Bronchogenic Cyst and Pericardial Agenesis: A Case Report.

Bronchogenic cysts are a rare congenital condition, and their association with pericardial agenesis is even more uncommon. We present the case of a 23-year-old patient who was diagnosed with an upper lobe bronchogenic cyst and subsequently underwent an upper lobectomy. Further evaluation revealed the presence of complete left pericardial agenesis.

Aggregation-Induced Emission Enhancement and Solid-State Photoswitching of Crystalline Carbazole N-Salicylidene Anilines.

The development of fluorescent stimuli-responsive organic materials has attracted substantial interest due to their increasing optoelectronic applications. This study systematically introduces fluorine atoms on one end of carbazole-based N-salicylidene anilines 5a-5f to elucidate the impact in their solution and solid-state photophysics. The addition of fluorine atoms at one end of the molecule induced significant changes, for example, a reduction in the quantum yield (QY) fluorescence emission in solution, going from QY near unity in compound 5a (QY ∼ 100%) to a negligible emission in 5f (QY < 1%). Similarly, compound 5a showed a very strong aggregation-induced enhancement emission behavior, whereas compounds with a higher fluorine content were almost quenched. Furthermore, the crystalline solid-state photoisomerization in N-salicylidene anilines is not trivial, and only compounds with three (5e) and five fluorine atoms (5f) exhibited reversible solid-state photoisomerization under 405 nm light source irradiation. We propose that the presence of the arene-perfluoroarene interaction in the crystalline array facilitates the latter behavior. Our findings present a comprehensive study of crystal engineering for the obtention of photoswitchable crystalline materials and adjustable photophysics response, paving the way for its implementation in other systems.

Racial disparities in end-of-life suffering within surgical intensive care units.

Background: End-of-life (EOL) care is associated with high resource utilization. Recognizing and effectively communicating that EOL is near promotes more patient-centered care, while decreasing futile interventions. We hypothesize that provider assessment of futility during the surgical intensive care unit (SICU) admission would result in higher rates of Do Not Resuscitate (DNR). Methods: We performed a retrospective review of a prospective SICU registry of all deceased patients across a health system, 2018-2022. The registry included a subjective provider assessment of patient's expected survival. We employed multivariable logistic regression to adjust for clinical factors while assessing for association between code status at death and provider's survival assessment with attention to race-based differences. Results: 746 patients-105 (14.1%) traumatically injured and 641 (85.9%) non-traumatically injured-died over 4.5 years in the SICU (mortality rate 5.9%). 26.3% of these deaths were expected by the ICU provider. 40.9% of trauma patients were full code at the time of death, compared with 15.6% of non-traumatically injured patients. Expected death was associated with increased odds of DNR code status for non-traumatically injured patients (OR 1.8, 95% CI 1.03 to 3.18), but not for traumatically injured patients (OR 0.82, 95% CI 0.22 to 3.08). After adjusting for demographic and clinical characteristics, black patients were less likely to be DNR at the time of death (OR 0.49, 95% CI 0.32 to 0.75). Conclusion: 20% of patients who died in our SICU had not declared a DNR status, with injured black patients more likely to remain full code at the time of death. Further evaluation of this cohort to optimize recognition and communication of EOL is needed to avoid unnecessary suffering. Level of evidence: Level III/prognostic and epidemiological.

Association between papillary thyroid cancer and primary aldosteronism in individuals with hypertension.

BACKGROUND: Aldosterone excess chronically induces oxidative stress and cell proliferation. Previously, a single study investigated primary aldosteronism (PA) in patients with papillary thyroid cancer (PTC), albeit without a matched control group. METHODS: We conducted a propensity score matched case-control study to investigate the association between PA and PTC in individuals with arterial hypertension (HT). PA was investigated in 137 patients with PTC and HT. The control group included 137 (1:1) age, sex-, and body mass index (BMI)-matched individuals with HT. We conducted a secondary analysis in which the controls were also matched according to HT stage. RESULTS: The prevalence of PA was 29.20% (95% confidence interval [CI], 21.91%-37.68%) in the PTC group and 20.44% (95% CI, 14.22%-28.35%) in the controls not matched for HT stage (p = 0.093). Although the PA prevalence was similar in both groups, the frequency of severe HT (stage III or resistant) was significantly lower in the PTC group (23%) compared to the hypertensive controls (73%, p < 0.001). After matching the controls by HT stage, the prevalence of PA in the PTC group was significantly higher compared to the hypertensive controls (9.56%; 95% CI, 5.39%-16.1%, p < 0.0001). In the multivariable analysis, PTC was independently associated with PA in both unmatched hypertensive individuals (odds ratio [OR] 4.74; 95% CI, 2.26-10.55; p< 0.001) and in those matched for HT stage (OR 5.88, 95% CI, 2.79-13.37; p< 0.001). CONCLUSION: PTC was an independent variable associated with a diagnosis of PA in hypertensive individuals. Therefore, we propose the association between PTC and HT as a new recommendation for PA screening regardless of HT severity.

Non-Hermitian Fermi-Dirac Distribution in Persistent Current Transport.

Persistent currents circulate continuously without requiring external power sources. Here, we extend their theory to include dissipation within the framework of non-Hermitian quantum Hamiltonians. Using Green's function formalism, we introduce a non-Hermitian Fermi-Dirac distribution and derive an analytical expression for the persistent current that relies solely on the complex spectrum. We apply our formula to two dissipative models supporting persistent currents: (i) a phase-biased superconducting-normal-superconducting junction; (ii) a normal ring threaded by a magnetic flux. We show that the persistent currents in both systems exhibit no anomalies at any emergent exceptional points, whose signatures are only discernible in the current susceptibility. We validate our findings by exact diagonalization and extend them to account for finite temperatures and interaction effects. Our formalism offers a general framework for computing quantum many-body observables of non-Hermitian systems in equilibrium, with potential extensions to nonequilibrium scenarios.

Positive sensory symptoms, in surgically managed patients with carpal tunnel syndrome: A long term follow­up.

Carpal tunnel syndrome (CTS) is the most frequent entrapment neuropathy. Patients commonly experience neuropathic pain, leading them to seek medical advice. However, other symptoms experienced in patients with CTS, such as paresthesia, dysesthesia and allodynia, classed as positive sensory symptoms (PSS), are often under-reported. In the present study, patients with surgically-managed CTS were observed pre- and post-surgery to evaluate PSS, using the symptoms scale component of the Boston Carpal Tunnel Questionnaire (BCTQ) and the Sensory Frequency of Symptoms Scale. In total, 19 patients were included in the present study, with 79% female patients, and a mean age of 54±10.59 years. In addition, the mean follow-up was 63±29.91 months. The results of the present study revealed a pre-surgery BCTQ score of 3.52±0.63 and a post-surgery BCTQ score of 1.58±0.61. Notably, improvements in pain were observed, at 7.7±2.26 pre-surgery compared with 1.65±2.88 post-surgery. Compared with pre-surgery, post-surgery paresthesia scores were reduced from 2.94±0.82 to 0.47±0.45, dysesthesia scores were reduced from 2.52±0.84 to 0.47±0.39 and allodynia scores were reduced from 0.63±0.75 to 0.26±0.47. In conclusion, the results of the present study demonstrated that median nerve decompression ameliorated CTS symptoms, such as paresthesia and dysesthesia. However, further investigations are required to verify the benefits of surgery in relieving allodynia.

Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model.

The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized. We performed a detailed histological study to determine the anatomical distribution of different molecular phenotypes within identified midbrain neurons and their selective vulnerability in control and MPTP-treated monkeys. In the ventral tier of the SNc (nigrosome), neurons rich in Aldh1a1 and Girk2 are intermingled, whereas calbindin is the marker that best identifies the most resilient neurons located in the dorsal tier and ventral tegmental area, recapitulating the well-defined dorsoventral axis of susceptibility to degeneration of dopaminergic neurons. In particular, a loss of Aldh1a1+ neurons in the ventral SNc was observed in parallel to the progressive development of parkinsonism. Aldh1a1+ neurons were the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while Aldh1a1- neurons giving rise to nigropallidal projections remained relatively preserved. Moreover, bundles of entwined Aldh1a1+ dendrites with long trajectories extending towards the substantia nigra pars reticulata emerged from clusters of Aldh1a1+ neurons and colocalized with dense cannabinoid receptor 1 afferent fibers likely representing part of the striatonigral projection that is affected in human disorders, including Parkinson´s disease. In conclusion, vulnerable nigrostriatal-projecting neurons can be identified by using Aldh1a1 and Girk2. Further studies are needed to define the afferent/efferent projection patterns of these most vulnerable neurons.

Recommendations for Cardiac Point-of-Care Ultrasound Nomenclature.

Point-of-care ultrasound (POCUS) involves the acquisition, interpretation, and immediate clinical integration of ultrasonographic imaging performed by a treating clinician. The current state of cardiac POCUS terminology is heterogeneous and ambiguous, in part because it evolved through siloed specialty practices. In particular, the medical literature and colloquial medical conversation contain a wide variety of terms that equate to cardiac POCUS. While diverse terminology aided in the development and dissemination of cardiac POCUS throughout multiple specialties, it also contributes to confusion and raises patient safety concerns. This statement is the product of a diverse and inclusive Writing Group from multiple specialties, including medical linguistics, that employed an iterative process to contextualize and standardize a nomenclature for cardiac POCUS. We sought to establish a deliberate vocabulary that is sufficiently unrelated to any specialty, ultrasound equipment, or clinical setting to enhance consistency throughout the academic literature and patient care settings. This statement (1) reviews the evolution of cardiac POCUS-related terms; (2) outlines specific recommendations, distinguishing between intrinsic and practical differences in terminology; (3) addresses the implications of these recommendations for current practice; and (4) discusses the implications for novel technologies and future research.

A florigen-expressing subpopulation of companion cells expresses other small proteins and reveals a nitrogen-sensitive FT repressor.

The precise onset of flowering is crucial to ensure successful plant reproduction. The gene FLOWERING LOCUS T (FT) encodes florigen, a mobile signal produced in leaves that initiates flowering at the shoot apical meristem. In response to seasonal changes, FT is induced in phloem companion cells located in distal leaf regions. Thus far, a detailed molecular characterization of the FT-expressing cells has been lacking. Here, we used bulk nuclei RNA-seq and single nuclei RNA (snRNA)-seq to investigate gene expression in FT-expressing cells and other phloem companion cells. Our bulk nuclei RNA-seq demonstrated that FT-expressing cells in cotyledons and in true leaves differed transcriptionally. Within the true leaves, our snRNA-seq analysis revealed that companion cells with high FT expression form a unique cluster in which many genes involved in ATP biosynthesis are highly upregulated. The cluster also expresses other genes encoding small proteins, including the flowering and stem growth inducer FPF1-LIKE PROTEIN 1 (FLP1) and the anti-florigen BROTHER OF FT AND TFL1 (BFT). In addition, we found that the promoters of FT and the genes co-expressed with FT in the cluster were enriched for the consensus binding motifs of NITRATE-INDUCIBLE GARP-TYPE TRANSCRIPTIONAL REPRESSOR 1 (NIGT1). Overexpression of the paralogous NIGT1.2 and NIGT1.4 repressed FT expression and significantly delayed flowering under nitrogen-rich conditions, consistent with NIGT1s acting as nitrogen-dependent FT repressors. Taken together, our results demonstrate that major FT-expressing cells show a distinct expression profile that suggests that these cells may produce multiple systemic signals to regulate plant growth and development.

WOX11-mediated cell size control in Arabidopsis attenuates growth and fecundity of endoparasitic cyst nematodes.

Cyst nematodes establish permanent feeding structures called syncytia inside the host root vasculature, disrupting the flow of water and minerals. In response, plants form WOX11-mediated adventitious lateral roots at nematode infection sites. WOX11 adventitious lateral rooting modulates tolerance to nematode infections; however, whether this also benefits nematode parasitism remains unknown. Here, we report on bioassays using a 35S::WOX11-SRDX transcriptional repressor mutant to investigate whether WOX11 adventitious lateral rooting promotes syncytium development and thereby female growth and fecundity. Moreover, we chemically inhibited cellulose biosynthesis to verify if WOX11 directly modulates cell wall plasticity in syncytia. Finally, we performed histochemical analyses to test if WOX11 mediates syncytial cell wall plasticity via reactive oxygen species (ROS). Repression of WOX11-mediated transcription specifically enhanced the radial expansion of syncytial elements, increasing both syncytium size and female offspring. The enhanced syncytial hypertrophy observed in the 35S::WOX11-SRDX mutant could be phenocopied by chemical inhibition of cellulose biosynthesis and was associated with elevated levels of ROS at nematode infection sites. We, therefore, conclude that WOX11 restricts radial expansion of nematode-feeding structures and female growth and fecundity, likely by modulating ROS-mediated cell wall plasticity mechanisms. Remarkably, this novel role of WOX11 in plant cell size control is distinct from WOX11 adventitious lateral rooting underlying disease tolerance.

Concentrations of polychlorinated naphthalenes in food and human dietary exposure: A review of the scientific literature.

In general, for most environmental persistent organic pollutants (POPs), dietary intake is the main way of exposure. Polychlorinated naphthalenes (PCNs) are a family of two-ringed aromatic compounds, which are ubiquitous environmental contaminants, being structurally similar to PCDD/Fs and PCBs. Although the production and use of PCNs were banned in the USA and Europe some decades ago, due to their persistent properties, PCNs remain still present in the environment, being able to enter the food chain. The present paper was aimed at reviewing the results of the studies focused on determining the levels of PCNs in foods. The human dietary intake of these compounds was also reviewed with the few available data. The information on the levels of PCNs in foodstuffs is currently more abundant than that found in a previous review (Domingo, 2004). Since then, China is the country that has contributed with the greatest number of studies. The results of most surveys seem to suggest that human health risks of PCNs due to dietary exposure should not be worrying. However, because of the important differences in the methodology of the published studies, the comparison of the results is not easy, although there seems to be a general trend towards a decrease in the levels of PCNs in foods. In the next few years, a continued reduction of the environmental levels of PCNs is still expected. Therefore, a direct repercussion of the concentrations of these pollutants in foodstuffs must be also noted. Consequently, a reduction of the dietary exposure to PCNs should be expected. Anyway, to establish the tolerable dietary intake of PCNs is a key issue for assessing human health risks of these pollutants.

Does Relative Energy Deficiency in Sport (REDs) Syndrome Exist?

Relative energy deficiency in sport (REDs) is a widely adopted model, originally proposed by an International Olympic Committee (IOC) expert panel in 2014 and recently updated in an IOC 2023 consensus statement. The model describes how low energy availability (LEA) causes a wide range of deleterious health and performance outcomes in athletes. With increasing frequency, sports practitioners are diagnosing athletes with "REDs," or "REDs syndrome," based largely upon symptom presentation. The purpose of this review is not to "debunk" REDs but to challenge dogmas and encourage rigorous scientific processes. We critically discuss the REDs concept and existing empirical evidence available to support the model. The consensus (IOC 2023) is that energy availability, which is at the core of REDs syndrome, is impossible to measure accurately enough in the field, and therefore, the only way to diagnose an athlete with REDs appears to be by studying symptom presentation and risk factors. However, the symptoms are rather generic, and the causes likely multifactorial. Here we discuss that (1) it is very difficult to isolate the effects of LEA from other potential causes of the same symptoms (in the laboratory but even more so in the field); (2) the model is grounded in the idea that one factor causes symptoms rather than a combination of factors adding up to the etiology. For example, the model does not allow for high allostatic load (psychophysiological "wear and tear") to explain the symptoms; (3) the REDs diagnosis is by definition biased because one is trying to prove that the correct diagnosis is REDs, by excluding other potential causes (referred to as differential diagnosis, although a differential diagnosis is supposed to find the cause, not demonstrate that it is a pre-determined cause); (4) observational/cross-sectional studies have typically been short duration (< 7 days) and do not address the long term "problematic LEA," as described in the IOC 2023 consensus statement; and (5) the evidence is not as convincing as it is sometimes believed to be (i.e., many practitioners believe REDs is well established). Very few studies can demonstrate causality between LEA and symptoms, most studies demonstrate associations and there is a worrying number of (narrative) reviews on the topic, relative to original research. Here we suggest that the athlete is best served by an unbiased approach that places health at the center, leaving open all possible explanations for the presented symptoms. Practitioners could use a checklist that addresses eight categories of potential causes and involve the relevant experts if and when needed. The Athlete Health and Readiness Checklist (AHaRC) we introduce here simply consists of tools that have already been developed by various expert/consensus statements to monitor and troubleshoot aspects of athlete health and performance issues. Isolating the purported effects of LEA from the myriad of other potential causes of REDs symptoms is experimentally challenging. This renders the REDs model somewhat immune to falsification and we may never definitively answer the question, "does REDs syndrome exist?" From a practical point of view, it is not necessary to isolate LEA as a cause because all potential areas of health and performance improvement should be identified and tackled.

A solution NMR methodology enabling the elucidation of small molecule phospholipid membrane adhesion and passive permeation parameters.

Quantifying small molecule uptake across a biological membrane of a target cell is crucial for the development of efficacious and selective drugs. However, current methods to obtaining such data are not trivial. Herein, we present an accessible, higher-throughput (20 minutes), 1H NMR spectroscopy assay, which enables the quantification of small molecule phospholipid passive membrane permeation and membrane adhesion parameters.

Predictive and dynamic signature for anti-angiogenics in combination with PD-1 inhibitor in soft-tissue sarcoma: correlative studies linked to the IMMUNOSARC trial.

PURPOSE: IMMUNOSARC trial combined an anti-angiogenic agent (sunitinib) with a PD-1 inhibitor (nivolumab) in advanced sarcomas. Here we present the first correlative studies of the STS cohort enrolled in this trial. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) and peripheral blood samples were collected at baseline and week 13. FFPE were used for transcriptomics and multiplex immunofluorescence, while peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. RESULTS: The density of intratumoral CD8+ T cells, measured by multiplexed immuno-phenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in gene expression of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1, and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at W13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated two groups with distinct progression-free survival (PFS): 4.1 months (95% CI 3.5-NR) vs 17 months (95% CI 12.0 - NR), p=0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. CONCLUSIONS: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T cell density and the expression of several genes/ proteins with relevance in the response to PD-1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of anti-angiogenics plus PD-1 inhibitor.

Polymelia and concurrent intestinal duplication and cloacal atresia in a broiler chick: case report and literature review.

Congenital malformations are a highly diverse group of conditions reported in both humans and animals, characterized by defects in morphogenesis observed at birth. Although most cases are idiopathic, genetic and environmental factors may be involved. The frequency of such conditions varies with species, geographic regions, and the specific malformation involved. In polymelia, supernumerary limbs are attached to different parts of the body. Gastrointestinal duplications are described less frequently and can be associated with polymelia. Cloacal atresia is among the least-reported malformations in avian species, described only once in a kiwi. Here we describe a case with these 3 malformations in a single broiler chick (Gallus gallus domesticus) and provide a literature review about the occurrence of these malformations in birds. The 3-d-old chick also had an unidentified structure projecting from the pygostyle region. We performed clinical, radiographic, and postmortem examinations. The intestinal duplication was identified only during the postmortem evaluation. Detailed descriptions of avian congenital malformations are scarce. Although similar cases have been reported, we retrieved no cases of concurrent polymelia, intestinal duplication, and cloacal atresia in broiler chickens in our literature search, suggesting that the simultaneous occurrence of these conditions has not been reported previously in this species.

Novel Clinical, Immunological, and Metabolic Features Associated with Persistent Post-Acute COVID-19 Syndrome.

The coronavirus disease 2019 (COVID-19) survivors are frequently observed to present persistent symptoms constituting what has been called "post-acute COVID-19 syndrome" (PACS) or "long COVID-19". Some clinical risk factors have been identified to be associated with PACS development; however, specific mechanisms responsible for PACS pathology remain unknown. This study investigates clinical, immunological, and metabolomic risk factors associated with post-acute COVID-19 syndrome (PACS) in 51 patients, assessed 7-19 months after acute infection. Among the participants, 62.7% were male and 37.2% were female, with an average age of 47.8 years. At the follow-up, 37.2% met the criteria for PACS, revealing significant differences in immunological and metabolomic profiles at the time of acute infection. Patients with PACS were characterized by elevated levels of mature low-density granulocytes (LDGs), interleukin-8 (IL-8), pyruvate, pseudouridine, and cystine. Baseline multivariate analysis showed increased pyruvate and decreased alpha tocopherol levels. At follow-up, there was a decrease in absolute B lymphocytes and an increase in non-classical monocytes and 3-hydroxyisovaleric acid levels. These findings suggest that specific immunological and metabolomic markers during acute infection can help identify patients at higher risk of developing persistent PACS.

Epidemiology of Neuro-Behçet's Disease in Northern Spain 1999-2019: A Population-Based Study.

Background/Objectives: Neuro-Behçet's disease (NBD) is one of the most severe complications of Behçet's disease (BD). The incidence of NBD varies widely worldwide. This study aimed to estimate its current incidence in Northern Spain. Methods: This was a retrospective population-based cohort study of 120 patients in Northern Spain diagnosed with BD according to the 2013 International Criteria for BD (ICBD) between 1 January 1999 and 31 December 2019. NBD diagnoses were made according to International Consensus Recommendation (ICR) criteria. Overall, 96 patients were included, and their demographic and clinical data were collected. The incidence of NBD was estimated by age, gender, and year of diagnosis between 1999-2019. Results: NBD was diagnosed in 23 of 96 (24%) patients (15 women/8 men) (mean age: 44 ± 13.9 years). HLA-B51 was positive in 5 of 13 (38.4%) cases tested. A total of 10 (43.5%) patients had parenchymatous NBD, 10 (43.5%) had non-parenchymatous NBD, and 3 (13%) had mixed NBD. Incidence during the study period was 0.13 (95% CI, 0.11-0.26) per 100,000 people-years. There were no significant differences in gender in the incidence rate stratified by age (p > 0.05). Furthermore, there was a linear relationship with a mild decrease in age at diagnosis over time. Conclusions: Epidemiological characteristics of NBD in Northern Spain are similar to those of neighboring countries, except female gender predominance.

Early life movements and mortality of Egyptian vultures: Implications for transcontinental conservation.

Understanding the movements and mortality of individuals across different life stages is crucial for the effective conservation of wild populations. We used data from 32 Egyptian vultures (Neophron percnopterus) tagged with GPS transmitters as nestlings in three Iberian breeding areas to study their dependence period, migration routes, movements in Africa, and mortality at each stage. Our results show no significant differences in the timing of nest departure or the duration of the dependence period between individuals of different sexes or breeding nuclei. Most juveniles migrated to sub-Saharan Africa in their first year, but some (3 of 32, 9.4%) remained in the Iberian Peninsula. Individuals that migrated to Africa did so annually, while those remaining in Iberia never migrated to the Sahel, indicating distinct migratory and non-migratory strategies. Non-migratory individuals consistently moved northward during the breeding season to their natal territories. Siblings did not coordinate their migration strategy or timing. All juveniles showed extensive overlap in the vast areas used in Africa, where females arrived before males, and in the Iberian Peninsula. Our study also revealed that no juveniles died immediately after fledging, but that none of the tagged individuals lived more than 7 years or were recruited as breeders. Although most casualties occurred during the longer stay in the Sahel, the mortality rate was highest during the few days of the first migration. Our results show that despite small variations in movement patterns between breeding nuclei and sexes, Egyptian vultures face similar challenges during the years before recruitment as breeders, mostly determined by their migratory strategy. These findings are relevant for designing conservation strategies, both in breeding areas and, more importantly, in wintering areas and along migration pathways. Such strategies will significantly impact the entire Iberian population of this endangered species.

Magnetic and pH-responsive magnetite/chitosan (core/shell) nanoparticles for dual-targeted methotrexate delivery in cancer therapy.

Methotrexate successful therapy encounters various challenges in chemotherapy, such as poor oral bioavailability, low specificity, side effects and the development of drug resistances. In this study, it is proposed a dual-targeted nanocarrier comprising magnetite/chitosan nanoparticles for an efficient Methotrexate delivery. The formation of the particles was confirmed through morphological analysis using electron microscopy and elemental mappings via energy dispersive X-ray spectroscopy. These nanoparticles exhibited a size of ≈ 270 nm, a zeta potential of ≈ 24 mV, and magnetic responsiveness, as demonstrated by hysteresis cycle analysis and visual observations under a magnetic field. In addition, these particles displayed high stability, as evidenced by size and surface electric charge measurements, during storage at both 4 ºC and 25 ºC for at least 30 days. Electrophoretic properties were examined in relation to pH and ionic strength, confirming these core/shell nanostructure. The nanoparticles demonstrated a pH-responsive drug release as observed by a sustained Methotrexate release over the next 90 h under pH ≈ 7.4, while complete release occurred within 3 h under acidic conditions (pH ≈ 5.5). In the biocompatibility assessment, the magnetite/chitosan particles showed excellent hemocompatibility ex vivo and no cytotoxic effects on normal MCF-10 A and cancer MCF-7 cells. Furthermore, the Methotrexate-loaded nanoparticles significantly enhanced the antitumor activity reducing the half-maximal inhibitory concentration by ≈ 2.7-fold less compared to the free chemotherapeutic.