Presynaptic and postsynaptic mesolimbic dopamine D3 receptors play distinct roles in cocaine versus opioid reward in mice.

BACKGROUND: Past research illuminated pivotal roles of dopamine D3 receptors (D3Rs) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms underlying these actions remain unclear. METHODS: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1R-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics, microdialysis, and behavioral assays (n≥8) to functionally characterize the roles of presynaptic versus postsynaptic D3Rs in cocaine and opioid actions. RESULTS: Our results revealed D3R expression in ∼20% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While D2R was expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3Rs from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked NAc dopamine release. Conversely, D3R deletion from D1R-expressing neurons attenuated locomotor responses to D1-like and D2-like agonists. Strikingly, D3R deletion from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia. CONCLUSIONS: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. The mesolimbic D3Rs are critically involved in the actions of opioids but not cocaine.

Stereolithographic Rapid Prototyping of Clear, Foldable, Non-Refractive Intraocular Lens Designs: A Proof-of-Concept Study.

PURPOSE: A cataract is a cloudy area in the crystalline lens. Cataracts are the leading cause of blindness and the second cause of severe vision impairment worldwide. During cataract surgery, the clouded lens is extracted and replaced with an artificial intraocular lens, which restores the optical power. The fabrication of intraocular lenses using existing molding and lathing techniques is a complex and time-consuming process that limits the development of novel materials and designs. To overcome these limitations, we have developed a stereolithography-based process for producing models of clear lens designs without refractive function, serving as a proof of concept. This process has the potential to contribute toward new lens development, allowing for unlimited design iterations and an expanded range of materials for scientists to explore. METHODS: Lens-like 3D objects without refractive function were fabricated by using stereolithography. A photopolymerizable resin containing 2-phenoxyethyl acrylate, poly (ethylene glycol) dimethacrylate, and a suitable photoinitiator was developed for the production of lens-like 3D object prototypes. The morphology of the printed devices was characterized by scanning electron microscopy. The transparency and thermal properties were analyzed using spectrophotometry and differential scanning calorimetry, respectively. The biocompatibility of the devices was investigated in a cultured human lens cell line (FHL-124), using a standard lactate dehydrogenase assay, and the lenses were folded and implanted in the human capsular bag model. RESULTS: One-piece lens-like 3D objects without refractive function and with loop-haptic design were successfully fabricated using Stereolithography (SLA) technique. The resulting 3D objects were transparent, as determined by UV spectroscopy. The lactate dehydrogenase test demonstrated the tolerance of lens cells to the prototyping material, and apparent foldability and shape recovery was observed during direct injection into a human capsular bag model in vitro. CONCLUSIONS: This proof-of-principle study demonstrated the potential and significance of the rapid prototyping process for research and development of lens-like 3D object prototypes, such as intraocular lenses.

Leveraging Biomaterial Platforms to Study Aging-Related Neural and Muscular Degeneration.

Aging is a complex multifactorial process that results in tissue function impairment across the whole organism. One of the common consequences of this process is the loss of muscle mass and the associated decline in muscle function, known as sarcopenia. Aging also presents with an increased risk of developing other pathological conditions such as neurodegeneration. Muscular and neuronal degeneration cause mobility issues and cognitive impairment, hence having a major impact on the quality of life of the older population. The development of novel therapies that can ameliorate the effects of aging is currently hindered by our limited knowledge of the underlying mechanisms and the use of models that fail to recapitulate the structure and composition of the cell microenvironment. The emergence of bioengineering techniques based on the use of biomimetic materials and biofabrication methods has opened the possibility of generating 3D models of muscular and nervous tissues that better mimic the native extracellular matrix. These platforms are particularly advantageous for drug testing and mechanistic studies. In this review, we discuss the developments made in the creation of 3D models of aging-related neuronal and muscular degeneration and we provide a perspective on the future directions for the field.

Malignant carotid body tumors: What we know, what we do, and what we need to achieve. A systematic review of the literature.

Malignant carotid body tumors (MCBT) are rare and diagnosed after detection of nodal or distant metastases. This systematic review (SR) focuses on MCBT initially approached by surgery. Preferred Reporting Items for SR and Meta-Analysis (MA) guided the articles search from 2000 to 2023 on PubMed, Scopus, and Web of Science. Among 3548 papers, 132 (337 patients) were considered for SR; of these, 20 (158 patients) for MA. Malignancy rate was 7.3%, succinate dehydrogenase (SDH) mutation 17%, age at diagnosis between 4th and 6th decades, with a higher prevalence of females. MCBTs were mostly Shamblin III, with nodal and distant metastasis in 79.7% and 44.7%, respectively. Malignancy should be suspected if CBT >4 cm, Shamblin III, painful or otherwise symptomatic, at the extremes of age, bilateral, with multifocal disease, and SDHx mutations. Levels II-III clearance should be performed to exclude nodal metastases and adjuvant treatments considered on a case-by-case basis.

Genomic Characterization of Two NDM-5-Producing Isolates of Klebsiella pneumoniae ST11 from a Single Patient.

Two metallo-ß-lactamase-producing Klebsiella pneumoniae (HA30 and HA31) were isolated in a hospital in Argentina during 2018. K. pneumoniae HA30 was isolated from a rectal swab during the epidemiological surveillance for carbapenemase-producing strains, while K. pneumoniae HA31 was collected from the same patient 4 days after hospitalization. The aim of the present study was to identify the clonal relationships and resistome of these two NDM-producing K. pneumoniae strains isolated from a patient with a fatal outcome. Whole-genome sequencing (WGS) was performed using Illumina MiSeq-I, and subsequent analysis involved genome assembly, annotation, antibiotic resistance gene identification, multilocus sequence typing (MLST), and plasmid characterization using bioinformatics tools. Conjugation assays to E. coli J53 was conducted as previously described. K. pneumoniae HA30 exhibited extensively drug-resistant phenotype, while HA31 was multidrug-resistant as defined by Magiorakos et al., including both resistance to carbapenems, aminoglycosides and ciprofloxacin with blaNDM-5, blaCTX-M-15 and rmtB genes found in both strains. MLST analysis showed that both strains belonged to ST11, differing by only 4 cgSNPs, indicating that K. pneumoniae HA30 and HA31 were the same strain. Conjugation assays revealed that K. pneumoniae HA31 strain possessed a transferable plasmid to E. coli J53. Bioinformatics studies identified that the same strain colonizing an inpatient during hospital admission subsequently caused the infection leading to a fatal outcome, being the first report of blaNDM-5, rmtB and blaCTX-M-15 genes in a K. pneumoniae ST11 strain from Latin America. Our results also highlighted the importance of focusing on epidemiological surveillance programs.

Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking.

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson's-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

Clinical Significance of SOX10 Expression in Human Pathology.

The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, SOX10, a member of the SOX gene family, stands out. Located on chromosome 22q13, the SOX10 gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in SOX10 have been associated with congenital disorders such as Waardenburg-Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.

Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons.

Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs). Methods: Cre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed. Results: Innate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2, a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP-Drd2HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. Conclusions: This study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling.

Small bowel cavernous hemangioma as an uncommon cause of iron-deficiency anemia.

Small bowel hemangiomas are benign congenital vascular lesions that can be asymptomatic or cause anemia, gastrointestinal bleeding, obstruction, or intestinal perforation. We report the case of a 75-year-old woman who, after years of study for iron-deficiency anemia, was diagnosed with a cavernous hemangioma of the jejunum by capsule endoscopy, which was confirmed after surgical resection.

Understanding of the Effect of the Adsorption of Atom and Cluster Silver on Chitosan: An In Silico Analysis.

In this work, the structural, electronic, and optical stability properties of the chitosan monomer (M-Ch) and atomic silver complex are reported, as well as a unitary cell of a silver cluster in the gas phase and acetic acid. The generalized gradient approximation HSEh1PBE/def2-TZVPP50 results established the structures' anionic charge (Q = -1|e|) and the doublet state (M = 2). The high cohesive energy indicates structural stability, and the quantum-mechanical descriptors show a high polarity and low chemical reactivity. Also, the quantum-mechanical descriptors present a low work function that shows the structures are suitable for applications in light-emitting diodes. Finally, the electronic behavior observed by the |HOMO-LUMO| gap energy changes depending on the atomic silver incorporated into the complex.

Novel Imaging-Based Biomarkers for Identifying Carotid Plaque Vulnerability.

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.

Menstrual blood-derived mesenchymal stromal cells: impact of preconditioning on the cargo of extracellular vesicles as potential therapeutics.

BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown to exert their therapeutic effects through the secretion of broad spectrum of paracrine factors, including extracellular vesicles (EVs). Accordingly, EVs are being pursued as a promising alternative to cell-based therapies. Menstrual blood-derived stromal cells (MenSCs) are a type of MSC that, due to their immunomodulatory and regenerative properties, have emerged as an innovative source. Additionally, new strategies of cell priming may potentially alter the concentration and cargo of released EVs, leading to modification of their biological properties. In this study, we aimed to characterize the EVs released by MenSCs and compare their therapeutic potential under three different preconditioning conditions (proinflammatory stimuli, physioxia, and acute hypoxia). METHODS: MenSCs were isolated from five healthy women. Following culturing to 80% confluence, MenSCs were exposed to different priming conditions: basal (21% O2), proinflammatory stimuli (IFNγ and TNFα, 21% O2), physioxia (1-2% O2), and acute hypoxia (< 1% O2) for 48-72 h. Conditioned media from MenSCs was collected after 48 h and EVs were isolated by a combination of ultra-filtration and differential centrifugation. An extensive characterization ranging from nano-flow cytometry (nFC) to quantitative high-throughput shotgun proteomics was performed. Bioinformatics analyses were used to derive hypotheses on their biological properties. RESULTS: No differences in the morphology, size, or number of EVs released were detected between priming conditions. The proteome analysis associated with basal MenSC-EVs prominently revealed their immunomodulatory and regenerative capabilities. Furthermore, quantitative proteomic analysis of differentially produced MenSC-EVs provided sufficient evidence for the utility of the differential preconditioning in purpose-tailoring EVs for their therapeutic application: proinflammatory priming enhanced the anti-inflammatory, regenerative and immunomodulatory capacity in the innate response of EVs, physioxia priming also improves tissue regeneration, angiogenesis and their immunomodulatory capacity targeting on the adaptive response, while acute hypoxia priming, increased hemostasis and apoptotic processes regulation in MenSC-EVs, also by stimulating immunomodulation mainly through the adaptive response. CONCLUSIONS: Priming of MenSCs under proinflammatory and hypoxic conditions affected the cargo proteome of EVs released, resulting in different therapeutic potential, and thus warrants experimental exploration with the aim to generate better-defined MSC-derived bioproducts.

The Acinetobacter baumannii website (Ab-web): a multidisciplinary knowledge hub, communication platform, and workspace.

Acinetobacter baumannii is a Gram-negative bacterium increasingly implicated in hospital-acquired infections and outbreaks. Effective prevention and control of such infections are commonly challenged by the frequent emergence of multidrug-resistant strains. Here we introduce Ab-web (https://www.acinetobacterbaumannii.no), the first online platform for sharing expertise on A. baumannii. Ab-web is a species-centric knowledge hub, initially with 10 articles organized into two main sections, 'Overview' and 'Topics', and three themes, 'epidemiology', 'antibiotic resistance', and 'virulence'. The 'workspace' section provides a spot for colleagues to collaborate, build, and manage joint projects. Ab-web is a community-driven initiative amenable to constructive feedback and new ideas.

Identification of a Specific Biomarker of Acinetobacter baumannii Global Clone 1 by Machine Learning and PCR Related to Metabolic Fitness of ESKAPE Pathogens.

Since the emergence of high-risk clones worldwide, constant investigations have been undertaken to comprehend the molecular basis that led to their prevalent dissemination in nosocomial settings over time. So far, the complex and multifactorial genetic traits of this type of epidemic clones have allowed only the identification of biomarkers with low specificity. A machine learning algorithm was able to recognize unequivocally a biomarker for early and accurate detection of Acinetobacter baumannii global clone 1 (GC1), one of the most disseminated high-risk clones. A support vector machine model identified the U1 sequence with a length of 367 nucleotides that matched a fragment of the moaCB gene, which encodes the molybdenum cofactor biosynthesis C and B proteins. U1 differentiates specifically between A. baumannii GC1 and non-GC1 strains, becoming a suitable biomarker capable of being translated into clinical settings as a molecular typing method for early diagnosis based on PCR as shown here. Since the metabolic pathways of Mo enzymes have been recognized as putative therapeutic targets for ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens, our findings highlight that machine learning can also be useful in knowledge gaps of high-risk clones and provides noteworthy support to the literature to identify relevant nosocomial biomarkers for other multidrug-resistant high-risk clones. IMPORTANCE A. baumannii GC1 is an important high-risk clone that rapidly develops extreme drug resistance in the nosocomial niche. Furthermore, several strains have been identified worldwide in environmental samples, exacerbating the risk of human interactions. Early diagnosis is mandatory to limit its dissemination and to outline appropriate antibiotic stewardship schedules. A region with a length of 367 bp (U1) within the moaCB gene that is not subjected to lateral genetic transfer or to antibiotic pressures was successfully found by a support vector machine model that predicts A. baumannii GC1 strains. At the same time, research on the group of Mo enzymes proposed this metabolic pathway related to the superbug's metabolism as a potential future drug target site for ESKAPE pathogens due to its central role in bacterial fitness during infection. These findings confirm that machine learning used for the identification of biomarkers of high-risk lineages can also serve to identify putative novel therapeutic target sites.

Menstrual blood-derived stromal cells: insights into their secretome in acute hypoxia conditions.

BACKGROUND: Despite constant advances in regenerative medicine, the closure of chronic wounds is still challenging. Therapeutic approaches using locally administered MSCs have been considered a promising option. However, the viability of these cells is seriously threatened by acute hypoxic stress linked to wound healing. In this work, we aimed to study the tolerance of Menstrual blood-derived stromal cells (MenSCs) to acute hypoxia and their therapeutic paracrine effect. METHODS: Isolated MenSCs were phenotypically characterized and evaluated in terms of proliferation, viability, and gene expression, under acute hypoxia (AH) compared with conventional cultured condition or normoxia (N). A step further, the secretome of MenSCs under acute hypoxia was analyzed with respect to their miRNAs content and by in vitro functional assays. For the analysis of differences between the two groups, Student's t-test was performed and one-way ANOVA and Tukey's multiple comparisons test for multiple groups were used. RESULTS: Our results revealed that the viability of MenSCs was not affected under acute hypoxia, although proliferation rate slowed down. Gene analysis revealed 5 up-regulated (BNIP3, ANGPTL4, IL6, IL1B, and PDK1) and 4 down-regulated genes (IDO1, HMOX1, ANGPTL2, and HGF) in AH compared to N. Global gene expression analysis revealed a decrease in the gene ontology functions of migration and wound response with respect to the normoxic condition. In contrast, functions such as angiogenesis were enriched under the AH condition. Regarding the secretome analysis, two miRNAs involved in angiogenic processes (hsa-miR-148a-3p and hsa-miR-378a-3p), were significantly up-expressed when compared to the normoxic condition, being MYC gene, the unique target of both. Functional assays on HUVECs revealed a potential pro-angiogenic capacity of MenSCs cultured in both oxygen conditions (N and AH) based on the wound closure and tube formation results of their released paracrine factors. However, when compared to normoxia, the paracrine factors of MenSCs under acute hypoxia slightly reduced the proliferation, migration, and in vitro wound closure of HUVECs. CONCLUSIONS: MenSC exhibited a good survival capacity under acute hypoxic conditions as well as beneficial properties applicable in the field of tissue regeneration through their secretome, which makes them a potential cell source for wound healing interventions.

Transcriptome Profile Reveals Differences between Remote and Ischemic Myocardium after Acute Myocardial Infarction in a Swine Model.

Acute myocardial infarction (AMI) is the consequence of an acute interruption of myocardial blood flow delimiting an area with ischemic necrosis. The loss of cardiomyocytes initiates cardiac remodeling in the myocardium, leading to molecular changes in an attempt to recover myocardial function. The purpose of this study was to unravel the differences in the molecular profile between ischemic and remote myocardium after AMI in an experimental model. To mimic human myocardial infarction, healthy pigs were subjected to occlusion of the mid-left anterior descending coronary artery, and myocardial tissue was collected from ischemic and remote zones for omics techniques. Comparative transcriptome analysis of both areas was accurately validated by proteomic analysis, resulting in mitochondrion-related biological processes being the most impaired mechanisms in the infarcted area. Moreover, Immune system process-related genes were up-regulated in the remote tissue, mainly due to the increase of neutrophil migration in this area. These results provide valuable information regarding differentially expressed genes and their biological functions between ischemic and remote myocardium after AMI, which could be useful for establishing therapeutic targets for the development of new treatments.

Antimicrobial resistance dissemination associated with intensive animal production practices in Argentina: A systematic review and meta-analysis

Resumen El abuso y mal uso de los antimicrobianos aceleró la propagación de bacterias resistentes. La asociación entre las infecciones que presentan resistencia a antimicrobianos (RAM) en humanos y el uso de antimicrobianos en la producción agropecuaria es compleja, pero está bien documentada. Proporcionamos una revisión sistemática y metaanálisis sobre la diseminación de la resistencia a antimicrobianos designados como críticamente importantes por la Organización Mundial de la Salud (OMS) en cerdos, aves y bovinos de producción intensiva y extensiva en Argentina. Se buscó información en bases de datos electrónicas (Medline-PubMed, Web of Science, SciELO, Sistema Nacional de Repositorios Digitales de Argentina) y en la literatura gris. Se incluyeron estudios epidemiológicos sobre la RAM en las principales bacterias transmitidas por los alimentos - Salmonella spp., Campylobacter spp., Escherichia coli y Enterococcus spp. - y bacterias causantes de mastitis aisladas de cerdos, pollos y bovinos. Los resultados de este estudio apoyan la hipótesis de que la RAM de las bacterias transmitidas por los alimentos alcanza niveles alarmantes. Los metaanálisis seguidos de análisis por subgrupos mostraron asociación entre la RAM y (a) el animal (p<0,01) para estreptomicina, ampicilina y tetraciclina o (b) el sistema productivo (p<0,05) para estreptomicina, cefotaxima, ampicilina, ácido nalidíxico y tetraciclina. La mayor prevalencia conjunta de multirresistencia se detectó en cerdos (0,47 [0,29; 0,66]) y producción intensiva (0,62 [0,34; 0,83]), mientras que la menor correspondió a bovinos de leche (0,056 [0,003; 0,524]) y producción extensiva (0,107 [0,043; 0,240]). Se observó un vacío de información respecto de los bovinos de feedlot. Es urgente adoptar medidas políticas para coordinar y armonizar la vigilancia de la RAM y regular el uso de antimicrobianos en animales.

Abstract Abuse and misuse of antimicrobial agents has accelerated the spread of antimicrobial-resistant bacteria. The association between antimicrobial-resistant infections in humans and antimicrobial use in agriculture is complex, but well-documented. This study provides a systematic review and meta-analysis of the dissemination of antimicrobial resistance (AMR) to antimicrobials defined as critically important by the WHO, in swine, chicken, and cattle from intensive and extensive production systems in Argentina. We conducted searches in electronic databases (MEDLINE-PubMed, Web of Science, SciELO, the National System of Digital Repositories from Argentina) as well as in the gray literature. Inclusion criteria were epidemiological studies on AMR in the main food-transmitted bacteria, Salmonella spp., Campylobacter spp., Escherichia coli and Enterococcus spp., and mastitis-causing bacteria, isolated from swine, chicken, dairy and beef cattle from Argentina. This study gives evidence for supporting the hypothesis that AMR of common food-transmitted bacteria in Argentina is reaching alarming levels. Meta-analyses followed by subgroup analyses confirmed the association between the prevalence of AMR and (a) animal species (p<0.01) for streptomycin, ampicillin and tetracycline or (b) the animal production system (p<0.05) for streptomycin, cefotaxime, nalidixic acid, ampicillin and tetracycline. Moreover, swine (0.47 [0.29; 0.66]) and intensive production (0.62 [0.34; 0.83]) showed the highest pooled prevalence of multidrug resistance while dairy (0.056 [0.003; 0.524]) and extensive production (0.107 [0.043; 0.240]) showed the lowest. A research gap regarding beef-cattle from feedlot was identified. Finally, there is an urgent need for political measures meant to coordinate and harmonize AMR surveillance and regulate antimicrobial use in animal production.

On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Genomic data reveals the emergence of the co-occurrence of blaKPC-2 and blaCTX-M-15 in an Escherichia coli ST648 strain isolated from rectal swab within the framework of hospital surveillance.

OBJECTIVES: The worldwide dissemination of carbapenemase-producing Escherichia coli lineages belonging to high-risk clones poses a challenging public health menace. The aim of this work was to investigate genomic features of a colonizing multidrug-resistant strain of Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli from our institution. METHODS: Whole-genome sequencing was done by Illumina MiSeq-I, and de novo assembly was achieved using SPAdes. Resistome, mobilome, plasmids, virulome, and integrons were analysed using ResFinder, AMRFinder, ISFinder, PlasmidFinder, MOB-suite, VirulenceFinder, and IntegronFinder. Sequence types (STs) were identified with pubMLST and BIGSdb databases. Conjugation assays were also performed. RESULTS: Escherichia coli HA25pEc was isolated from a rectal swab sample taken within the framework of the hospital epidemiological surveillance protocol for detection of carbapenemase-producing Enterobacterales. Escherichia coli HA25pEc corresponded to the first report of ST648 co-harbouring blaKPC-2 and blaCTX-M-15 in Latin America from a colonized patient. It had 19 antibiotic resistance genes (ARGs), including blaKPC-2, located on a Tn4401a isoform. Conjugation assays revealed that blaKPC-2 was not transferred by conjugation to E. coli J53 under our experimental conditions. CONCLUSION: Escherichia coli ST648 has been detected previously in companion and farm animals as well as in hospital- and community-acquired infections worldwide. Although scarcely reported as KPC-producers, our finding in a culture surveillance with several acquired ARGs, including blaCTX-M-15, alerts the potential of this clone for worldwide unnoticed spreading of extreme drug resistance to ß-lactams. These data reinforce the importance of carrying out molecular surveillance to identify reservoirs and warn about the dissemination of new international clones in carbapenemase-bearing patients.