Functional anatomy of the orbit in strabismus surgery: Connective tissues, pulleys, and the modern surgical implications of the "arc of contact" paradigm.

Oculomotricity is a multidimensional domain characterised by a delicate interplay of anatomical structures and physiological processes. This manuscript meticulously dissects the nuances of this interplay, bringing to the fore the integral role of the extraocular muscles (EOMs) and their intricate relationship with the myriad orbital connective tissues as it harmoniously orchestrates binocular movements, ensuring synchronised and fluid visual tracking. Historically, the peripheral oculomotor apparatus was conceptualised as a rudimentary system predominantly driven by neural directives. While widely accepted, this perspective offered a limited view of the complexities inherent in ocular movement mechanics. The twentieth century heralded a paradigm shift in this understanding. With advances in anatomical research and imaging techniques, a much clearer picture of the gross anatomy of the EOMs emerged. This clarity challenged traditional viewpoints, suggesting that the inherent biomechanical properties of the EOMs, coupled with their associated tissue pulleys, play a pivotal role in dictating eye movement dynamics. Central to this revised understanding is the "arc of contact" paradigm. This concept delves deep into the mechanics of eye rotation, elucidating the significance of the point of contact between the EOMs and the eyeball. The arc of contact is not just a static anatomical feature; its length and orientation play a crucial role in determining the effective torque generated by a muscle, thereby influencing the amplitude and direction of eye rotation. The dynamic nature of this arc, influenced by the position and tension of the muscle pulleys, offers a more comprehensive model for understanding ocular kinematics. Previously overlooked in traditional models, muscle pulleys have now emerged as central players in the biomechanics of eye movement. These anatomical structures, formed by dense connective tissues, guide the paths of the EOMs, ensuring that their pulling angles remain optimal across a range of gaze directions. The non-linear paths resulting from these pulleys provide a more dynamic and intricate understanding of eye movement, challenging two-dimensional, linear models of orbital anatomy. The implications of these revelations extend beyond mere theoretical knowledge. The insights garnered from this research promise transformative potential in the realm of strabismus surgery. Recognising the pivotal role of muscle pulleys and the "arc of contact" paradigm allows for more precise surgical interventions, ensuring better post-operative outcomes and minimising the risk of complications. Surgical procedures that previously relied on basic mechanical principles now stand to benefit from a more nuanced understanding of the underlying anatomical and physiological dynamics. In conclusion, this manuscript serves as a testament to the ever-evolving nature of scientific knowledge. Challenging established norms and introducing fresh perspectives pave the way for more effective and informed clinical interventions in strabismus surgery.

Shedding light on the impacts of Spirulina platensis on gut microbiota and related health benefits.

Spirulina (S.) platensis is a blue-green algae with reported nutritional and health-promoting properties, such as immunomodulating, antioxidant, cholesterol-lowering properties, and beneficial effects on inflammatory diseases. Spirulina platensis can improve the function and composition of the gut microbiota and exert systemic beneficial effects. Gut dysbiosis is characterized by an imbalance in the composition and function of gut microbiota and is associated with several diseases. Some dietary bioactive compounds can restore the composition, diversity, and function of the gut microbiota and improve health-related parameters. This review proposes to gather relevant information on the effects of S. platensis supplementation on the modulation of the function and composition of gut microbiota and local and systemic measures related to gut health, such as inflammation, oxidative stress, and glucose and lipid metabolism. The body of evidence conducted with animals and clinical studies shows that S. platensis supplementation increased gut microbiota diversity and improved gut microbiota composition, as reported by a decrease in the Firmicutes/Bacteroides ratio, increase in the relative abundance of Prevotella and Lactobacillaceae, increase in short-chain fatty acid production and decrease of gut permeability. Improvements in gut microbiota have been associated with host health benefits such as anti-obesity, anti-diabetic, anti-hypertensive, anti-lipemic, anti-inflammatory, and antioxidant effects.

Synergistic activity between conventional antifungals and chalcone-derived compound against dermatophyte fungi and Candida spp.

The scarce antifungal arsenal, changes in the susceptibility profile of fungal agents, and lack of adherence to treatment have contributed to the increase of cases of dermatomycoses. In this context, new antimicrobial substances have gained importance. Chalcones are precursors of the flavonoid family that have multiple biological activities, have high tolerability by humans, and easy synthesis. In this study, we evaluated the in vitro antifungal activity, alone and in combination with conventional antifungal drugs, of the VS02-4'ethyl chalcone-derived compound against dermatophytes and Candida spp. Susceptibility testing was carried out by broth microdilution. Experiments for determination of the target of the compound on the fungal cell, time-kill kinetics, and toxicity tests in Galleria mellonella model were also performed. Combinatory effects were evaluated by the checkerboard method. Results showed high activity of the compound VS02-4'ethyl against dermatophytes (MIC of 7.81-31.25 µg/ml). The compound targeted the cell membrane, and the time-kill test showed the compound continues to exert gradual activity after 5 days on dermatophytes, but no significant activity on Candida. Low toxicity was observed at 250 mg/kg. Excellent results were observed in the combinatory test, where VS02-4'ethyl showed synergistic interactions with itraconazole, fluconazole, terbinafine, and griseofulvin, against all isolates tested. Although further investigation is needed, these results revealed the great potential of chalcone-derived compounds against fungal infections for which treatments are long and laborious.

Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Advances in the synthesis of rearranged homoisoflavonoids.

Rearranged homoisoflavonoids constitute a unique group of natural products, renowned for their structural diversity and complexity. These compounds, derived from modifications in the 3-benzylchroman skeleton, are categorized into four subclasses: brazilin, caesalpin, protosappanin, and scillascillin homoisoflavonoids. This review examines the advancements in the total synthesis of these complex structures, aiming to highlight the challenges and opportunities encountered. A comparative analysis of the strategies employed thus far to synthesize these compounds provides a comprehensive understanding of the progress in this field.

Microarray data analysis of antileukemic action of Cinnamoylated benzaldehyde LQB-461 in Jurkat cell line.

BACKGROUND: Leukemias stand out for being the main type of childhood cancer in the world. Current treatments have strong side effects for patients, and there is still a high rate of development of resistance to multidrug therapy. Previously, our research group developed a structure-activity study with novel synthetic molecules analogous to LQB-278, described as an essential molecule with in vitro antileukemic action. Among these analogs, LQB-461 stood out, presenting more significant antileukemic action compared to its derivative LQB-278, with cytostatic and cytotoxicity effect by apoptosis, inducing caspase-3, and increased sub-G1 phase on cell cycle analysis. METHODS AND RESULTS: Deepening the study of the mechanism of action of LQB-461 in Jurkat cells in vitro, a microarray assay was carried out, which confirmed the importance of the apoptosis pathway in the LQB-461 activity. Through real-time PCR, we validated an increased expression of CDKN1A and BAX genes, essential mediators of the apoptosis intrinsic pathway. Through the extrinsic apoptosis pathway, we found an increased expression of the Fas receptor by flow cytometry, showing the presence of a more sensitive population and another more resistant to death. Considering the importance of autophagy in cellular resistance, it was demonstrated by western blotting that LQB-461 decreased LC-3 protein expression, an autophagic marker. CONCLUSIONS: These results suggest that this synthetic molecule LQB-461 induces cell death by apoptosis in Jurkat cells through intrinsic and extrinsic pathways and inhibits autophagy, overcoming some mechanisms of cell resistance related to this process, which differentiates LQB-461 of other drugs used for the leukemia treatment.

DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway.

DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3'end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells.

Probiotics for infantile colic: Is there evidence beyond doubt? A meta-analysis and systematic review.

AIM: This study is a systematic review and meta-analysis of randomised controlled trials that employed probiotics and symbiotics for treating infantile colic. METHODS: We performed electronic systematic literature searches in Embase, PubMed and Web of Science, to identify articles published between 1950 and April 2023. Only RCT involving infants with infantile colic under 3 months were included. The treatment plan comprised 15 probiotics, which included Lactobacillus reuteri DSM 17938 and Bifidobacterium animalis lactis BB-12. The probiotics were administered alone or in combination with a prebiotic, vs. no intervention or a placebo. RESULTS: Probiotics resulted in an average reduction of 51 min of crying per day (p = 0.001). Further analysis of subgroups showed that the reduction was -39.30 min for vaginal delivery (p = 0.003), -64.66 min for Lactobacillus reuteri DSM 17938 (p = 0.03), -40.45 min for other strains (p < 0.00001), -74.28 min for exclusively breastfed infants (p = 0.0003) and -48.04 min for mixed feeding (p < 0.00001). CONCLUSION: All probiotic strains seem effective in treating infantile colic. Exclusively breastfed infants have demonstrated more significant reduction in crying time. However, the available evidence on the effectiveness of probiotics in formula-fed and caesarean-born infants is limited.

Optimization of the molecular detection assay of Salmonella (MDS®) for drag swab samples of aviaries.

Detection of Salmonella sp. is important for the broiler chicken production chain because it is one microorganisms involved in food-borne diseases. Thus, this study performed the optimization of a technique of Loop-mediated isothermal DNA amplification (LAMP) through the 3MTM Molecular Detection Assay 2: Salmonella (MDS®), in accordance with Ordinance number 126 of the Ministry of Agriculture, for the detection of Salmonella sp. in drag swab. The methodology followed ISO 16140-2: 2016, with the analysis naturally contaminated drag swab samples collected from broiler aviaries and artificially contaminated with salmonella ATCCs. Of the 300 samples processed in protocol A (pre-enrichment tetrathionate broth (TT)), 45 were positive for Salmonella sp., 242 negative, one false-positive, and 12 false-negative, while of the 300 samples analyzed in protocol B (pre-enrichment brain-heart infusion broth (BHI)), 40 were positive, 256 negative, one false-positive, and three false-negative. The result for protocol A was a sensitivity of 79%, specificity of 99.6%, Positive Predictive Value (PPV) of 98%, and Negative Predictive Value (NPV) of 95%; and for protocol B, 93% sensitivity, 99.6% specificity, 98% PPV, and 99% NPV. Both protocols were associated with the reference method (p>0.05), concluding that the MDS® can be used for the qualitative detection of Salmonella sp.

Integrating Cosmic Microwave Background Readings with Celestial Navigation to Enhance Deep Space Navigation.

This research unveils a cutting-edge navigation system for deep space missions that utilizes cosmic microwave background (CMB) sensor readings to enhance spacecraft positioning and velocity estimation accuracy significantly. By exploiting the Doppler-shifted CMB spectrum and integrating it with optical measurements for celestial navigation, this approach employs advanced data processing through the Unscented Kalman Filter (UKF), enabling precise navigation amid the complexities of space travel. The simulation results confirm the system's exceptional precision and resilience in deep space missions, marking a significant advancement in astronautics and paving the way for future space exploration endeavors.

Compilation of Evidence Supporting the Role of a T Helper 2 Reaction in the Pathogenesis of Acute Appendicitis.

Despite being the most common abdominal surgical emergency, the cause of acute appendicitis (AA) remains unclear, since in recent decades little progress has been made regarding its etiology. Obstruction of the appendicular lumen has been traditionally presented as the initial event of AA; however, this is often the exception rather than the rule, as experimental data suggest that obstruction is not an important causal factor in AA, despite possibly occurring as a consequence of the inflammatory process. Type I hypersensitivity reaction has been extensively studied, involving Th2 lymphocytes, and cytokines such as IL-4, IL-5, IL-9 and IL-13, which have well-defined functions, such as a positive-feedback effect on Th0 for differentiating into Th2 cells, recruitment of eosinophils and the release of eosinophilic proteins and the production of IgE with the activation of mast cells, with the release of proteins from their granules. Cytotoxic activity and tissue damage will be responsible for the clinical manifestation of the allergy. AA histological features are similar to those found in allergic reactions like asthma. The intestine has all the components for an allergic immune response. It has contact with hundreds of antigens daily, most of them harmless, but some can potentially induce an allergic response. In recent years, researchers have been trying to assess if allergy is a component of AA, with their latest advances in the understanding of AA as a Th2 reaction shown by the authors of this article.

Tryptase in Acute Appendicitis: Unveiling Allergic Connections through Compelling Evidence.

The aetiology of acute appendicitis (AA), the most frequent abdominal surgical emergency, is still unclarified. Recent epidemiologic, clinical and laboratorial data point to an allergic component in the pathophysiology of AA. Mastocytes participate in the Th2 immune response, releasing inflammatory mediators from their granules upon stimulation by IgE-specific antigens. Among the well-known mediators are histamine, serotonin and tryptase, which are responsible for the clinical manifestations of allergies. We conducted a prospective single-centre study to measure histamine and serotonin (commercial ELISA kit) and tryptase (ImmunoCAP System) concentrations in appendicular lavage fluid (ALF) and serum. Consecutive patients presenting to the emergency department with a clinical diagnosis of AA were enrolled: 22 patients with phlegmonous AA and 24 with gangrenous AA The control group was composed of 14 patients referred for colectomy for colon malignancy. Appendectomy was performed during colectomy. Tryptase levels were strikingly different between histological groups, both in ALF and serum (p < 0.001); ALF levels were higher than serum levels. Tryptase concentrations in ALF were 109 times higher in phlegmonous AA (APA) (796.8 (194.1-980.5) pg/mL) and 114 times higher in gangrenous AA (AGA) (837.4 (272.6-1075.1) pg/mL) than in the control group (7.3 (4.5-10.3) pg/mL. For the diagnosis of AA, the discriminative power of serum tryptase concentration was good (AUC = 0.825), but discriminative power was weak (AUC = 0.559) for the differential diagnosis between APA and AGA. Mastocytes are involved in AA during clinical presentations of both phlegmonous and gangrenous appendicitis, and no significant differences in concentration were found. No differences were found in serum and ALF concentrations of histamine and serotonin between histological groups. Due to their short half-lives, these might have elapsed by the time the samples were collected. In future research, these determinations should be made immediately after appendectomy. Our findings confirm the hypersensitivity type I reaction as an event occurring in the pathogenesis of AA: tryptase levels in ALF and serum were higher among patients with AA when compared to the control group, which is in line with a Th2 immune response and supports the concept of the presence of an allergic reaction in the pathogenesis of acute appendicitis. Our results, if confirmed, may have clinical implications for the treatment of AA.

The effect of the simulated aging by thermocycling on the elastic modulus of ethylene-vinyl acetate brands and stress/strain development during an impact: An in vitro and 3D-FEA analysis.

BACKGROUND/AIM: Mouthguards are used to prevent dental trauma and orofacial injuries. The aim of this study was to evaluate the influence of ethylene-vinyl acetate (EVA) aging by thermocycling on elastic modulus, stress, strain and shock absorption ability of different ethylene-vinyl acetate brands used for mouthguards. METHODS: Thirty EVA samples with a dimension of 70 × 10 × 3 mm were obtained from four commercial brands (Bioart®, Erkodent®, Polyshok® and Proform®). Fifteen samples were submitted to 10,000 cycles (5°C-55°C) in a thermocycling machine with an immersion time of 30 s and a transfer time of 5 s. The samples were submitted to a uniaxial tensile test in a universal testing machine to calculate the elastic modulus. Data were statistically evaluated by two-way ANOVA and Holm-Sidak test. A three-dimensional model of the anterior maxilla was created using Rhinoceros 5.0. A 3 mm custom-fitted mouthguard was simulated. The three-dimensional volumetric mesh was generated using the Patran software (MSC Software) with isoparametrics, 4-noded tetrahedral elements and exported to Marc/Mentat (MSC Software) as element number 134. A non-linear dynamic impact analysis was performed in which a rigid object struck the central incisor at a speed of 5 m/s. The stresses were evaluated by the modified von Mises criteria and the strains were also recorded. RESULTS: Statistically significant differences were observed for elastic modulus values (p < .001). Mean and standard deviation values (MPa) without thermocycling were: Bioart (34.5 ± 0.9), Erkodent (15.0 ± 0.4), Polyshok (17.3 ± 0.4), Proform: (20.6 ± 0.8); and with thermocycling: Bioart (25.4 ± 0.8), Erkodent (10.7 ± 0.5), Polyshok (13.3 ± 0.6), Proform (13.1 ± 0.6). The thermocycling process reduced stress and strain levels regardless of the mouthguard materials. Shock absorption ability calculated based on the strain values was increased with thermocycling process. CONCLUSION: The thermocycling process, regardless of the commercial brand, reduced the stress/strain and increased the shock absorption ability of mouthguards.

Translation, cultural adaptation, and validation of the Nurse Self-Concept Questionnaire (NSCQ) for Portuguese nursing students.

BACKGROUND: The professional self-concept of nursing students significantly influences their attitude and identity within the profession, ultimately impacting their mental health and overall well-being. Recent evidence underscores the importance of assessing students' professional self-concept to prevent adverse outcomes such as burnout and stress. Since there are currently no validated instruments available in Portugal for this purpose, our objective was to translate, adapt, and validate the Nurse Self-Concept Questionnaire (NSCQ) with nursing students in Portugal. METHODS: A two-phase research study with a non-probabilistic sample of 216 undergraduate nursing students, using the QualtricsXM electronic platform for data collection. An exploratory factor analysis was performed to verify the validity of the theoretical construct and its internal consistency. Cronbach's alpha was calculated, and a confirmatory factor analysis was performed to assess the model fit. RESULTS: The final instrument, designated as Questionário de Autoconceito dos/as Enfermeiros/as (Pt - NSCQ), is composed of 24 items distributed across five dimensions: "General self-concept", "Staff relations", "Leadership", "Communication-care" and "Knowledge", which explain 67.71% of the total variance. All dimensions and the global scale revealed good internal consistency values, ranging from 0.775 to 0.927. The resulting factorial structure is coherent with the theoretical framework. CONCLUSION: The Pt - NSCQ proved to be a valid and reliable instrument to assess Portuguese nursing students' professional self-concept. Future studies should be carried out on larger samples and different educational contexts, aligned with the importance to ensure the continuity of the psychometric analysis of the instrument.

Textbook Oncological Outcome in European GASTRODATA.

OBJECTIVE: To assess the rate of textbook outcome (TO) and textbook oncological outcome (TOO) in the European population based on the GASTRODATA registry. BACKGROUND: TO is a composite parameter assessing surgical quality and strongly correlates with improved overall survival. Following the standard of treatment for locally advanced gastric cancer, TOO was proposed as a quality and optimal multimodal treatment parameter. METHODS: TO was achieved when all the following criteria were met: no intraoperative complications, radical resection according to the surgeon, pR0 resection, retrieval of at least 15 lymph nodes, no severe postoperative complications, no reintervention, no admission to the intensive care unit, no prolonged length of stay, no postoperative mortality and no hospital readmission. TOO was defined as TO with the addition of perioperative chemotherapy compliance. RESULTS: Of the 2558 patients, 1700 were included in the analysis. TO was achieved in 1164 (68.5%) patients. The use of neoadjuvant chemotherapy [odds ratio (OR) = 1.33, 95% CI: 1.04-1.70] and D2 or D2+ lymphadenectomy (OR = 1.55, 95% CI: 1.15-2.10) had a positive impact on TO achievement. Older age (OR = 0.73, 95% CI: 0.54-0.94), pT3/4 (OR = 0.79, 95% CI: 0.63-0.99), ASA 3/4 (OR = 0.68, 95% CI: 0.54-0.86) and total gastrectomy (OR = 0.56, 95% CI: 0.45-0.70), had a negative impact on TO achievement. TOO was achieved in 388 (22.8%) patients. Older age (OR = 0.37, 95% CI: 0.27-0.53), pT3 or pT4 (OR = 0.52, 95% CI: 0.39-0.69), and ASA 3 or 4 (OR = 0.58, 95% CI: 0.43-0.79) had a negative impact on TOO achievement. CONCLUSIONS: Despite successively improved surgical outcomes, stage-appropriate chemotherapy in adherence to the current guidelines for multimodal treatment of gastric cancer remains poor. Further implementation of oncologic quality metrics should include greater emphasis on perioperative chemotherapy and adequate lymphadenectomy.

Diastereoselectivity Switch During Alkene Reductions: Diastereodivergent Syntheses of Molecular Fossils via MHAT or Homogeneous Catalytic Hydrogenation Reactions.

Sixteen geosterane derivatives were synthesized in up to 57 % overall yields in four steps harnessing the olefin cross-metathesis (OCM) and Metal hydride H atom transfer (MHAT) or homogeneous hydrogenation reactions as key steps. Drawing on this strategy, the diastereomeric ratio (d. r.) reached up to 24 : 1 for the thermodynamic isomer and 7 : 1 for the other isomer in the hydrogenation step. In a geological sample from northeast Brazil, we confirmed the putative structures previously assumed as methyl 2-(3α-5αH-cholestan) acetate, methyl 2-(3ß-5αH-cholestan)acetate, and methyl 6-(3ß-5αH-cholestan)hexanoate, as well three new molecular fossils of approximately 120 million years old. We also proved the migration marking ability of those carboxylic acids derived from forerunner geosteranes during an oil migration event, which suggests their aptitudes as molecular odometers. Our approach demonstrated swiftness and effectiveness in preparing a molecular library of geological biomarkers would also be appropriate to generate stereochemical diversity in molecular libraries for medicinal chemistry and natural product anticipation.

Sex and suicide: The curious case of Toll-like receptors.

During in vitro fertilisation (IVF), pharmacological activation of the murine X chromosome-encoded receptor proteins Toll-like receptor (TLR) 7 and TLR8 reportedly results in male-biased litters by selectively disrupting the motility of X-bearing sperm cells. Thus-in the context of agonist treatment during IVF-these receptors act as 'suicidal' segregation distorters that impair their own transmission to the next generation. Such behaviour would, from an evolutionary perspective, be strongly selected against if present during natural fertilisation. Consequently, TLR7/8 biology in vivo must differ significantly from this in vitro situation to allow these genes to persist in the genome. Here, we use our current understanding of male germ cell biology and TLR function as a starting point to explore the mechanistic and evolutionary aspects of this apparent paradox.

Bradykinin promotes murine melanoma cell migration and invasion through endogenous production of superoxide and nitric oxide.

Spatial confinement and temporal regulation of signaling by nitric oxide (NO) and reactive oxygen species (ROS) occurs in cancer cells. Signaling mediated by NO and ROS was investigated in two sub clones of the murine melanoma B16F10-Nex2 cell line, Nex10C and Nex8H treated or not with bradykinin (BK). The sub clone Nex10C, similar to primary site cells, has a low capacity for colonizing the lungs, whereas the sub clone Nex8H, similar to metastatic cells, corresponds to a highly invasive melanoma. BK-treated Nex10C cells exhibited a transient increase in NO and an inhibition in basal O2- levels. Inhibition of endogenous NO production by l-NAME resulted in detectable levels of O2-. l-NAME promoted Rac1 activation and enhanced Rac1-PI3K association. l-NAME in the absence of BK resulted in Nex10C cell migration and invasion, suggesting that NO is a negative regulator of O2- mediated cell migration and cell invasion. BK-treated Nex8H cells sustained endogenous NO production through the activation of NOS3. NO activated Rac1 and promoted Rac1-PI3K association. NO stimulated cell migration and cell invasion through a signaling axis involving Ras, Rac1 and PI3K. In conclusion, a role for O2- and NO as positive regulators of Rac1-PI3K signaling associated with cell migration and cell invasion is proposed respectively for Nex10C and Nex8H murine melanoma cells.

Assessment of Halogen Off-Center Point-Charge Models Using Explicit Solvent Simulations.

Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (ΔGhyd), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict ΔGhyd values. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the ΔGhyd when compared with the models without EP, especially for the chlorinated compounds; however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds. We also highlight the importance of the choice of the EP model, especially for the iodinated molecules, since a slight tendency to improve the prediction is observed for compounds with a larger σ-hole but significantly worse results were obtained for compounds that are weaker XB donors.

Intrinsic bond strength index as a halogen bond interaction energy predictor.

Halogen bonds (XBs) have become increasingly popular over the past few years with numerous applications in catalysis, material design, anion recognition, and medicinal chemistry. To avoid a post factum rationalization of XB trends, descriptors can be tentatively employed to predict the interaction energy of potential halogen bonds. These typically comprise the electrostatic potential maximum at the tip of the halogen, VS,max, or properties based on the topological analysis of the electronic density. However, such descriptors either can only be used with confidence for specific families of halogen bonds or require intense computations and, therefore, are not particularly attractive for large datasets with diverse compounds or biochemical systems. Therefore, the development of a simple, widely applicable, and computationally cheap descriptor remains a challenge as it would facilitate the discovery of new XB applications while also improving the existing ones. Recently, the Intrinsic Bond Strength Index (IBSI) has been proposed as a new tool to evaluate any bond strength, however, it has not been extensively explored in the context of halogen bonding. In this work, we show that IBSI values linearly correlate with the interaction energy of diverse sets of closed-shell halogen-bonded complexes in the ground state, and therefore, can be used to quantitatively predict this property. Although the linear fit models that use quantum-mechanics-based electron density provided MAEs typically below 1 kcal mol-1, this type of calculation might still be computationally heavy in large sets or systems. Therefore, we also explored the exciting possibility of using a promolecular density approach (IBSIPRO), which only requires the geometry of the complex as an input, being computationally cheap. Surprisingly, the performance was comparable to the QM-based methods, thus opening the door for the usage of IBSIPRO as a fast, yet accurate, XB energy descriptor in large datasets but also in biomolecular systems such as protein-ligand complexes. We also show that the δgpair descriptor emerging from the Independent Gradient Model that leads to IBSI can be seen as a term proportional to the overlapping van der Waals volume of the atoms at a given interaction distance. Overall, ISBI can be thought of as a complementary descriptor to VS,max for situations where the geometry of the complex is available and QM calculations are not feasible whereas the latter still remains a hallmark of XB descriptors.