < 0.001), and 5-year OS (−0.99 (95% CI: −1.44 to −0.53)), p < 0.001) between TL and RT alone. Conclusions and Significance: TL followed with adjuvant (chemo)radiation on indication and CRT with salvage surgery in reserve appear to have similar OS outcomes. Both resulted in better OS outcomes compared to RT alone in the treatment of T3 laryngeal cancers. If patients are unfit for chemotherapy, making CRT impossible, surgery may become the choice of treatment.

Twin pregnancies are highly undesirable in dairy cattle; they compromise the health and wellbeing of a cow and dramatically impair the farm economy. Recently, a genomic prediction for twin pregnancies has been developed. The objective of this study was to assess environmental and management risk factors affecting the incidence of twin pregnancies in high-producing dairy cows in their first lactation, with a special emphasis placed on the genomic prediction values of twin pregnancy. Our study population of primiparous cows proved valuable in identifying factors other than genomic predictive values that influence twin pregnancy rates. The odds ratio for twin pregnancies was 0.85 (p < 0.0001) for each unit of a prediction value increase, 3.5 (p = 0.023) for cows becoming pregnant during the negative photoperiod, and 0.33 (p = 0.016) for cows producing ≥42 kg of milk at AI, compared with the remaining cows who produced

Prostate cancer is the most commonly diagnosed cancer among men around the world. Radiotherapy is a standard of care treatment option for men with localized prostate cancer. Over the years, radiation delivery modalities have contributed to increased precision of treatment, employing radiobiological insights to shorten the overall treatment time, improving the control of the disease without increasing toxicities. Stereotactic body radiation therapy (SBRT) represents an extreme form of hypofractionated radiotherapy in which treatment is usually delivered in 1–5 fractions. This review assesses the main efficacy and toxicity data of SBRT in non-metastatic prostate cancer and discusses the potential to implement this scheme in routine clinical practice.

Esta investigación se realizó con el objetivo de conocer la implementación y uso de sistemas de costos adecuados, ya que es básico para que las empresas conozcan y optimicen sus costos y gastos ya que sirven para fijar sus precios correctamente y poder ser más competitivos maximizando su rentabilidad y ofrecer sus productos y servicios con mayor calidad, esto también se presenta en los despachos de contadores públicos de la ciudad de Chihuahua, donde existe una gran competencia entre los mismos. El objetivo de la investigación fue conocer los sistemas de costos y su relación con los honorarios de los servicios profesionales que se prestan en los diversos tipos de despachos de contadores públicos en la ciudad. El estudio se realizó con una muestra de 63 despachos, la investigación fue de naturaleza cuantitativa, aplicada y de carácter no experimental, la forma de investigación fue con enfoque descriptivo, y con un tipo de muestreo probabilístico. Los resultados mostraron, que la gran mayoría de los despachos locales sin representación internacional no usan un sistema de costos, determinan los honorarios a un precio global estimado y no relacionan los sistemas de costos y la determinación de los honorarios por servicios profesionales. Los despachos con representación internacional cuentan con sistemas de costos, determinan los honorarios con base a horas incurridas asignando la cuota por hora determinada y relacionando los sistemas de costos y la determinación de los honorarios, conociendo la relación tiempo-costo-utilidad por cada servicio prestado.

Larger consumption of natural fine aggregates (NFA) leads to an increase in cost, energy, and negative environmental impact. On the contrary, the larger production of construction waste results in the generation of recycled fine aggregate (RFA), which requires safe disposal. The aim of study, is to the hunt for such alternatives, compares the mortar mechanical and durability properties with and without RFA. High strength mortar specimens were produced with mix proportion as 1:3 using RFA as partial replacement for NFA as 0%, 25%, 50% and 100%. The mechanical and durability performance of all specimens was assessed in the terms of compressive strength, flexural strength, water absorption and mercury intrusion porosimetry. Mechanical performance is confirmed by microscopic studies. The main results display that the mortar with 25% of RFA, performed better, which are related to pore structures and their distribution. It is noted that the, pores also increase with the increase in RFA content. The effect of pores on the strength and their relationships are assessed.

This study sought to establish whether temperature gradients between the cervix, vagina, and rectum at and 7 days post-artificial insemination (AI) were associated with the incidence of pregnancy in lactating dairy cows (Experiment I; n = 90 ovulating cows) and to evaluate temperature gradient dynamics from the time of insemination to 7 days post-AI under heat stress conditions (Experiment II; n = 16 ovulating and 4 non-ovulating cows). In Experiment I, 39 cows (43.3%) became pregnant. The odds ratio for pregnancy was 2.5 for each one-tenth of a degree drop in cervical temperature with reference to the control rectal temperature at the time of AI (P = 0.01), whereas the same decrease in the cervix–rectum temperature differential 7 days post-AI resulted in an odds ratio of 0.44 (P = 0.02). In Experiment II, 5 of the ovulating cows (31.3%) became pregnant. The mean values of the vagina–rectum, vagina–cervix, and cervix–rectum temperature differentials at AI (day 0), 8 h, 24 h, and 7 days post-AI changed significantly from day 0 to day 7 (within-subject effect; P < 0.02) in ovulating cows but not in non-ovulating cows. Temperature differentials on days 0 and 7 were similar between ovulating cows and cows of Experiment I. Overall, our findings support the notion that a temperature differential between the caudal cervical canal and rectum at AI may be an indicator of the likelihood of pregnancy. Possible prospects of confirming estrus at the herd-level are also suggested.

In terms of military control of the Prefecture of Gaul throughout the fifth century, the Goth army was clearly lacking sufficient manpower. However, the support network provided both by the strategically important via Domitia and by the prosperous region of Aquitania made this control finally possible. At the core of the Aquitanian region, and nearby the newly created Southern Gallic limes, stood the excellent walls of the city of Toulouse, able to quarter the Visigoth army when necessary. Therefore, and during the years between 414 and 507, the Visigoth monarchy of Toulouse, fully identified with the Roman power in Arles, could focus on maintaining effective control on the essentials of the Roman Prefecture of Gaul.

This study provides new unique information on bovine twin pairs during the late embryonic period (28–34 days of pregnancy) in relation to (1) a predictive ultrasound measurement that was differential for sexing heterosexual twins; (2) intrauterine embryonic growth patterns in twin pairs; and (3) a higher vulnerability of female embryos compared to males following an induced embryo reduction in heterosexual twins. The study population comprised 92 dairy cows carrying bilateral twins. A length difference between co-twins equal to or greater than 25% in around 50% of pregnancies served to determine the sex of embryos with 100% accuracy in heterosexual twins, which was assessed four weeks later on the remaining fetus after twin reduction. The apparent rates of growth of twin pairs and of individual male and female embryos from day 28 to 34 of gestation were similar to established growth pattern standards for singletons. Mean embryo sizes in relation to gestational age were smaller by some 5 days’ growth equivalent in twins compared to singletons. After the reduction in the female embryo in heterosexual twins, the risk of male embryo loss was null. This new information allowed for sex selection at the time of twin reduction.