Quantification of Lymphangiogenesis in the Murine Lymphedema Tail Model Using Intravital Microscopy.

Background: Lymphedema is chronic limb swelling resulting from lymphatic dysfunction. It affects an estimated five million Americans. There is no cure for this disease. Assessing lymphatic growth is essential in developing novel therapeutics. Intravital microscopy (IVM) is a powerful imaging tool for investigating various biological processes in live animals. Tissue nanotransfection technology (TNT) facilitates a direct, transcutaneous nonviral vector gene delivery using a chip with nanochannel poration in a rapid (<100 ms) focused electric field. TNT was used in this study to deliver the genetic cargo in the murine tail lymphedema to assess the lymphangiogenesis. The purpose of this study is to experimentally evaluate the applicability of IVM to visualize and quantify lymphatics in the live mice model. Methods and Results: The murine tail model of lymphedema was utilized. TNT was applied to the murine tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: TNTpCMV6 group receives pCMV6 (expression vector backbone alone) (n = 6); TNTProx1 group receives pCMV6-Prox1 (n = 6). Lymphatic vessels (fluorescein isothiocyanate [FITC]-dextran stained) and lymphatic branch points (indicating lymphangiogenesis) were analyzed with the confocal/multiphoton microscope. The experimental group TNTProx1 exhibited reduced postsurgical tail lymphedema and increased lymphatic distribution compared to TNTpCMV6 group. More lymphatic branching points (>3-fold) were observed at the TNT site in TNTProx1 group. Conclusions: This study demonstrates a novel, powerful imaging tool for investigating lymphatic vessels in live murine tail model of lymphedema. IVM can be utilized for functional assessment of lymphatics and visualization of lymphangiogenesis following gene-based therapy.

Impact of Universal Use of the McGrath Videolaryngoscope as a Device for All Intubations in the Cardiac Operating Room. A Prospective Before-After VIDEOLAR-CAR Study.

OBJECTIVE: Tracheal intubation in cardiac surgery patients has a higher incidence of difficult laryngoscopic views compared with patients undergoing other types of surgery. The authors hypothesized that using the McGrath Mac videolaryngoscope as the first intubation option for cardiac surgery patients improves the percentage of patients with "easy intubation" compared with using a direct Macintosh laryngoscope. DESIGN: A prospective, observational, before-after study. SETTING: At a tertiary-care hospital. PARTICIPANTS: One thousand one hundred nine patients undergoing cardiac surgery. INTERVENTION: Consecutive patients undergoing cardiac surgery were intubated using, as the first option, a Macintosh laryngoscope (preinterventional phase) or a McGrath Mac videolaryngoscope (interventional phase). MEASUREMENTS AND MAIN RESULTS: The main objective was to assess whether the use of the McGrath videolaryngoscope, as the first intubation option, improves the percentage of patients with "easy intubation," defined as successful intubation on the first attempt, modified Cormack-Lehane grades of I or IIa, and the absence of the need for adjuvant airway devices. A total of 1,109 patients were included, 801 in the noninterventional phase and 308 in the interventional phase. The incidence of "easy intubation" was 93% in the interventional phase versus 78% in the noninterventional phase (p < 0.001). First-success-rate intubation was higher in the interventional phase (304/308; 98.7%) compared with the noninterventional phase (754/801, 94.1%; p = 0.005). Intubation in the interventional phase showed decreases in the incidence of difficult laryngoscopy (12/308 [3.9%] v 157/801 [19.6%]; p < 0.001), as well as moderate or difficult intubation (5/308 [1.6%] v 57/801 [7.1%]; p < 0.001). CONCLUSIONS: The use of the McGrath videolaryngoscope as the first intubation option for tracheal intubation in cardiac surgery improves the percentage of patients with "easy" intubation," increasing glottic view and first-success-rate intubation and decreasing the incidence of moderate or difficult intubation.

Visceral Aorta Electrocautery Septotomy to Allow Branched Endovascular Aortic Repair in Ruptured Chronic Post-Dissection Thoraco-Abdominal Aneurysm.

PURPOSE: Endovascular repair of chronic post-dissection thoraco-abdominal aortic aneurysms (PD-TAAA) presents specific technical challenges due to the presence of chronic septum. Small true lumen diameter and false lumen visceral vessel origin can make branched endograft prohibitive. Septotomy may allow to overcome these challenges in cases of high complex anatomy. TECHNIQUE: We describe the application of electrocautery septotomy to the visceral aorta segment to deploy an off-the-shelf branched endograft in a chronic PD-TAAA rupture with true lumen collapse. CONCLUSIONS: Electrocautery septotomy can be an effective adjunctive technique to facilitate branched endograft, overcoming technical challenges associated with the endovascular treatment of chronic PD-TAAA. CLINICAL IMPACT: Electrocautery septotomy is an adjunctive technique that can facilitate endovascular treatment of post-dissection thoraco-abdominal aneurysm. By creating a common lumen, this technique might reduce the number of re-interventions associated with PD-TAAA endovascular exclusion.

Relationships between Patient-Reported Outcome Measures and Clinical Measures in Naïve Neovascular Age-Related Macular Degeneration Patients Treated with Intravitreal Ranibizumab.

Our objective was to evaluate changes in patient-reported outcome measures using the NEI-VFQ 25 questionnaire during a treat and extend regimen in naive neovascular Age-Related Macular Degeneration patients, and its correlation with anatomical and functional data. We conducted a prospective observational study. Patients underwent a treat and extend regimen with intravitreal ranibizumab for neovascular Age-Related Macular Degeneration. Initial response was evaluated at 4th month, and subsequently in every follow-up visit. If a clinical response was achieved, the injection interval was extended in two-week increments, up to a maximum of 12 weeks. Quality of life was assessed using the NEI-VFQ 25 questionnaire at baseline, 4th months, and 12th months. Patients were categorized as good or poor responders based on Best corrected visual acuity, central foveal thickness, intraretinal fluid, or subretinal fluid. Treatment with ranibizumab led to a significant improvement in quality of life, with a mean increase in NEI-VFQ 25 score of 4.27 points in the 12th month. No significant differences in improvement were observed between good and poor responders. Quality of life scores in neovascular Age-Related Macular Degeneration patients improved with intravitreal treatment regardless of the clinical response. The early response following the loading phase could indicate better quality of life after one year of treatment, with Best corrected visual acuity being the clinical parameter with the greatest influence on quality of life.

Treatment of Equine Tarsus Long Medial Collateral Ligament Desmitis with Allogenic Synovial Membrane Mesenchymal Stem/Stromal Cells Enhanced by Umbilical Cord Mesenchymal Stem/Stromal Cell-Derived Conditioned Medium: Proof of Concept.

Horses are high-performance athletes prone to sportive injuries such as tendonitis and desmitis. The formation of fibrous tissue in tendon repair remains a challenge to overcome. This impels regenerative medicine to develop innovative therapies that enhance regeneration, retrieving original tissue properties. Multipotent Mesenchymal Stem/Stromal Cells (MSCs) have been successfully used to develop therapeutic products, as they secrete a variety of bioactive molecules that play a pivotal role in tissue regeneration. These factors are released in culture media for producing a conditioned medium (CM). The aforementioned assumptions led to the formulation of equine synovial membrane MSCs (eSM-MSCs)-the cellular pool that naturally regenerates joint tissue-combined with a medium enriched in immunomodulatory factors (among other bioactive factors) produced by umbilical cord stroma-derived MSCs (eUC-MSCs) that naturally contribute to suppressing the immune rejection in the maternal-fetal barrier. A description of an equine sport horse diagnosed with acute tarsocrural desmitis and treated with this formulation is presented. Ultrasonographic ligament recovery occurred in a reduced time frame, reducing stoppage time and allowing for the horse's return to unrestricted competition after the completion of a physical rehabilitation program. This study focused on the description of the therapeutic formulation and potential in an equine desmitis treatment using the cells themselves and their secretomes.

Topical tissue nanotransfection of Prox1 is effective in the prophylactic management of lymphedema.

Lymphedema is chronic limb swelling resulting from lymphatic dysfunction. There is no cure for the disease. Clinically, a preventive surgical approach called immediate lymphatic reconstruction (ILR) has gained traction. Experimental gene-based therapeutic approaches (e.g., using viral vectors) have had limited translational applicability. Tissue nanotransfection (TNT) technology uses a direct, transcutaneous nonviral vector, gene delivery using a chip with nanochannel poration in response to a rapid (<100 ms) focused electric field. The purpose of this study was to experimentally prevent lymphedema using focal delivery of a specific gene Prox1 (a master regulator of lymphangiogenesis). TNT was applied to the previously optimized lymphedematous mice tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: group I (sham) was given pCMV6 (expression vector backbone alone) and group II was treated with pCMV6-Prox1. Group II mice had decreased tail volume (47.8%) compared to sham and greater lymphatic clearance on lymphangiography. Immunohistochemistry showed greater lymphatic vessel density and RNA sequencing exhibited reduced inflammatory markers in group II compared to group I. Prox1 prophylactically delivered using TNT to the surgical site on the day of injury decreased the manifestations of lymphedema in the murine tail model compared to control.

The patient journey of fibromyalgia in Latin America.

OBJECTIVES: To explore the patient journey of people with fibromyalgia (FM) in Latin American countries in order to identify problems in health care and other areas that may be resolvable. METHODS: Qualitative study with phenomenological and content analysis approach through focus groups and patient journey (Ux; User Experience) methodology. Nine virtual focus groups were conducted with FM patients and healthcare professionals in Argentina, Mexico and Colombia recruited from key informants and social networks. RESULTS: Forty-three people participated (33 were clinicians and 10 were patients). The agents interacting with the patient in their disease journey are found in three spheres: healthcare (multiple medical specialists and other professionals), support and work life (including patient associations) and socioeconomic context. The line of the journey presents two large sections, two loops and a thin dashed line. The two major sections represent the time from first symptoms to medical visit (characterized by self-medication and denial) and the time from diagnosis to follow-up (characterized by high expectations and multiple contacts to make life changes that are not realized). The two loop phases include (1) succession of misdiagnoses and mistreatments and referrals to specialists and (2) new symptoms every so often, visits to specialists, diagnostic doubts, and impatience. Very few patients manage to reach the final phase of autonomy. CONCLUSION: The journey of a person with FM in Latin America is full of obstacles and loops. The desired goal is for all the agents involved to understand that self- management by the patient with FM is an essential part of success, and this can only be achieved with early access to resources and guidance from professionals.

El viaje del paciente con fibromialgia en Latinoamérica / The patient journey of fibromyalgia in Latin America

Objetivos: Explorar la experiencia de las personas con fibromialgia (FM) en países latinoamericanos con objeto de identificar problemas en la atención sanitaria y otros ámbitos potencialmente solucionables. Métodos: Estudio cualitativo con enfoque fenomenológico y de análisis de contenido a través de grupos focales y metodología de viaje del paciente (Ux del inglés User Experience). Se llevaron a cabo 9 grupos focales virtuales con pacientes con FM y profesionales sanitarios en Argentina, México y Colombia reclutados a partir de informantes clave y redes sociales. Resultados: Participaron 43 personas (33 clínicos y 10 pacientes). Los agentes que interaccionan con el paciente en la enfermedad se encuentran en 3 esferas: la de la atención sanitaria, la del apoyo y vida laboral y la del contexto socioeconómico. La línea del viaje presenta 2 grandes tramos, 2 bucles y una línea discontinua delgada. Los 2 grandes tramos representan los tiempos que van desde los primeros síntomas hasta la visita médica y desde el diagnóstico hasta el seguimiento. Los bucles incluyen: 1.°) sucesión de diagnósticos, tratamientos erróneos y derivaciones a especialistas y 2.°) nuevos síntomas cada cierto tiempo, visitas a especialistas y dudas diagnósticas. Pocos pacientes logran la fase final de autonomía. Conclusión: El viaje de una persona con FM en Latinoamérica está lleno de obstáculos. La meta deseada es que todos los agentes entiendan que el automanejo por parte del paciente con FM es una parte indispensable del éxito, y solo se puede lograr accediendo a recursos de forma precoz y guiado por profesionales.(AU)

Objectives: To explore the patient journey of people with fibromyalgia (FM) in Latin American countries in order to identify problems in health care and other areas that may be resolvable. Methods: Qualitative study with phenomenological and content analysis approach through focus groups and patient journey (Ux; User Experience) methodology. Nine virtual focus groups were conducted with FM patients and healthcare professionals in Argentina, Mexico and Colombia recruited from key informants and social networks. Results: Forty-three people participated (33 were clinicians and 10 were patients). The agents interacting with the patient in their disease journey are found in three spheres: healthcare (multiple medical specialists and other professionals), support and work life (including patient associations) and socioeconomic context. The line of the journey presents two large sections, two loops and a thin dashed line. The two major sections represent the time from first symptoms to medical visit (characterized by self-medication and denial) and the time from diagnosis to follow-up (characterized by high expectations and multiple contacts to make life changes that are not realized). The two loop phases include (1) succession of misdiagnoses and mistreatments and referrals to specialists and (2) new symptoms every so often, visits to specialists, diagnostic doubts, and impatience. Very few patients manage to reach the final phase of autonomy. Conclusion: The journey of a person with FM in Latin America is full of obstacles and loops. The desired goal is for all the agents involved to understand that self-management by the patient with FM is an essential part of success, and this can only be achieved with early access to resources and guidance from professionals.(AU)

Help Comes from Unexpected Places: How a Tiny Fairy and a Tropical Fish may help us Model Mucopolysaccharidoses.

INTRODUCTION: When it comes to disease modeling, countless models are available for Lysosomal Storage Diseases (LSD). Historically, two major approaches are well-established: in vitro assessments are performed in patient fibroblasts, while in vivo pre-clinical studies are performed in mouse models. Still, both platforms have a series of drawbacks. Thus, we implemented two alternative and innovative protocols to mimic a particular sub-group of LSDs, the Mucopolysaccharidoses both in vitro and in vivo. METHODS: The first one relies on a non-invasive approach using dental pulp stem cells from deciduous teeth (SHEDs). SHEDs are multipotent neuronal precursors that can easily be collected. The second uses a state-of-the-art gene editing technology (CRISPR/Cas9) to generate zebrafish disease models. RESULTS: Even though this is an ongoing project, we have already established and characterized two MPS II and one MPS VI SHED cell models. These cells self-maintain through several passages and can give rise to a variety of cells including neurons. Furthermore, all MPS-associated sub-cellular phenotypes we have assessed so far are easily observable in these cells. Regarding our zebrafish models, we have successfully knocked down both naglu and hgsnat and the first results we got from the behavioral analysis are promising ones, as we can observe altered activity and sleep patterns in the genetically modified fish. For this particular approach we chose MPS III forms as our target disorders, since their neurological features (hyperactivity, seizures and motor impairment) and lifespan decrease would be easily recognizable in zebrafish. CONCLUSION: Now that these methods are well-established in our lab, their potential is immense. On one hand, the newly developed models will be of ultimate value to understand the mechanisms underlying MPS sub-cellular pathology, which have to be further elucidated. On the other hand, they will constitute an optimal platform for drug testing in house. Also noteworthy, our models will be published as lab resources and made available for the whole LSD community.

Exploring the Traditional Uses of Thymbra capitata Infusion in Algarve (Portugal): Anti-Inflammatory, Wound Healing, and Anti-Aging.

Inflammation plays a pivotal role in the resolution of infection or tissue damage. In addition, inflammation is considered a hallmark of aging, which in turn compromises wound healing. Thymbra capitata is an aromatic plant, whose infusion is traditionally used as an anti-inflammatory and wound-healing agent. In this study, a T. capitata infusion was prepared and characterized by HPLC-PDA-ESI-MSn and its safety profile determined by the resazurin metabolic assay. The anti-inflammatory potential was revealed in lipopolysaccharide (LPS)-stimulated macrophages by assessing nitric oxide (NO) release and levels of inducible nitric oxide synthase (iNOS) and the interleukin-1ß pro-form (pro-IL-1ß). Wound-healing capacity was determined using the scratch assay. The activity of senescence-associated ß-galactosidase was used to unveil the anti-senescent potential, along with the nuclear accumulation of yH2AX and p21 levels. The antiradical potential was assessed by DPPH and ABTS scavenging assays. The infusion contains predominantly rosmarinic acid and salvianolic acids. The extract decreased NO, iNOS, and pro-IL-1ß levels. Interestingly, the extract promoted wound healing and decreased ß-galactosidase activity, as well as yH2AX and p21 levels. The present work highlights strong antiradical, anti-inflammatory, and wound healing capacities, corroborating the traditional uses ascribed to this plant. We have described, for the first time for this extract, anti-senescent properties.

Early clonal extinction in glioblastoma progression revealed by genetic barcoding.

Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field.

Allogenic Synovia-Derived Mesenchymal Stem Cells for Treatment of Equine Tendinopathies and Desmopathies-Proof of Concept.

Tendon and ligament injuries are frequent in sport horses and humans, and such injuries represent a significant therapeutic challenge. Tissue regeneration and function recovery are the paramount goals of tendon and ligament lesion management. Nowadays, several regenerative treatments are being developed, based on the use of stem cell and stem cell-based therapies. In the present study, the preparation of equine synovial membrane mesenchymal stem cells (eSM-MSCs) is described for clinical use, collection, transport, isolation, differentiation, characterization, and application. These cells are fibroblast-like and grow in clusters. They retain osteogenic, chondrogenic, and adipogenic differentiation potential. We present 16 clinical cases of tendonitis and desmitis, treated with allogenic eSM-MSCs and autologous serum, and we also include their evaluation, treatment, and follow-up. The concerns associated with the use of autologous serum as a vehicle are related to a reduced immunogenic response after the administration of this therapeutic combination, as well as the pro-regenerative effects from the growth factors and immunoglobulins that are part of its constitution. Most of the cases (14/16) healed in 30 days and presented good outcomes. Treatment of tendon and ligament lesions with a mixture of eSM-MSCs and autologous serum appears to be a promising clinical option for this category of lesions in equine patients.

Early Experience of Inner Branch Retrograde Cannulation With E-nside Branch Stent Graft for Thoracoabdominal Aortic Aneurysms.

PURPOSE: The aim of our study is to investigate the feasibility of retrograde cannulation using devices with inner branches (IB) for the endovascular treatment of thoracoabdominal aortic aneurysms (TAAAs). MATERIALS AND METHODS: A retrospective analysis using IB configuration with retrograde cannulation was carried out on TAAAs patients undergoing endovascular treatment. RESULTS: Seven patients underwent IB endovascular treatment with retrograde cannulation between September 2020 and November 2021. The mean age was 80.4 years and 4 patients were male. A total of 26 of 28 target vessels were cannulated by retrograde access with a technical success of 93% (2 of 26 target vessels). Two intra-procedural complications were observed (1 renal artery dissection and 1 collateral renal artery rupture). In total, 26 of 28 treated vessels were retrograde cannulated with a technical success of 93%. A total of 39 stent bridges were used (all Viabahn VBX devices). The mean duration of the procedure was 321±102 minutes, and the mean scan time was 134±62 minutes. Mortality at 30 days was observed in 1 case. During the follow-up, 1 stent bridge occlusion was observed without the need for reintervention. CONCLUSION: Retrograde cannulation can also be successfully performed in the case of inner branches. CLINICAL IMPACT: In inner branched cases, retrograde cannulation should be taken into consideration in particular cases or it could become the option of choice. Dedicated endovascular material available such as steerable catheters and latest generation covered stents is fundamental for the success of the treatment.

Intensity Ratio of Kß/Kα in Selected Elements from Mg to Cu, and the Chemical Effects of Cr Kα1,2 Diagram Lines and Cr Kß/Kα Intensity Ratio in Cr Compounds.

Kα,ß X-ray lines from photon excitation were measured in selected elements from Mg to Cu using a high-resolution double-crystal X-ray spectrometer with a proportional counter, and the Kß/Kα intensity ratio for each element was obtained, after correcting for self-absorption, detection efficiency, and crystal reflectance. This intensity ratio increases rapidly from Mg to Ca but, in the 3d elements region, the increase becomes slower. This is related to the intensity of the Kß line involving valence electrons. The slow increase of this ratio in the 3d elements region is thought to be due to the correlation between 3d and 4s electrons. Moreover, the chemical shifts, FWHM, asymmetry indices, and Kß/Kα intensity ratios of the Cr compounds, due to different valences, were also investigated using the same double-crystal X-ray spectrometer. The chemical effects were clearly observed, and the Kß/Kα intensity ratio was found to be compound-dependent for Cr.

Advances in the Phytochemical Characterisation and Bioactivities of Salvia aurea L. Essential Oil.

The Salvia L. genus (Lamiaceae) is largely used in the pharmaceutical and food industry. Several species of biological relevance are extensively employed in traditional medicine, including Salvia aurea L. (syn. S. africana-lutea L.), which is used as a traditional skin disinfectant and in wounds as a healing remedy; nevertheless, these properties have not been validated yet. The aim of the present study is to characterise S. aurea essential oil (EO), unveiling its chemical composition and validating its biological properties. The EO was obtained by hydrodistillation and subsequently analysed by GC-FID and GC-MS. Different biological activities were assessed: the antifungal effect on dermatophytes and yeasts and the anti-inflammatory potential by evaluating nitric oxide (NO) production and COX-2 and iNOS protein levels. Wound-healing properties were assessed using the scratch-healing test, and the anti-aging capacity was estimated through the senescence-associated beta-galactosidase activity. S. aurea EO is mainly characterised by 1,8-cineole (16.7%), ß-pinene (11.9%), cis-thujone (10.5%), camphor (9.5%), and (E)-caryophyllene (9.3%). The results showed an effective inhibition of the growth of dermatophytes. Furthermore, it significantly reduced protein levels of iNOS/COX-2 and simultaneously NO release. Additionally, the EO exhibited anti-senescence potential and enhanced wound healing. Overall, this study highlights the remarkable pharmacological properties of Salvia aurea EO, which should be further explored in order to develop innovative, sustainable, and environmentally friendly skin products.

Rationalizing the Design of Pluronics-Surfactant Mixed Micelles through Molecular Simulations and Experiments.

Aqueous systems comprising polymers and surfactants are technologically important complex fluids with tunable features dependent on the chemical nature of each constituent, overall composition in mixed systems, and solution conditions. The phase behavior and self-assembly of amphiphilic polymers can be changed drastically in the presence of conventional ionic surfactants and need to be clearly understood. Here, the self-aggregation dynamics of a triblock copolymer (Pluronics L81, EO3PO43EO3) in the presence of three cationic surfactants (with a 12C long alkyl chain but with different structural features), viz., dodecyltrimethylammonium bromide (DTAB), didodecyldimethylammonium bromide (DDAB), and ethanediyl-1,2-bis(dimethyldodecylammonium bromide) (12-2-12), were investigated in an aqueous solution environment. The nanoscale micellar size expressed as hydrodynamic diameter (Dh) of copolymer-surfactant mixed aggregates was evaluated using dynamic light scattering, while the presence of a varied micellar geometry of L81-cationic surfactant mixed micelles were probed using small-angle neutron scattering. The obtained findings were further validated from molecular dynamics (MD) simulations, employing a simple and transferable coarse-grained molecular model based on the MARTINI force field. L81 remained molecularly dissolved up to ∼20 °C but phase separated, forming turbid/translucent dispersion, close to its cloud point (CP) and existed as unstable vesicles. However, it exhibited interesting solution behavior expressed in terms of the blue point (BP) and the double CP in the presence of different surfactants, leading to mixed micellar systems with a triggered morphology transition from unstable vesicles to polymer-rich micelles and cationic surfactant-rich micelles. Such an amendment in the morphology of copolymer nanoaggregates in the presence of cationic surfactants has been well observed from scattering data. This is further rationalized employing the MD approach, which validated the effective interactions between Pluronics-cationic surfactant mixed micelles. Thus, our experimental results integrated with MD yield a deep insight into the nanoscale interactions controlling the micellar aggregation (Pluronics-rich micelles and surfactant-rich micelles) in the investigated mixed system.

What is the Optimal Dipole Moment for Nonpolarizable Models of Liquids?

In classical nonpolarizable models, electrostatic interactions are usually described by assigning fixed partial charges to interaction sites. Despite the multitude of methods and theories proposed over the years for partial charge assignment, a fundamental question remains─what is the correct degree of polarization that a fixed-charge model should possess to provide the best balance of interactions (including induction effects) and yield the best description of the potential energy surface of a liquid phase? We address this question by approaching it from two separate and independent viewpoints: the QUantum mechanical BEspoke (QUBE) approach, which assigns bespoke force field parameters for individual molecules from ab initio calculations with minimal empirical fitting, and the Polarization-Consistent Approach (PolCA) force field, based on empirical fitting of force field parameters with an emphasis on transferability by rigorously accounting for polarization effects in the parameterization process. We show that the two approaches yield consistent answers to the above question, namely, that the dipole moment of the model should be approximately halfway between those of the gas and the liquid phase. Crucially, however, the reference liquid-phase dipole needs to be estimated using methods that explicitly consider both mean-field and local contributions to polarization. In particular, continuum dielectric models are inadequate for this purpose because they cannot account for local effects and therefore significantly underestimate the degree of polarization of the molecule. These observations have profound consequences for the development, validation, and testing of nonpolarizable models.

Microdosing Sprint Distribution as an Alternative to Achieve Better Sprint Performance in Field Hockey Players.

Introduction: The implementation of optimal sprint training volume is a relevant component of team sport performance. This study aimed to compare the efficiency and effectiveness of two different configurations of within-season training load distribution on sprint performance over 6 weeks. Methods: Twenty male professional FH players participated in the study. Players were conveniently assigned to two groups: the experimental group (MG; n = 11; applying the microdosing training methodology) and the control group (TG; n = 9; traditional training, with players being selected by the national team). Sprint performance was evaluated through 20 m sprint time (T20) m and horizontal force−velocity profile (HFVP) tests before (Pre) and after (Post) intervention. Both measurements were separated by a period of 6 weeks. The specific sprint training program was performed for each group (for vs. two weekly sessions for MG and TG, respectively) attempting to influence the full spectrum of the F-V relationship. Results: Conditional demands analysis (matches and training sessions) showed no significant differences between the groups during the intervention period (p > 0.05). No significant between-group differences were found at Pre or Post for any sprint-related performance (p > 0.05). Nevertheless, intra-group analysis revealed significant differences in F0, Pmax, RFmean at 10 m and every achieved time for distances ranging from 5 to 25 m for MG (p < 0.05). Such changes in mechanical capabilities and sprint performance were characterized by an increase in stride length and a decrease in stride frequency during the maximal velocity phase (p < 0.05). Conclusion: Implementing strategies such as microdosed training load distribution appears to be an effective and efficient alternative for sprint training in team sports such as hockey.

Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes.

Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large-scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non-neuronal) cell types. Next to the set "trait" of cellular context, the "state" of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single-cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation.

Restricted effects of androgens on glucocorticoid signaling in the mouse prefrontal cortex and midbrain.

Glucocorticoids are key executors of the physiological response to stress. Previous studies in mice showed that the androgen receptor (AR) influenced the transcriptional outcome of glucocorticoid treatment in white and brown adipocytes and in the liver. In the brain, we observed that chronic hypercorticism induced changes in gene expression that tended to be more pronounced in male mice. In the present study, we investigated if glucocorticoid signaling in the brain could be modulated by androgen. After chronic treatment with corticosterone, dihydrotestosterone, a combination of both, and corticosterone in combination with the AR antagonist enzalutamide, we compared the expression of glucocorticoid receptor (NR3C1, also abbreviated GR) target genes in brain regions where AR and GR are co-expressed, namely: prefrontal cortex, hypothalamus, hippocampus, ventral tegmental area and substantia nigra. We observed that androgen affected glucocorticoid signaling only in the prefrontal cortex and the substantia nigra. Dihydrotestosterone and corticosterone independently and inversely regulated expression of Sgk1 and Tsc22d3 in prefrontal cortex. AR antagonism with enzalutamide attenuated corticosterone-induced expression of Fkbp5 in the prefrontal cortex and of Fkbp5 and Sgk1 in the substantia nigra. Additionally, in the substantia nigra, AR antagonism increased expression of Th and Slc18a1, two genes coding for key components of the dopaminergic system. Our data indicate that androgen influence over glucocorticoid stimulation in the brain is not a dominant phenomenon in the context of high corticosterone levels, but can occur in the prefrontal cortex and substantia nigra.