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Abstract Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enables us to correctly reidentify a genomic variant causally linked to anthracycline-induced cardiotoxicity and predict genomic variants potentially associated with TKI-induced cardiotoxicity. We conclude that mRNA expression profiles when integrated with publicly available genomic, pathway, and single cell transcriptomic datasets, provide multiscale signatures for cardiotoxicity that could be used for drug development and patient stratification.

The spatial distribution and diversity of plant pathogens and other microbial communities in commercial operations is the first step in identifying critical control points where crops may be at risk of disease. Our objective was to characterize the spatial variation of oomycete pathogens and bacteria across the production system of a greenhouse producing lettuce in hydroponics. We utilized DNA metabarcoding to identify oomycetes and 16S rRNA gene sequencing of bacteria from different production stages and sample types (surfaces, solutions, and roots) collected from a commercial greenhouse producing lettuce in deepwater culture. Pythium was the genus with the highest relative abundance (41 to 100%) across all production stages. P. dissotocum was detected in most samples, except for sowing and seedling surfaces and municipal water, where P. myriotylum was the most abundant species. Oomycete communities showed distinct clustering by production stages and sample types, where sowing and seedling surfaces and municipal water were separated from the rest. Proteobacteria had the highest relative abundance in the surfaces at the sowing (98%) and seedling (85%) stages. Municipal water was the only sample with less than 20% relative abundance of Proteobacteria and dominated by Cyanobacteria. Negative correlations between Pythium and 13 bacteria genera point to potential antagonists in hydroponics that should be further studied. Mapping the spatial variation of oomycetes and bacterial communities in a commercial greenhouse indicates that production stage and sample type influence microbial composition and potentially the risk to disease.

Se reporta el caso clínico de una paciente que presenta una cardiopatía denominada síndrome de takotsubo, la cual se empezó a describir a partir de los años 1980. Este síndrome es una patología cardiaca con presentación clínica similar al infarto agudo de miocardio, pero con cambios tanto bioquímicos como electrocardiográficos diferentes y que se acompaña principalmente de alteraciones en la contractilidad del músculo cardiaco, los cuales pueden ser evidenciados por ultrasonografía y al realizar una ventriculografía izquierda se confirma la clásica imagen de trampa para pulpos (takotsubo) que se utiliza en Japón, ya que fue ahí donde se empezaron a reportar los primeros casos. Su prevalencia es mayor en las mujeres que en los hombres y se relaciona con factores desencadenantes de estrés o emociones, principalmente por un efecto generado por catecolaminas. Su pronóstico es bueno siempre y cuando se trate la causa desencadenante y se favorezca con el tratamiento farmacológico adecuado.

Escherichia coli phytase (AppA) is widely used as an exogenous enzyme in monogastric animal feed mainly because of its ability to degrade phytic acid or its salt (phytate), a natural source of phosphorus. Currently, successful recombinant production of soluble AppA has been achieved by gene overexpression using both bacterial and yeast systems. However, some methods for the biomembrane immobilization of phytases (including AppA), such as surface display on yeast cells and bacterial spores, have been investigated to avoid expensive enzyme purification processes. This study explored a homologous protein production approach for displaying AppA on the cell surface of E. coli by engineering its outer membrane (OM) for extracellular expression. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of total bacterial lysates and immunofluorescence microscopy of non-permeabilized cells revealed protein expression, whereas activity assays using whole cells or OM fractions indicated functional enzyme display, as evidenced by consistent hydrolytic rates on typical substrates (i.e., p-nitrophenyl phosphate and phytic acid). Furthermore, the in vitro results obtained using a simple method to simulate the gastrointestinal tract of poultry suggest that the whole-cell biocatalyst has potential as a feed additive. Overall, our findings support the notion that biomembrane-immobilized enzymes are reliable for the hydrolysis of poorly digestible substrates relevant to animal nutrition.

Macroalgal blooms are increasing globally, with those linked to pelagic Sargassum affecting over 30 nations since 2011. As Sargassum mats traverse the Atlantic Ocean and the Caribbean Sea, they entrap and transport plastic to coastal areas, intensifying pollution in diverse ecosystems. This research assessed microplastics (MPs) within Sargassum fluitans III collected from the northern Mexican Caribbean coast (March 2021 to January 2022). The study employed a hydrogen peroxide protocol for macroalgae pretreatment to optimize MP extraction. All samples analyzed contained MPs at monthly mean concentrations that ranged from 3.5 to 15.3 MPs g−1 DW, with fibers constituting ≥90%. Fiber colors, mainly transparent, blue, and black, exhibited diverse sizes and wear stages. The study underscores the pervasive and consistent presence of MPs in pelagic Sargassum reaching the Mexican Caribbean. Considering the documented Sargassum influxes to this coast in recent years (2789–11,297 tons km−1 yr−1), potential annual MP influxes range from 0.1 × 109 to 17.3 × 109 km−1 yr−1. Efficiently removing beach-cast Sargassum and directing it to landfills could serve as a viable strategy for the simultaneous removal of attached MPs from the ocean and coastal waters, offering a promising mitigation strategy to combat plastic pollution in the examined marine environment.

Antecedentes: Los avances en la generación de sustitutos para órganos dañados utilizando células mesenquimales como fuente celular y soporte con diferentes materiales proporcionan una alternativa en la cirugía reconstructiva. Objetivo: Comparar la formación de tejido condral hialino a partir de células troncales mesenquimales (CTM) derivadas del tejido adiposo de conejo, en tres diferentes andamios. Material y Métodos: Para los cultivos in vitro se utilizaron andamios de: ácido poliláctico y poliglicólico (PLA-PGA), colágeno tipo I (col I) e hidroxiapatita (HA). Los parámetros utilizados fueron, 1 (adhesión), 7 y 14 (proliferación) días después de la siembra. La diferenciación se evaluó al final del estudio mediante marcadores condrales de matriz extracelular (SOX 9, agrecano y colágeno tipo II). Resultados: El PLA-PGA mostró mayor número de células adheridas (p < 0.001). El col I, mostró mayor proliferación (60.1 ± 6.1 × 103) al día 14 (p < 0.001). Las células condrales mostraron el porcentaje más alto de diferenciación en el PLA-PGA (células (+) agrecano 40.2 [31.5-55.3], colágeno II 23.4 [18.5-44.4]). La generación de cartílago semejante al hialino se observó en los 3 andamios. Conclusiones: El andamio de PLA-PGA in vitro presentó un mayor porcentaje de diferenciación de CTM a tejido condral hialino, 14 días después de la siembra.

Antioxidants undergo molecular association with dietary fibers in plant foods, and the actual nutritional functions depend on the conditions of association. As an approach to quantitative interpretation of the association effects, the present study proposes a method to evaluate association capacity, based on fluorometric titration of ferulic and p-coumaric acids with pectin and algin. The titration curve is formulated on the model that active sites on a fiber chain consist of segments each capable of binding to a single antioxidant molecule. The average segment sizes NS determined from observed curves range from 5 to 12 monomer units, and the mean association constant KA from 5 × 104 to 18 × 104 M−1 per segment, depending on fiber–antioxidant combinations. These parameters suggest that, although individual monomer units have weak binding forces, each segment involves multiple binding sites so that accumulating forces lead to the high thermodynamic stability of the molecular associates; the association capacity is presented by the half association concentration of antioxidant CG1/2 = 2Cm/NS – 2/KA at a monomer-based fiber concentration Cm. The extended application of the method to selected fiber–nutrient combinations would help to describe the association at molecular levels and to design better nutritional agents.

A large group of horticulture species are propagated vegetatively through shoot-tip cuttings harvested from stock plants and planted to form adventitious roots. Adventitious rooting leads to establishing a carbohydrate sink in the region of root regeneration that is highly dependent on energy and carbon skeletons. We hypothesized that the timing of exogenous applications of cytokinin (CK) and boron (B)–molybdenum (Mo)-based products during adventitious root development can affect the flow of sugars from leaves to sinks, carbon allocation to the adventitious roots, and the quality of rooted cuttings. During this project, we aimed to determine if the application time of a CK/B-Mo-based product during the adventitious root development of unrooted cuttings would impact the source-to-sink relationship and, hence, affect plug growth and quality. A sink-strengthening commercial product based on cytokinin, B, and Mo was applied at four plug development stages plus a negative control as follows: T1, plants without product (control); T2, sticking stage (starting 24 hours after the sticking); T3, callus formation stage; T4, root development stage; and T5, toning stage. The root and shoot lengths and dry matter, number of leaves, leaf chlorophyll content, root-to-shoot ratio (based on dry matter), and nonstructural carbohydrate contents were measured. The timing of the application of the product impacted the root development, quality of the cuttings, and nonstructural carbohydrate content. Product application during the adventitious root dedifferentiation and induction phases (T2) resulted in the shortest root and shoot lengths, lowest dry matter accumulation, lowest nonstructural carbohydrate contents, and some phytotoxicity. Application during the initiation phase (T3) resulted in greater root length, total dry matter, and total soluble sugar contents compared with the control. Application during the expression phase (T4) resulted in the largest root length and mass and the highest sucrose contents. Applying the product when the roots had grown and reached all the edges of the growing media (T5) did not have any benefits compared with the control. This study provides new insights into the application timing of exogenous CKs, B, and Mo to generate a well-toned rooted coleus cutting and potential explanations in relation to nonstructural carbohydrate metabolism.

Trichoderma strains used in vineyards for the control of grapevine trunk diseases (GTDs) present a promising alternative to chemical products. Therefore, the isolation and characterization of new indigenous Trichoderma strains for these purposes is a valuable strategy to favor the adaptation of these strains to the environment, thus improving their efficacy in the field. In this research, a new Trichoderma species, Trichoderma carraovejensis, isolated from vineyards in Ribera de Duero (Spain) area, has been identified and phylogenetically analyzed using 20 housekeeping genes isolated from the genome of 24 Trichoderma species. A morphological description and comparison of the new species has also been carried out. In order to corroborate the potential of T. carraovejensis as a biological control agent (BCA), confrontation tests against pathogenic fungi, causing various GTDs, have been performed in the laboratory. The compatibility of T. carraovejensis with different pesticides and biostimulants has also been assessed. This new Trichoderma species demonstrates the ability to control pathogens such as Diplodia seriata, as well as high compatibility with powdered sulfur-based pesticides. In conclusion, the autochthonous species T. carraovejensis can be an effective alternative to complement the currently used strategies for the control of wood diseases in its region of origin.

Background: The receptor activator of the nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is a determining pathway in the balance between bone formation and resorption, and disruptions in this complex can affect bone metabolism. Methods: This study analyzes the changes in RANKL, OPG, and 25(OH)D levels; the RANKL/OPG ratio; and other bone turnover markers (BTMs) from diagnosis to complete remission in children with acute lymphoblastic leukemia (ALL). This is a prospective observational cohort study, carried out at the Instituto Mexicano del Seguro Social, Mexico City, including 33 patients (4–17 years) with newly diagnosed B-cell ALL. The patients were treated with the HP09 chemotherapy protocol. Children who had previously been treated with corticosteroids were excluded. A peripheral blood sample at diagnosis and remission was collected to determine the 25(OH)D and BTM concentrations. Results: Increased RANKL (p = 0.001) and osteocalcin (p < 0.001) levels and RANKL/OPG ratio (p = 0.005) were observed at remission, predominantly in the high-risk (HR) relapse and vitamin D deficiency groups. A negative association between RANKL and OPG (r = −0.454, p = 0.008) was observed. Conclusions: we suggest that the RANKL/OPG ratio could serve as a bone remodeling marker in ALL patients.

Esta comunicación de carácter polifónico reúne tres intervenciones producidas a raíz de la presentación del libro La fantasía de la historia feminista, de la historiadora feminista estadounidense Joan W. Scott, traducido por primera vez al español y publicado en marzo de 2023 por Editorial Omnívora. Dicha presentación se llevó a cabo el 24 de agosto de 2023, en la Facultad de Humanidades y Ciencias de la Educación de la Universidad Nacional de La Plata. Allí, Juan Ignacio Veleda propuso una introducción a la obra, la profesora Rosa Belvedresi realizó su comentario, titulado “Cuando la historia crítica y feminista va a la búsqueda del pasado” y la profesora Adriana Valobra expuso “Reverberos desde el Sur del Sur”.

Since 2011, the distribution, abundance, and composition of holopelagic Sargassum spp. (sargasso) have changed by the emergence of the Great Atlantic Sargasso Belt (GASB) in the northern tropical Atlantic. We expected that the north of the Cuban coast would receive sargasso from both the original Sargasso Sea and the GASB. We systematically monitored six beaches on the NW coast of Cuba to assess changes in sargasso composition from June 2019 to June 2021. During landing months, mean Sargasso wet biomass was at 1.54 kg/m2 (SE: 0.7), which was considerably lower than the sargasso on the Atlantic coasts directly impacted by GASB. Eleven out of 13 landings occurred in the autumn-winter seasons 2019–2020 and 2020–2021, with a dominance of S. natans I (accounting for 41–63% of total biomass), followed by S. fluitans III (25–36%) and S. natans VIII (12–31%). This composition is similar to those observed on the Sargasso Sea. During this season, dominant winds (≥14 km/h) came from northern (N), eastern (E), and east-northeastern (ENE) directions. In May and August 2020 (spring-summer season), S. fluitans III dominated (52–56%), followed by S. natans VIII (33–43%) and S. natans I (5–12%). This composition is similar to those observed on GASB-impacted Atlantic coasts in the spring-summer seasons (April to September). During this season, dominant winds (≥20 km/h) came from eastern (E) and east-northeastern (ENE) directions. Thus, the NW Cuba’s morphotype composition suggests that landings have different origin sources depending on season and specific meteorological and oceanographic conditions.

Each year, the amount of residue generated from food production increases, caused by the continuous population growth. Banana is one of the most consumed fruits in the world, with an annual production of 116.78 million tonnes. However, just 12 wt% of the plant, corresponding to the bunch, is effectively used. After the bunch is harvested, the rest of the plant is disposed of as residue, the pseudostem (PS) being the main constituent. Aiming to give an added-value application to the PS, this work is focused on the extraction of cellulose from this waste. For this, three different fractions of PS particles—a non-classified fraction (milled but without sieving), a fine fraction (≤180 μm), and a coarse fraction (≥2000 μm)—and three extraction methods—alkaline-acid hydrolysis, enzymatic hydrolysis, and TEMPO oxidation—were studied to determine the most promising method for the cellulose extraction from the PS. The alkaline-acid hydrolysis samples presented a higher number of amorphous compounds, resulting in lower crystallinity (13.50% for the non-classified fraction). The TEMPO-oxidation process, despite allowing the highest cellulose extraction yield (25.25 ± 0.08% on a dried basis), resulted in samples with lower thermal stability (up to 200 °C). The most promising extraction method was enzymatic, allowing the extraction of 14.58 ± 0.30% of cellulose (dried basis) and obtaining extracts with the highest crystallinity (68.98% for the non-classified fraction) and thermal stability (until 250 °C).

Knowledge of the time of deposition is pivotal in forensic investigations. Recent studies show that changes in intrinsic fluorescence over time can be used to estimate the age of body fluids. These changes have been attributed to oxidative modifications caused by protein–lipid interactions. This pilot study aims to explore the impact of these modifications on body fluid fluorescence, enhancing the protein–lipid model system for age estimation. Lipid and protein oxidation markers, including protein carbonyls, dityrosine, advanced glycation end-products (AGEs), malondialdehyde (MDA), and 4-hydroxynonenal (HNE), were studied in aging semen, urine, and saliva over 21 days. Surface plasmon resonance imaging (SPRi), enzyme-linked immunosorbent assay (ELISA), and fluorescence spectroscopy were applied. Successful detection of AGE, dityrosine, MDA, and HNE occurred in semen and saliva via SPRi, while only dityrosine was detected in urine. Protein carbonyls were measured in all body fluids, but only in saliva was a significant increase observed over time. Additionally, protein fluorescence loss and fluorescent oxidation product formation were assessed, showing significant decreases in semen and saliva, but not in urine. Although optimization is needed for accurate quantification, this study reveals detectable markers for protein and lipid oxidation in aging body fluids, warranting further investigation.

Abstract Background This study investigated the effect of sex and age at type 2 diabetes (T2D) diagnosis on the influence of T2D-related genes, parental history of T2D, and obesity on T2D development. Methods In this case–control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤ 45 years; late, ≥ 46 years). Sixty-nine T2D-associated single nucleotide polymorphisms were explored and the percentage contribution (R 2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist–hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models. Results T2D-related genes influenced T2D development most in males who were diagnosed early (R 2 = 23.5%; females, R 2 = 13.5%; males and females diagnosed late, R 2 = 11.9% and R 2 = 7.3%, respectively). With an early diagnosis, insulin production-related genes were more influential in males (76.0% of R 2) while peripheral insulin resistance-associated genes were more influential in females (52.3% of R 2). With a late diagnosis, insulin production-related genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and genes associated with inflammation and other processes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males. Conclusions The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.

Resumen: En este trabajo consideraremos algunas de las críticas que ha recibido la tesis del tiempo histórico que lo entiende como un producto de la Modernidad, ligado a la expectativa de un futuro (mejor) que espera por venir. Dos líneas de argumentación nos interesan abordar en este trabajo. La primera, señalar que el supuesto del futuro como el tiempo de la esperanza (en clave política, no religiosa) ha entrado en crisis como consecuencia de la persistencia de formas del pasado que se resisten a pasar. La segunda, subrayar la necesidad de redefinir el tiempo de manera tal que no solo involucre al tiempo social en clave humana, sino que también tenga en cuenta a la especie humana como un factor determinante de lo que sucede en el planeta al resto de los seres vivos. Lo que queremos señalar es, por un lado, que las tesis que cuestionan la idea tradicional del tiempo tienen razón al afirmar que esa idea del tiempo ya no se sostiene, aunque señalaremos algunas diferencias. Por otro lado, queremos marcar la persistencia de ciertas formas del tiempo que se resisten a ser obsoletas y obturan la imaginación de nuevos futuros.

Southern Mexico’s tropical forests are home to the country’s highest richness of mammal species; La Chinantla region is situated within this area, its name from the indigenous group residing in the area and holding territorial ownership, namely the Chinantecos. In La Chinantla, there are no Protected Areas; instead, there are Areas Destined Voluntarily for Conservation (ADVC) and “Voluntary Conservation Areas” (VCA), that are managed by local inhabitants through social consensus. These ADVC may function as an archipelago reserve, which represents regional diversity, including the social context, through complementarity. To verify its biodiversity, we analyzed the richness, composition, distribution, and conservation of wild mammals in the region. Records were obtained from four sources—primary data collection, databases, scientific literature, and community monitoring—and were organized into four zones based on altitudinal and vegetation gradients. We compared the diversity between zones for three categories of mammals: small (100 gr.). 134 species were identified comprising 11 orders, 26 families and 86 genera. The zone with highest elevation presented the greatest species richness for the assemblage of mammals and terrestrial mammals, while the zone with the lowest elevation had the highest richness of bats. For each mammal category, the zone with the most species also registered the highest number of exclusive species. For the assemblage of mammals and for medium and large mammals, the similarity index was highest between the two intermediate zones, while for small mammals and bats, the greatest similarity occurred between the areas of higher altitude. The study region was found to have the second highest richness of mammals in Mexico. Finally, we suggest that the conservation proposals by indigenous people could function as a set of “islands” that promote the conservation of biodiversity, possibly as an Archipelago Reserve.

Abstract Purkinje cell (PC) loss occurs at an early age in patients and animal models of Niemann-Pick Type C (NPC), a lysosomal storage disease caused by mutations in the Npc1 or Npc2 genes. Although degeneration of PCs occurs early in NPC, little is known about how NPC1 deficiency affects the postnatal development of PCs. Using the Npc1 nmf164 mouse model, we found that NPC1 deficiency significantly affected the postnatal development of PC dendrites and synapses. The developing dendrites of Npc1 nmf164 PCs were significantly deficient in mitochondria and lysosomes. Furthermore, anabolic (mTORC1) and catabolic (TFEB) signaling pathways were not only perturbed but simultaneously activated in NPC1-deficient PCs, suggesting a loss of metabolic balance. We also found that mice with conditional heterozygous deletion of the Phosphatase and Tensin Homolog Deleted on Chromosome 10 gene (Pten-cHet), an inhibitor of mTORC1, showed similar early dendritic alterations in PCs to those found in Npc1-deficient mice. However, in contrast to Npc1 nmf164 mice, Pten-cHet mice exhibited the overactivation of the mTORC1 pathway but with a strong inhibition of TFEB signaling, along with no dendritic mitochondrial reductions by the end of their postnatal development. Our data suggest that disruption of the lysosomal-metabolic signaling in PCs causes dendritic and synaptic developmental deficits that precede and promote their early degeneration in NPC.

Antecedentes: La gasometría sanguínea se utiliza para monitorear el intercambio gaseoso y la homeostasis en el equilibrio ácido-base. Objetivo: Evaluar los cambios gasométricos en cachorros de perros con traqueostomía expuesta al oxígeno directo. Métodos: Se utilizaron 12 cachorros de 60 días de vida a los que se realizó traqueostomía y se colocó a 10 cm del orificio traqueal una manguera con O2 a una concentración del 100% a 3 l. Se tomaron muestras de sangre venosa antes de la anestesia, con la tráquea expuesta, al cerrar la traqueostomía y posterior a la recuperación anestésica. Se utilizó un analizador de gases sanguíneos. Se realizó estadística con t de Student pareada y se realizaron gráficas de error estándar y de caja. Resultados: Los valores de pCO2 y pO2 se comportaron inversamente durante las dos primeras tomas sanguíneas; hubo variaciones en los valores de pO2 y pCO2, TCO2 y SO2 durante la intervención quirúrgica. Los valores de glucosa presentan un comportamiento de campana y los de lactato en forma de U. El pH y el HCO3 no cambiaron, mientras que el sodio, el potasio, el calcio y el hematocrito sí mostraron diferencias estadísticas. Conclusiones: El perro es un buen modelo para el estudio del intercambio gaseoso en cirugía de tráquea.

Currently, numerous studies highlight the importance of technology as an effective resource for improving the quality of education. Like other countries in the region, Mexico greatly emphasizes improving its education system comprehensively and competitively, and technology has become a fundamental strategy to achieve this goal. Technology has allowed it to fill existing gaps and introduce innovative models in the digital age, promoting human capital development and fostering thriving communities. Technology also facilitates the development of competencies, such as complex thinking and the skills required to utilize Education 4.0 resources. However, these advances are at risk without examining the possibilities for technology transfer in the region's educational institutions. Accordingly, the following questions arise: a) What is the probability of achieving technology transfer to primary education institutions; b) What investments or modifications are necessary in the existing infrastructure to transfer educational and other technologies? We aimed to develop a quantitative data analysis model to examine the capacity of primary education institutions, applicable also to higher education, to adapt, assimilate, and transfer technology to improve educational quality in Mexico, as proposed by González Sabater in 2011. The results suggest the feasibility of a technology management system validated through a reliable database, considering the existing infrastructure as a basis for technology transfer. This research is relevant in establishing the probability of success of an educational institution in completing the process of assimilation and technology transfer, thus also contributing to governmental decision-making on educational spending.

There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.

IntroductionNeurons transport mRNA and translational machinery to axons for local translation. After spinal cord injury (SCI), de novo translation is assumed to enable neurorepair. Knowledge of the identity of axonal mRNAs that participate in neurorepair after SCI is limited. We sought to identify and understand how axonal RNAs play a role in axonal regeneration.MethodsWe obtained preparations enriched in axonal mRNAs from control and SCI rats by digesting spinal cord tissue with cold-active protease (CAP). The digested samples were then centrifuged to obtain a supernatant that was used to identify mRNA expression. We identified differentially expressed genes (DEGS) after SCI and mapped them to various biological processes. We validated the DEGs by RT-qPCR and RNA-scope.ResultsThe supernatant fraction was highly enriched for mRNA from axons. Using Gene Ontology, the second most significant pathway for all DEGs was axonogenesis. Among the DEGs was Rims2, which is predominately a circular RNA (circRNA) in the CNS. We show that Rims2 RNA within spinal cord axons is circular. We found an additional 200 putative circRNAs in the axonal-enriched fraction. Knockdown in primary rat cortical neurons of the RNA editing enzyme ADAR1, which inhibits formation of circRNAs, significantly increased axonal outgrowth and increased the expression of circRims2. Using Rims2 as a prototype we used Circular RNA Interactome to predict miRNAs that bind to circRims2 also bind to the 3’UTR of GAP-43, PTEN or CREB1, all known regulators of axonal outgrowth. Axonally-translated GAP-43 supports axonal elongation and we detect GAP-43 mRNA in the rat axons by RNAscope.DiscussionBy enriching for axonal RNA, we detect SCI induced DEGs, including circRNA such as Rims2. Ablation of ADAR1, the enzyme that regulates circRNA formation, promotes axonal outgrowth of cortical neurons. We developed a pathway model using Circular RNA Interactome that indicates that Rims2 through miRNAs can regulate the axonal translation GAP-43 to regulate axonal regeneration. We conclude that axonal regulatory pathways will play a role in neurorepair.

Massive arrivals of pelagic Sargassum to the coasts of several countries in the Atlantic Ocean began in 2011. Monitoring the abundance and distribution of Sargassum in the ocean and along the coasts is necessary to understand the phenomena better and develop forecasting products and management protocols. Most Sargassum monitoring has been conducted in the open ocean through traditional remote sensing techniques. However, since the most significant ecologic and socioeconomic impacts occur on the coasts, it is necessary to monitor these macroalgae on nearshore waters and beaches. This manuscript reviews the remote sensing algorithms used in Sargassum observation reported in the last 17 years in more than sixty high-impact scientific publications. The discussion regarding the evolution of the methodologies used for monitoring these macroalgae allowed us to conclude that the synergy generated by incorporating new disciplines like artificial intelligence and citizen science has positively impacted the development of this field. Additionally, the current state-of-the-art methods, the fundamental challenges, and the directions for future research are also discussed.

Increasing demand on agricultural water resources have caused a greater need for the use of municipal recycled wastewater (MRW) globally. However, in the United States, greenhouse growers have been slow to use it in their greenhouse operations. In this study, we seek to understand the factors that motivate and limit use of MRW among US growers. Using national survey data from 2019 through 2020, we developed a logistic regression model to understand the many factors influencing growers’ willingness to use MRW on food crops. We find that MRW quality is a primary concern and that growers’ willingness to use MRW is shaped by their direct and indirect knowledge of MRW, garnered from their own and others’ experiences using it. Given these findings, improving adoption of MRW requires collective experiential learning opportunities that gather target audiences with educators, policymakers, end users, and local authorities to simultaneously provide hands-on experience tailored to growers’ particular knowledge and concerns with feedback from peers.

Chlorine is a disinfectant commonly used to treat water. The United States Environmental Protection Agency (USEPA) has set a standard limit of up to 4 mg·L−1 chlorine for drinking water. The objective of this project was to identify chlorine phytotoxicity thresholds on ‘Rex’ lettuce (Lactuca sativa) when the water source contained chlorine levels within the USEPA standard limits. The nutrient solution to grow lettuce was prepared with reverse osmosis–treated water treated with 0, 0.5, 1, 1.5, 2, and 4 mg·L−1 chlorine and then fertilizers were added. Lettuce plants were grown in a deep-water culture hydroponic system. Visual toxicity symptoms on leaves, relative leaf greenness, and fresh and dry biomass were measured. Our results indicate that irrigation water sources with ≥1 mg·L−1 chlorine used to prepare nutrient solutions can cause phytotoxicity in lettuce plants in just 3 days. Compared with the untreated control, lettuce shoot biomass was lower by 30%, 55%, 66%, 83%, and 92% at 0.5, 1, 1.5, 2, and 4 mg·L−1 of chlorine, respectively. Water sources with ≥ 1 mg·L−1 chlorine can cause significant marketable yield reduction in lettuce grown in deep-water culture.

Abstract Symptoms-based detection of SARS-CoV-2 infection is not a substitute for precise diagnostic tests but can provide insight into the likely level of infection in a given population. This study uses symptoms data collected in the Global COVID-19 Trends and Impact Surveys (UMD Global CTIS), and data on variants sequencing from GISAID. This work, conducted in January of 2022 during the emergence of the Omicron variant (subvariant BA.1), aims to improve the quality of infection detection from the available symptoms and to use the resulting estimates of infection levels to assess the changes in vaccine efficacy during a change of dominant variant; from the Delta dominant to the Omicron dominant period. Our approach produced a new symptoms-based classifier, Random Forest, that was compared to a ground-truth subset of cases with known diagnostic test status. This classifier was compared with other competing classifiers and shown to exhibit an increased performance with respect to the ground-truth data. Using the Random Forest classifier, and knowing the vaccination status of the subjects, we then proceeded to analyse the evolution of vaccine efficacy towards infection during different periods, geographies and dominant variants. In South Africa, where the first significant wave of Omicron occurred, a significant reduction of vaccine efficacy is observed from August-September 2021 to December 2021. For instance, the efficacy drops from 0.81 to 0.30 for those vaccinated with 2 doses (of Pfizer/BioNTech), and from 0.51 to 0.09 for those vaccinated with one dose (of Pfizer/BioNTech or Johnson & Johnson). We also extended the study to other countries in which Omicron has been detected, comparing the situation in October 2021 (before Omicron) with that of December 2021. While the reduction measured is smaller than in South Africa, we still found, for instance, an average drop in vaccine efficacy from 0.53 to 0.45 among those vaccinated with two doses. Moreover, we found a significant negative (Pearson) correlation of around − 0.6 between the measured prevalence of Omicron in several countries and the vaccine efficacy in those same countries. This prediction, in January of 2022, of the decreased vaccine efficacy towards Omicron is in line with the subsequent increase of Omicron infections in the first half of 2022.

Ultraviolet (UV) radiation harms the skin, causing oxidative damage, inflammation, and disruption of the skin’s barrier function. There is considerable interest in identifying new natural ingredients with antioxidant and anti-inflammatory properties to serve as adjuvants in sunscreens. The flavonoid morin (1) can undergo structural modifications to enhance its biological properties. The aim of this study was to synthesize two new morin-Schiff base derivatives, morin oxime (2) and morin semicarbazone (3), comparing their photoprotective effects with that of the parent compound on UVB-exposed HaCaT keratinocytes. The chemical structure of the novel compounds was revealed based on spectroscopic data analysis. Our findings demonstrated that derivatives 2 and 3 enhanced the light absorption capability in the UV–visible (vis) range compared to 1. Tested compounds exhibited a higher scavenger capacity than Trolox. Moreover, pre-treatment with all compounds protected HaCaT cells from UVB-induced cell death. Compound 3 demonstrated the strongest antioxidant effect, reducing reactive oxygen species (ROS) generation and, subsequently, malondialdehyde (MDA) levels. Additionally, compounds 2 and 3 exhibited greater anti-inflammatory effects than compound 1, significantly reducing interleukin (IL)-6 production levels at all tested concentrations. These findings have demonstrated, for the first time, a promising photoprotective activity of two new Schiff base derivatives and suggest their use as natural sunscreen ingredients.

Abstract Mucormycosis is a fungal infection caused by Mucorales, with a high mortality rate. However, only a few virulence factors have been described in these organisms. This study showed that deletion of rfs, which encodes the enzyme for the biosynthesis of rhizoferrin, a siderophore, in Mucor lusitanicus, led to a lower virulence in diabetic mice and nematodes. Upregulation of rfs correlated with the increased toxicity of the cell-free supernatants of the culture broth (SS) obtained under growing conditions that favor oxidative metabolism, such as low glucose levels or the presence of H2O2 in the culture, suggesting that oxidative metabolism enhances virulence through rhizoferrin production. Meanwhile, growing M. lusitanicus in the presence of potassium cyanide, N-acetylcysteine, a higher concentration of glucose, or exogenous cAMP, or the deletion of the gene encoding the regulatory subunit of PKA (pkaR1), correlated with a decrease in the toxicity of SS, downregulation of rfs, and reduction in rhizoferrin production. These observations indicate the involvement of the cAMP-PKA pathway in the regulation of rhizoferrin production and virulence in M. lusitanicus. Moreover, rfs upregulation was observed upon macrophage interaction or during infection with spores in mice, suggesting a pivotal role of rfs in M. lusitanicus infection.

Abstract Intra- and inter-layer integrity of components fabricated with advanced manufacturing techniques, such as laser powder bed fusion, is dependent upon rapid heating, melting, and solidification processes. There is a need for new techniques to provide in situ feedback of these processes. Here a laser-based ultrasonic technique to probe thermal effects induced by a high-power continuous wave laser in titanium samples is described. Numerical simulations were performed to show that, for a spatially uniform heating beam, laser-induced surface acoustic waves are strongly influenced by surface heating conditions, are dispersive in the case of rapid heating, and that an abrupt velocity reduction happens upon the onset of surface melting. Furthermore, laser-based ultrasound experimental results which monitor the transient change of surface wave travel time associated with high power laser surface heating are provided. A pulsed laser is used to generate high frequency surface acoustic waves that propagate through the laser-heated region and are detected using a photorefractive crystal-based interferometer. Qualitative agreement is observed between theory and experiment with both showing a rapid reduction in the surface wave velocity at the onset of illumination and further decrease in surface wave velocity associated with melting. It is demonstrated that changes in the surface wave velocity can be used to track local heating and detect the onset of surface melting in real time.

La medicina ha tenido un camino en paralelo con la tecnología durante las últimas décadas. El desarrollo de herramientas para la mejora del diagnóstico, pronóstico y tratamiento oportuno ha evolucionado el concepto de salud, la inteligencia artificial (IA) es ejemplo de ello. En esta revisión se abordan temas como la evolución de la historia de la IA por medio de los acontecimientos más importantes, además se presentan algunas aplicaciones de la IA dentro de la medicina asistencial, la educación, la investigación y la gestión médica. Así como novedosas aplicaciones de la IA en la imagenología y una pequeña visión del futuro de la IA como herramienta en la radiología.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

Abstract Background Infographics have become an increasingly popular method to present research findings and increase the attention research receives. As many scientific journals now use infographics to boost the visibility and uptake of the research they publish, infographics have become an important tool for medical education. It is unknown whether such infographics convey the key characteristics that are needed to make useful interpretations of the data such as an adequate description of the study population, interventions, comparators and outcomes; methodological limitations; and numerical estimates of benefits and harms. This study described whether infographics published in peer-reviewed health and medical research journals contain key characteristics that are needed to make useful interpretations of clinical research. Methods In this cross-sectional study, we identified peer-reviewed journals listed in the top quintile of 35 unique fields of medicine and health research listed in the Journal Citation Reports database. Two researchers screened journals for the presence of infographics. We defined an infographic as a graphical visual representation of research findings. We extracted data from a sample of two of the most recent infographics from each journal. Outcomes were the proportion of infographics that reported key characteristics such as study population, interventions, comparators and outcomes, benefits, harms, effect estimates with measures of precision, between-group differences and conflicts of interest; acknowledged risk of bias, certainty of evidence and study limitations; and based their conclusions on the study’s primary outcome. Results We included 129 infographics from 69 journals. Most infographics described the population (81%), intervention (96%), comparator (91%) and outcomes (94%), but fewer contained enough information on the population (26%), intervention (45%), comparator (20%) and outcomes (55%) for those components of the study to be understood without referring to the main paper. Risk of bias was acknowledged in only 2% of infographics, and none of the 69 studies that had declared a conflict of interest disclosed it in the infographics. Conclusions Most infographics do not report sufficient information to allow readers to interpret study findings, including the study characteristics, results, and sources of bias. Our results can inform initiatives to improve the quality of the information presented in infographics.

Background & Aims: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell–intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. Methods: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. Results: We have discovered that non–cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. Conclusions: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

BackgroundCow's milk protein allergy (CMPA) is the leading cause of food allergy in infants and young children. An extensively hydrolyzed formula (eHF) is the first choice of dietary management, however, not all of them have similar peptide profiles and degree of hydrolysis. The aim of this retrospective study was to investigate the use of two commercially available infant formulas in the clinical management of CMPA in Mexico in terms of symptoms' resolution and growth trajectories.MethodsMedical records of 79 subjects from four sites in Mexico were included to retrospectively evaluate the trajectory of atopic dermatitis, other symptoms of cow's milk protein allergy and growth outcomes. The study formulas were based on hydrolyzed whey protein (eHF-W) and hydrolyzed casein protein (eHF-C).ResultsMedical records of 79 patients were enrolled, 3 were excluded from analysis based on previous formula consumption. Seventy-six children with confirmed CMPA based on skin prick test and/or serum specific IgE levels were included in the analysis. 82% of patients (n = 65) consumed the eHF-C, reflecting the doctors' preference for formulas with a higher grade of hydrolysis and the high incidence of positive reactions to beta-lactoglobulin amongst subjects. During their first visit to the doctors, 55% of the subjects consuming the casein-based formula and 45% of subjects consuming the whey-based formula presented with mild or moderate dermatological symptoms. Other frequently reported symptoms included respiratory issues, enteropathies and colitis which improved during the consumption of both formulas. All CMPA-related symptoms showed improvement during formula consumption. During the period of retrospective observation, growth significantly improved for both groups.ConclusionConsumption of eHF-C and eHF-W effectively improved symptoms' resolution and growth outcomes among children with CMPA in Mexico. More preference was reported towards eHF-C due to its hydrolysate profile and lack of b-lactoglobulin.Trial registrationThe study was registered at ClinicalTrials.gov: NCT04596059.

Abstract Language processing is cognitively demanding, requiring attentional resources to efficiently select and extract linguistic information as utterances unfold. Previous research has associated changes in pupil size with increased attentional effort. However, it is unknown whether the behavioral ecology of speakers may differentially affect engagement of attentional resources involved in conversation. For bilinguals, such an act potentially involves competing signals in more than one language and how this competition arises may differ across communicative contexts. We examined changes in pupil size during the comprehension of unilingual and codeswitched speech in a richly-characterized bilingual sample. In a visual-world task, participants saw pairs of objects as they heard instructions to select a target image. Instructions were either unilingual or codeswitched from one language to the other. We found that only bilinguals who use each of their languages in separate communicative contexts and who have high attention ability, show differential attention to unilingual and codeswitched speech. Bilinguals for whom codeswitching is common practice process unilingual and codeswitched speech similarly, regardless of attentional skill. Taken together, these results suggest that bilinguals recruit different language control strategies for distinct communicative purposes. The interactional context of language use critically determines attentional control engagement during language processing.

The trichothecene toxin-producing fungus Trichoderma arundinaceum has potential as a biological control agent. However, most biocontrol studies have focused only on one strain, IBT 40837. In the current study, three Trichoderma isolates recovered from bean-field soils produced the trichothecene harzianum A (HA) and trichodermol, the latter being an intermediate in the HA biosynthesis. Based on phylogenetic analysis, the three isolates were assigned to the species T. arundinaceum. Their genome sequences had a high degree of similarity to the reference IBT 40837 strain, in terms of total genome size, number of predicted genes, and diversity of putative secondary metabolite biosynthetic gene clusters. HA production by these bean-field isolates conferred significant in vitro antifungal activity against Rhizoctonia solani and Sclerotinia sclerotiorum, which are some of the most important bean pathogens. Furthermore, the bean-field isolates stimulated germination of bean seeds and subsequent growth of above ground parts of the bean plant. Transcriptomic analysis of bean plants inoculated with these T. arundinaceum bean-field soil isolates indicated that HA production significantly affected expression of plant defense-related genes; this effect was particularly significant in the expression of chitinase-encoding genes. Together, these results indicate that Trichoderma species producing non-phytotoxic trichothecenes can induce defenses in plants without negatively affecting germination and development

Abstract Background The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. Methods Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice. Results We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus. Conclusion Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.

Background : Hyperactive heart fire syndrome is characterized by anxiety, insomnia, dream-disturbed sleep, tongue ulcers, heat in the hands, and palpitations. However, syndrome differentiation is often subjective due to a lack of objective, quantifiable variables. Objectives: To identify changes in heart rate variability (HRV) and psychometric analysis in patients with hyperactive heart fire syndrome. Methods : Healthy controls (n = 33) were compared to patients with hyperactive heart fire syndrome (n = 48) from the Integrative University Clinic of the State University of Ecatepec Valley (CIU-UNEVE). Physiological outcome measures included heart rate (HR), the standard deviation of the normal-to-normal heartbeat intervals (SDNN), low (LF) and high frequency (HF) power, and the LF/HF ratio. Psychometric outcome measures included the Athens Insomnia Scale (AIS) and the Hamilton Anxiety Rating Scale (HARS). Results : Compared to controls, hyperactive heart fire patients had higher HR (9.6 ± 2.62%), LF (22 ± 4.21%) and LF/HF ratio (23 ± 3.14%), and lower SDNN (21 ± 2.33%) and HF (18 ± 4.61%). Patients showed increased anxiety, both with somatic (33 ± 11.2%) and psychic symptoms (39 ± 10.5%) with more difficulty falling asleep (47 ± 9.9%) and diurnal impact of sleep (31 ± 9.6%). Conclusion : Hyperactive heart fire patients may have a sympathovagal imbalance due to a reduced parasympathetic tone and/or adominant sympathetic tone, which may be at the origin of the observed symptoms of insomnia and anxiety.

Phytochemicals (Pch) present in fruits, vegetables and other foods, are known to inhibit or induce drug metabolism and transport. An exhaustive search was performed in five databases covering from 2000 to 2021. Twenty-one compounds from plants were found to modulate CYP3A and/or P-gp activities and modified the pharmacokinetics and the therapeutic effect of 27 different drugs. Flavonols, flavanones, flavones, stilbenes, diferuloylmethanes, tannins, protoalkaloids, flavans, hyperforin and terpenes, reduce plasma concentration of cyclosporine, simvastatin, celiprolol, midazolam, saquinavir, buspirone, everolimus, nadolol, tamoxifen, alprazolam, verapamil, quazepam, digoxin, fexofenadine, theophylline, indinavir, clopidogrel. Anthocyanins, flavonols, flavones, flavanones, flavonoid glycosides, stilbenes, diferuloylmethanes, catechin, hyperforin, alkaloids, terpenes, tannins and protoalkaloids increase of plasma concentration of buspirone, losartan, diltiazem, felodipine, midazolam, cyclosporine, triazolam, verapamil, carbamazepine, diltiazem, aripiprazole, tamoxifen, doxorubicin, paclitaxel, nicardipine. Interactions between Pchs and drugs affect the gene expression and enzymatic activity of CYP3A and P-gp transporter, which has an impact on their bioavailability; such that co-administration of drugs with food, beverages and food supplements can cause a subtherapeutic effect or overdose. Therefore, it is important for the clinician to consider these interactions to obtain a better therapeutic effect.

TOR proteins, also known as targets of rapamycin, are serine/threonine kinases involved in various signaling pathways that regulate cell growth. The protozoan parasite Giardia lamblia is the causative agent of giardiasis, a neglected infectious disease in humans. In this study, we used a bioinformatics approach to examine the structural features of GTOR, a G. lamblia TOR-like protein, and predict functional associations. Our findings confirmed that it shares significant similarities with functional TOR kinases, including a binding domain for the FKBP-rapamycin complex and a kinase domain resembling that of phosphatidylinositol 3-kinase-related kinases. In addition, it can form multiprotein complexes such as TORC1 and TORC2. These results provide valuable insights into the structure–function relationship of GTOR, highlighting its potential as a molecular target for controlling G. lamblia cell proliferation. Furthermore, our study represents a step toward rational drug design for specific anti-giardiasis therapeutic agents.

Owners’ understanding of dog behaviour influences dog welfare. This study aimed to investigate owners’ experiences of living with dogs and perceptions of dog behaviour/behaviour change. Data from an ongoing UK/ROI longitudinal study of dogs were used. Open-ended survey data (n = 3577 comments, n = 1808 dogs) when dogs were 12/16 weeks (data combined), 6, 12, 18 and 24 months were analysed to cover the dog’s puppyhood/adolescence. To evaluate the usefulness of open-ended survey questions, both quantitative textual and qualitative thematic analyses were employed. Textual analysis identified an overall positive sentiment at all timepoints; the proportion of positive: negative sentiments increased with the dog’s age. Words related to ‘love’ were the most frequent descriptors at all but the first timepoint, when ‘bite’ was the most frequent descriptor. Qualitative analysis helped to identify that owners attribute dog behaviour to ‘Dog’s biology’, ‘Personality/deliberate action’ and ‘External influences’. Analysis of open-ended survey responses helped to identify changes in perception over time. When dogs were young, owners described problematic behaviours as ‘mischievous’, unintentional and context-specific. Similar behaviours shown by older dogs were seen as ‘deliberate’. Both positive and negative experiences of dog ownership were identified. However, as not all respondents answered open-ended questions, the generalisability of our findings is limited.

Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.

Abstract. To investigate changes in the corneal shape caused by fluid–gas exchange after vitrectomy. This retrospective case-control study included 43 eyes that underwent a combination of cataract surgery and vitrectomy. The corneal shape was measured using anterior segment optical coherence tomography CASIA2. The corneal shape measurements were performed preoperatively, 1 day, 1 week, 1 month, and 3 months after surgery. After calculating the real K value from the actual measured values of the posterior shape of the corneal refracting power and the single posterior corneal refracting power value, Fourier analysis values were examined. Fluid–gas exchange was performed in 23 eyes (gas group), while it was not performed in 20 eyes (nongas group). There was a significant increase in the real K value in the regular and asymmetry components (0.61 ± 0.36, 0.82 ± 0.64) in the gas group only on the first day after surgery (Steel–Dwass test; P

Enrico Gallo,1 Carlo Diaferia,2 Elisabetta Rosa,2 Giovanni Smaldone,1 Giancarlo Morelli,2 Antonella Accardo2 1IRCCS SDN, Naples, 80143, Italy; 2Department of Pharmacy and Research Centre on Bioactive Peptides (CIRPeB), University of Naples “Federico II”, Naples, 80134, ItalyCorrespondence: Antonella AccardoDepartment of Pharmacy and Research Centre on Bioactive Peptides (CIRPeB), University of Naples “Federico II”, Via Mezzocannone 16, Naples, 80134, ItalyTel +39 0812532045Fax +39 0812536642Email antonella.accardo@unina.itIntroduction: The clinical use of the antitumoral drug doxorubicin (Dox) is reduced by its dose-limiting toxicity, related to cardiotoxic side effects and myelosuppression. In order to overcome these drawbacks, here we describe the synthesis, the structural characterization and the in vitro cytotoxicity assays of hydrogels (HGs) and nanogels (NGs) based on short peptide sequences loaded with Dox or with its liposomal formulation, Doxil.Methods: Fmoc-FF alone or in combination with (FY)3 or PEG8-(FY)3 peptides, at two different ratios (1/1 and 2/1 v/v), were used for HGs and NGs formulations. HGs were prepared according to the “solvent-switch” method, whereas NGs were obtained through HG submicronition by the top-down methodology in presence of TWEEN® 60 and SPAN® 60 as stabilizing agents. HGs gelation kinetics were assessed by Circular Dichroism (CD). Stability and size of NGs were studied using Dynamic Light Scattering (DLS) measurements. Cell viability of empty and filled Dox HGs and NGs was evaluated on MDA-MB-231 breast cancer cells. Moreover, cell internalization of the drug was evaluated using immunofluorescence assays.Results: Dox filled hydrogels exhibit a high drug loading content (DLC=0.440), without syneresis after 10 days. Gelation kinetics (20– 40 min) and the drug release (16– 28%) over time of HGs were found dependent on relative peptide composition. Dox filled NGs exhibit a DLC of 0.137 and a low drug release (20– 40%) after 72 h. Empty HGs and NGs show a high cell viability (> 95%), whereas Dox loaded ones significantly reduce cell viability after 24 h (49– 57%) and 72 h (7– 25%) of incubation, respectively. Immunofluorescence assays evidenced a different cell localization for Dox delivered through HGs and NGs with respect to the free drug.Discussion: A modulation of the Dox release can be obtained by changing the ratios of the peptide components. The different cellular localization of the drug loaded into HGs and NGs suggests an alternative internalization mechanism. The high DLC, the low drug release and preliminary in vitro results suggest a potential employment of peptide-based HGs and NGs as drug delivery tools.Keywords: hydrogels, nanogels, drug delivery, peptide materials, doxorubicin, in vitro assays

Fusarium genus is a wide host phytopathogen causing significant losses in multiple crops, including hops. There is limited information on the sustainable management of Fusarium spp. in hop fields. Trichoderma is an endophytic fungus used in agriculture as a biological control agent (BCA) and as a plant growth promoter. It has been used to antagonize Fusarium spp. in other crops. The objective of the current study was to identify indigenous hop field Trichoderma isolates with biocontrol and hop growth promotion capabilities. Three isolates of Fusarium and eleven autochthonous Trichoderma isolates collected from sustainable hop fields were evaluated in this work. Direct confrontation tests (the physical interaction between the pathogen and BCA and their competition for space and nutrient resources) and membrane tests (the capacity of the BCA to produce metabolites or enzymes through a cellophane film and inhibit the development of the pathogen) assessed the antagonism of these Trichoderma isolates against Fusarium culmorum, F. sambucinum, and F. oxysporum. A bioassay with hop plantlets inoculated with a spore suspension of Trichoderma was performed to assess its hop growth enhancement. T. hamatum (T311 and T324), T. virens T312, and T. gamsii T327 showed high growth inhibition of Fusarium spp. phytopathogens and high plant growth promotion. Native Trichoderma isolates from sustainable hop-producing soils have great potential as BCAs and hop growth promoters.

Native strains of Trichoderma in vineyard soil represent an opportunity for reducing the incidence of grapevine trunk diseases (GTDs) in vineyards. Moreover, its relationship with the environment (physicochemical soil characteristics and farming management practices) remains unclear. In the current study, a survey was carried out on farming management used by viticulturists, and soil samples were studied to analyze their physicochemical properties and to isolate Trichoderma strains. Later, statistical analyses were performed to identify possible correlations between Trichoderma populations, soil management and soil characteristics. In addition, in vitro tests, including antibiosis and mycoparasitism, were performed to select those Trichoderma strains able to antagonize Phaeoacremonium minimum. In this study a positive correlation was found between the iron content and pH in the soil, and a lower pH increases Trichoderma populations in soils. Vineyard management also affects Trichoderma populations in the soil, negatively in the case of fertilization and tillage and positively in the case of herbicide spraying. Two Trichoderma native strains were selected as potential biocontrol agents (Trichoderma gamsii T065 and Trichoderma harzianum T087) using antibiosis and mycoparasitism as mechanisms of action. These results led to the conclusion that native Trichoderma strains hold great potential as biological control agents and as producers of secondary metabolites.

Objective The process of reflexivity is used to critically examine the experience of conducting qualitative research with functionally diverse older adults in a post disaster context. Methods The design of the study began with an interpretative phenomenological framework, using in-depth interviews. Fifteen individuals with functional and access needs living in Puerto Rico were interviewed regarding their experiences after Hurricane María of 2017. Findings In the field, it was necessary to expand the initial design, and adjust to participants’ preferences and needs, as well as situational characteristics, without compromising ethical standards of practice. The methodology transformed because of the need for flexibility requiring humility from the researchers. A more relational form of inquiry was warranted, which acknowledged the intersubjectivity of human experience. This entailed adapting to community involvement, building rapport with community leaders functioning as gatekeepers, and integrating family or friends in interviews. Discussion The reflexive approach allowed for a better understanding of the researcher’s positionalities and how they influence the ability or inability to develop trust (e.g. insider/ outsider status, Puerto Rican/ US, with functional and access needs/ without functional and access needs). Conclusions Given the shift toward relational inquiry and due to the challenges faced while carrying out the study, we suggest that post-disaster qualitative research would benefit from further including principles of indigenous decolonizing methodologies, which can be incorporated into studies using interpretative phenomenological analysis.