Integrated platform for multiscale molecular imaging and phenotyping of the human brain.

Understanding cellular architectures and their connectivity is essential for interrogating system function and dysfunction. However, we lack technologies for mapping the multiscale details of individual cells and their connectivity in the human organ-scale system. We developed a platform that simultaneously extracts spatial, molecular, morphological, and connectivity information of individual cells from the same human brain. The platform includes three core elements: a vibrating microtome for ultraprecision slicing of large-scale tissues without losing cellular connectivity (MEGAtome), a polymer hydrogel-based tissue processing technology for multiplexed multiscale imaging of human organ-scale tissues (mELAST), and a computational pipeline for reconstructing three-dimensional connectivity across multiple brain slabs (UNSLICE). We applied this platform for analyzing human Alzheimer's disease pathology at multiple scales and demonstrating scalable neural connectivity mapping in the human brain.

Comparing Mediators and Moderators of Mental Health Outcomes from the Implementation of Group Problem Management Plus (PM+) among Venezuelan Refugees and Migrants and Colombian Returnees in Northern Colombia.

Colombia hosts the largest number of refugees and migrants fleeing the humanitarian emergency in Venezuela, many of whom experience high levels of displacement-related trauma and adversity. Yet, Colombian mental health services do not meet the needs of this population. Scalable, task-sharing interventions, such as Group Problem Management Plus (Group PM+), have the potential to bridge this gap by utilizing lay workers to provide the intervention. However, the current literature lacks a comprehensive understanding of how and for whom Group PM+ is most effective. This mixed methods study utilized data from a randomized effectiveness-implementation trial to examine the mediators and moderators of Group PM+ on mental health outcomes. One hundred twenty-eight migrant and refugee women in northern Colombia participated in Group PM+ delivered by trained community members. Patterns in moderation effects showed that participants in more stable, less marginalized positions improved the most. Results from linear regression models showed that Group PM+-related skill acquisition was not a significant mediator of the association between session attendance and mental health outcomes. Participants and facilitators reported additional possible mediators and community-level moderators that warrant future research. Further studies are needed to examine mediators and moderators contributing to the effectiveness of task-shared, scalable, psychological interventions in diverse contexts.

Combined fructose and sucrose consumption from an early age aggravates cardiac oxidative damage and causes a dilated cardiomyopathy in SHR rats.

Obesity increases the risk of arterial hypertension in young adults and favors an early-onset cardiomyopathy by generating oxidative stress. In this sense, indiscriminate consumption of sucrose and fructose sweetened beverages from early ages causes obesity, however its consequences on the heart when there is a genetic predisposition to develop hypertension are not clear. We compared the effects of sucrose, fructose, and their combination in weanling male spontaneously hypertensive rats to determine the relationship between genetic hypertension, obesity, and consumption of these sugars on the degree of cardiac hypertrophy, oxidative stress and Ca2+/calmodulin dependent protein kinase II delta oxidation. Histological, biochemical, and Western blot studies were performed 12 weeks after treatment initiation. We found that chronic consumption of sucrose or fructose leads to obesity, exacerbates genetic arterial hypertension-induced metabolic alterations, and increases cardiac oxidative stress, Ca2+/calmodulin dependent protein kinase II delta oxidation and cardiac hypertrophy. Nonetheless, when sucrose and fructose are consumed together, metabolic alterations worsen and are accompanied by dilated cardiomyopathy. These data suggest that sucrose and fructose combined consumption starting from maternal weaning in rats with genetic predisposition to arterial hypertension accelerates the progression of cardiomyopathy resulting in an early dilated cardiomyopathy.

Synthesis, Characterization, and Energetic Properties of Nitrate Ester Acrylate Polymer.

An energetic nitrate ester acrylate monomer (4) was synthesized in a total yield of 68% and polymerized to form the energetic nitrate ester acrylate polymer (NEAP). Compound 4 is a liquid at room temperature with a melting point of -8.6 °C and NEAP is a solid with a glass-transition temperature of -8.8 °C. Intermediates leading to 4 and NEAP were characterized by high-resolution mass spectrometry, elemental analysis, Fourier transform infrared spectroscopy, and proton and carbon nuclear magnetic resonance spectroscopies (1H and 13C{1H} NMR). Both 4 and NEAP have electrostatic discharge, friction, and impact sensitivities comparable to those of trinitrotoluene, making NEAP a potential candidate for advanced energetic formulations.

Investigation into a Conformationally Locked (Z)-Azidoxime.

High nitrogen compounds find wide use in the development of new propellants and explosives as well as pharmaceutical chemistry as bioisosteres, bacterial stains, and antifungal agents. A class of underexplored high-nitrogen materials includes azidoximes and their 1-hydroxytetrazole isomers. Azidoximes possess an energetic azide group and are quite sensitive to impact, spark, and friction. Therefore, these materials are generated in situ and cyclized under mild acidic conditions to their 1-hydroxytetrazole isomers. Recently, we synthesized a novel 1,2,4-triazine-derived azidoxime; however, upon subjecting this material to established cyclization conditions, no reaction was observed, even after prolonged reaction times with heating. Additional 1,2,4-triazine-derived azidoximes also displayed a similar lack of reactivities. This observation led us to probe the reactivity of these materials with both a DFT investigation and crystallographically based electrostatic potential mapping. In all, the lack of reactivity toward cyclization was found to be due to an inability of 1,2,4-triazine-based azidoximes to isomerize into the reactive (E)-conformation, requiring an activation energy of 26.4 kcal mol-1.

Tomato lipidic extract plus selenium decrease prostatic hyperplasia, dihydrotestosterone and androgen receptor expression versus finasteride in rats.

PURPOSE: Evaluate the therapeutic effect of a tomato lipidic extract (STE) in combination with selenium (Se) on rats with prostatic hyperplasia (PH) and to observe its possible mechanisms of action and synergism versus finasteride. MATERIALS AND METHODS: 54 male Wistar rats of nine weeks old were divided in Control (C), PH, Finasteride (F), STE, Se, F + STE, F + Se, STE + Se and F + STE + Se with testosterone enanthate (except C). After 4 weeks of treatment administration, prostate weight, bladder weight, diuresis, prooxidant and antioxidant activity, dihydrotestosterone (DHT), androgen receptor (AR) expression and anatomopathological analysis were determined. RESULTS: STE + Se decreased prostate weight 53.8% versus 28% in F group, also STE + Se decreased significatively glandular hyperplasia, prooxidant activity, DHT and AR expression and increased diuresis and antioxidant activity versus finasteride which increased MDA in prostate. CONCLUSIONS: These results demonstrate a greater therapeutic and beneficial effect of tomato lipidic extract in combination with Se in young rats with PH with respect to finasteride without increase prooxidant activity.

Selenium in combination with a tomato lipid extract as a therapy for benign prostatic hyperplasia and its alterations in rats with induced BPH.

Benign prostatic hyperplasia (BPH) is the most common adenoma in old men. Tomatoes are a rich source of bioactive compounds that, as well as selenium (Se), possess antioxidant and antiproliferative activity. The aim was to evaluate the therapeutic effect of Se in combination with a tomato extract in aged rats with BPH. Aged male Wistar rats were divided in the following groups (n = 10 rats/group): Control (C), BPH, BPH + Finasteride (BPH + F), BPH + Tomato Lipidic Extract (BPH + E), BPH + Selenium (BPH + S) and BPH plus E plus S (BPH + E + S). After 4 weeks of treatment, prostate weight, diuresis, antioxidants enzymes, prooxidants and inflammatory markers, growth factors and androgens were determined. BPH + E + S reduced prostate weight by 59.29% and inhibited growth by 99.35% compared to BPH + F which only decreased weight and inhibited growth by 15.31% and 57.54%, respectively. Prooxidant markers were higher with BPH + F (49.4% higher vs. BPH), but BPH + E + S decreased these markers (94.27% vs. BPH) and increased antioxidant activity. Finally, diuresis was higher with the BPH + E + S combination and markers of inflammation and growth factors were significantly lower with respect to BPH + F. Our findings provide a beneficial and protective therapeutic option of E + S directed against androgens, oxidative stress and inflammation that regulates cell proliferation in the prostate gland.

Synthesis and Energetic Properties of N-Substituted 3,4- and 3,5-Dinitropyrazoles.

3,4- and 3,5-Dinitropyrazoles (DNPs) were substituted with acryl and allyl groups on the N1 nitrogen atom, resulting in three novel energetic materials. These compounds are all liquids at room temperature with melting points ranging from -60.2 to -38.6 °C and were fully characterized by high-resolution mass spectrometry, elemental analysis, proton and carbon nuclear magnetic resonance spectroscopy, and Fourier transform infrared spectroscopy. These materials were also tested for electrostatic discharge, friction, and impact sensitivities and then compared to DNP starting materials and to the explosive nitroglycerin (NG). These results indicate that the synthesized compounds are less sensitive to impact compared to NG and have higher thermal stabilities to decomposition.

Lipidic extract of whole tomato reduces hyperplasia, oxidative stress and inflammation on testosterone-induced BPH in obese rats.

PURPOSE: Tomato is an important source of lycopene, a carotenoid that has been emerging as a natural preventive agent for prostate disease. Moreover, tomato contains other components with a wide range of physiological properties, but their potential beneficial effects on prostatic hyperplasia (PH) during obesity have not been completely established. In this study, we compared the effect of a lipidic extract of tomato saladette (STE) with Serenoa repens (SR) on obese rats with PH. METHODS: Forty-eight Wistar rats were divided in Control (C) and Obese (Ob) treated without (n = 12) and with (n = 36) testosterone enanthate (TE), once a week for 8 weeks to induce PH. After 4 weeks, SR and STE were administered. Biochemical parameters, oxidative stress markers and inflammatory cytokines production were determined. RESULTS: TE increased prostate weight and caused prostatic hyperplasia in C group, and these effects were exacerbated by obesity. SR and STE reverted the increase in prostate weight and hyperplasia caused by TE in C and Ob groups. Obesity increased LDL, TGs, NOx and MAD, but decreased HDLc, GSx, SOD and CAT. SR reverted the effects of obesity, but these were significantly reduced and HDLc increased with STE. Obesity and TE increased TNFα, IL-1ß and IL-6 levels, but these were partially reverted by STE compared with SR. CONCLUSIONS: Excess of fat tissue increases the alterations by PH. STE diminishes these alterations compared with SR, suggesting its beneficial effect to improve prostate function. Whole tomato lipid extract could serve as sole therapy or as an adjunct to pharmacological treatment for PH.

Identifying incoherent mixing effects in the coherent two-dimensional photocurrent excitation spectra of semiconductors.

We have previously demonstrated that in the context of two-dimensional (2D) coherent electronic spectroscopy measured by phase modulation and phase-sensitive detection, an incoherent nonlinear response due to pairs of photoexcitations produced via linear excitation pathways contributes to the measured signal as an unexpected background [Grégoire et al., J. Chem. Phys. 147, 114201 (2017)]. Here, we simulate the effect of such incoherent population mixing in the photocurrent signal collected from a GaAs solar cell by acting externally on the transimpedance amplifier circuit used for phase-sensitive detection, and we identify an effective strategy to recognize the presence of incoherent population mixing in 2D data. While we find that incoherent mixing is reflected by the crosstalk between the linear amplitudes at the two time-delay variables in the four-pulse excitation sequence, we do not observe any strict phase correlations between the coherent and incoherent contributions, as expected from modeling of a simple system.

[3+2] click chemistry approach to tetrazine containing polymers.

We report a [3+2] cycloaddition using 3,6-bis-propargyloxy-1,2,4,5-tetrazine and azides to synthesize energetic polymers containing 1,2,4,5-tetrazine within the scaffold. This work also includes [3+2] cycloaddition to crosslink azide containing glycidyl azide polymer (GAP). These reactions provide pathways for incorporation of 1,2,4,5-tetrazine into novel energetic materials using click-chemistry and provide an alternative polymer curing approach.

Lung Transplantation for Multiple Giant Hamartomas: First Case Report and Review of the Literature.

BACKGROUND: To assess lung transplant as a solution for a rare complication of giant lung hamartoma, in which surgical resection was discouraged because of severe underlying chronic lung disease. METHODS: A 54-year-old woman had an episode of severe acute hemoptysis. Imaging techniques showed 2 masses in the right lung as hamartomas and severe pulmonary emphysema. After resolution of the acute episode of hemoptysis, the case could have been solved with a right pneumonectomy; however, a single-lung transplant was performed because of the underlying chronic obstructive pulmonary disease. RESULTS: The outcome of the surgery was satisfactory, although a second operation was required because of bleeding. The patient was discharged and currently has a good quality of life, with no recurrence of the disease. The pathologic anatomy of the surgical specimen confirmed the diagnosis of multiple giant hamartomas. CONCLUSIONS: Lung transplant could be a feasible procedure to treat life-threatening complications of benign tumors in selected patients with pulmonary end-stage disease.

Axon Tracing and Centerline Detection using Topologically-Aware 3D U-Nets.

As advances in microscopy imaging provide an ever clearer window into the human brain, accurate reconstruction of neural connectivity can yield valuable insight into the relationship between brain structure and function. However, human manual tracing is a slow and laborious task, and requires domain expertise. Automated methods are thus needed to enable rapid and accurate analysis at scale. In this paper, we explored deep neural networks for dense axon tracing and incorporated axon topological information into the loss function with a goal to improve the performance on both voxel-based segmentation and axon centerline detection. We evaluated three approaches using a modified 3D U-Net architecture trained on a mouse brain dataset imaged with light sheet microscopy and achieved a 10% increase in axon tracing accuracy over previous methods. Furthermore, the addition of centerline awareness in the loss function outperformed the baseline approach across all metrics, including a boost in Rand Index by 8%.

Consumption of combined fructose and sucrose diet exacerbates oxidative stress, hypertrophy and CaMKIIδ oxidation in hearts from rats with metabolic syndrome.

The prevalence of the metabolic syndrome (MetS) and its cardiac comorbidities as cardiac hypertrophy (CH) have increased considerably due to the high consumption of carbohydrates, such as sucrose and/or fructose. We compared the effects of sucrose (S), fructose (F) and their combination (S + F) on the development of MetS in weaned male Wistar rats and established the relationship between the consumption of these sugars and the degree of cardiac CH development, oxidative stress (OS) and Calcium/calmodulin-dependent protein kinase type II subunit delta oxidation (ox-CaMKIIδ). 12 weeks after the beginning of treatments with S, F or S + F, arterial pressure was measured and 8 weeks later (to complete 20 weeks) the animals were sacrificed and blood samples, visceral adipose tissue and hearts were obtained. Biochemical parameters were determined in serum and cardiac tissue to evaluate the development of MetS and OS. To evaluate CH, atrial natriuretic peptide (ANP), CaMKIIδ and ox-CaMKIIδ were determined by western blot and histological studies were performed in cardiac tissue. Our data showed that chronic consumption of S + F exacerbates MetS-induced CH which is related with a higher OS and ox-CaMKIIδ.

Frenkel biexcitons in hybrid HJ photophysical aggregates.

Frenkel excitons are unequivocally responsible for the optical properties of organic semiconductors and are predicted to form bound exciton pairs (biexcitons). These are key intermediates, ubiquitous in many photophysical processes such as the exciton bimolecular annihilation dynamics in such systems. Because of their spectral ambiguity, there has been, to date, only scant direct evidence of bound biexcitons. By using nonlinear coherent spectroscopy, we identify here bound biexcitons in a model polymeric semiconductor. We find, unexpectedly, that excitons with interchain vibronic dispersion reveal intrachain biexciton correlations and vice versa. Moreover, using a Frenkel exciton model, we relate the biexciton binding energy to molecular parameters quantified by quantum chemistry, including the magnitude and sign of the exciton-exciton interaction the intersite hopping energies. Therefore, our work promises general insights into the many-body electronic structure in polymeric semiconductors and beyond, e.g., other excitonic systems such as organic semiconductor crystals, molecular aggregates, photosynthetic light-harvesting complexes, or DNA.

El Contexto Escolar y la Salud Mental de Adolescentes Migrantes y no Migrantes en la Ciudad de Barcelona / School context and mental health of migrant and non-migrant adolescents in Barcelona

El constante flujo migratorio a nivel internacional invita a reinventarnos para crear sociedades inclusivas a nivel intercultural. La convivencia, como modelo basado en la integración mutua entre locales y migrantes, es todavía un desafío a enfrentar en Europa y España. Este estudio busca identificar qué variables de salud mental y resiliencia afectan a la integración escolar entendida como ejemplo del bienestar psicosocial, comparando una muestra de adolescentes migrantes con adolescentes locales. A través de una metodología cuantitativa, se estudiaron factores escolares, conductas problemáticas y factores de resiliencia en 132 estudiantes de entre 12 y 18 años. Los resultados revelan que los niveles de salud mental son semejantes en ambos grupos, pero la salud mental y la resiliencia contextual son más determinantes en la población adolescente migrante. Identificar con claridad las relaciones entre factores escolares y salud mental ofrece la posibilidad de diseñar intervenciones eficaces en el ámbito educativo. (AU)

The continuous international migration flow invites us to reinvent ourselves to create inclusive societies at intercultural level. Coexistence, as a model based on the mutual integration of locals and migrants, is still a challenge to face in Europe and Spain. This study aims to identify which mental health and resilience variables influence school integration used as a proxy for psychosocial well-being by comparing a sample of migrant and local adolescents. Through a quantitative methodology, school factors, disruptive behaviors, and resilience were measured in 132 students aged between 12 and 18 years old. The results reveal that although mental health scores are similar in both groups, mental health and contextual resilience are more critical for the migrant adolescent population than for the local one. Clearly identifying the relationships between school related factors and mental health offers the possibility of designing effective interventions within the educational context. (AU)

The effect of botulinum toxin on ureteral inflammation.

PURPOSE: The impact of onabotulinum toxin type A (BoNT-A) on bladder afferent nerve pathways and chemosensory functions is an active area of investigation. There may be a role for BoNT-A in disorders of the ureter; however, no histologic studies have assessed the effects of BoNT-A on ureteral tissue. Our objective was to develop an animal model of ureteral inflammation and determine the impact of ureteral BoNT-A instillation on known mechanisms of inflammation. METHODS: The safety and feasibility of a novel animal model of ureteral inflammation was assessed. Through open cystotomy, the effect of ureteral BoNT-A instillation on inflammation was determined through H&E, masson's trichrome, Ki-67 stain, and prostaglandin E (PGE) synthase expression, a known marker of pain and inflammation in ureteral tissue. Urothelial microstructure was assessed using electron microscopy and standard histologic techniques. RESULTS: All experiments were carried to completion, and no systemic signs of botulinum toxicity were seen. BoNT-A exposure was associated with a decrease in PGE synthase expression in a dose-dependent fashion. BoNT-A exposure was not found to impact collagen deposition or cell proliferation. Disruption of tight junctions between urothelial cells was observed under conditions of inflammation. CONCLUSION: We describe the feasibility of a novel in vivo model of ureteral inflammation and report the first histologic study of the effects of BoNT-A on the ureter. Preliminary findings show that BoNT-A attenuates ureteral PGE synthase expression under conditions of inflammation. The application of BoNT-A may provide anti-inflammatory and analgesic effects in the context of ureteral disorders.

Lanthanide Complexes of Bis(tetrazolato)amine: A Route to Lanthanide Nitride Foams.

Metal nitrides are strong refractory ceramic materials known for applications in the coatings, catalysis, and semiconductor industries. Lanthanide nitrides are difficult to prepare in high purity and often require high temperatures and sophisticated equipment. In this work, we present an approach to the synthesis of high-purity f-element nitrides through the use of simple lanthanide salts and the nitrogen-rich ligand 5,5'-bis(1H-tetrazolyl)amine (H2BTA) to form lanthanide complexes of 5,5'-bis(tetrazolato)amine (BTA2-). We have demonstrated that, when dehydrated, these types of complexes undergo a self-sustained combustion reaction under an inert atmosphere to yield nanostructured f-element nitride foams for lanthanum and cerium. The synthesis, characterization, and single-crystal X-ray crystallography of the BTA2- complexes of lanthanum, cerium, praseodymium, neodymium, and europium are also discussed.

Synthesis of Erythritol Tetranitrate Derivatives: Functional Group Tuning of Explosive Sensitivity.

Understanding the factors that affect explosive sensitivity is paramount to the safe handling and development of new explosives molecules. Erythritol tetranitrate (ETN) is an explosive that recently has attracted significant attention in the explosives community because of its ease of synthesis and physical properties. Herein, we report the synthesis of ETN derivatives using azide, nitramine, and nitrate ester functional groups. Impact, spark, and friction sensitivity measurements, computationally calculated explosive properties, and the crystal structure analysis of the ETN derivatives are reported. Mixing explosive functional groups led to changes in the explosive sensitivity, explosive performance as well as physical properties including melting point and physical state at room temperature. Overall, we have demonstrated that combining functional groups can enable the tuning of explosive and physical properties of a molecule. This tunability can potentially aid in the development of new explosives in which characteristics are varied to meet certain specifications.