Histochemical Analysis of Altered Arachnoid Tissue in Patients With Paroxysmal Trigeminal Neuralgia With Concomitant Continuous Pain.

Background Trigeminal neuralgia (TN) is a craniofacial pain characterized by sudden onset, brief, severe, recurrent shooting pain within one or more branches of the trigeminal nerve (CN V). Based on its clinical presentation, TN may be classified as purely paroxysmal or paroxysmal with concomitant continuous pain (CCP), previously known as typical and atypical, respectively. Microvascular decompression (MVD) surgery for releasing the CN V from a neurovascular conflict is an effective and safe treatment for TN. During MVD of patients manifesting TN with CCP, the involvement of an abnormal arachnoid tissue is a common finding. The etiology and pathophysiology behind the appearance of this tissue are unknown; however, it is more commonly found in this variant of the disease. Methods From January 2015 to December 2016, a total of 330 patients diagnosed with TN were evaluated at our clinic. Among them, 31 individuals (9.4%) presented with paroxysmal TN with CCP, with 16 patients (51.6%) undergoing MVD. During surgery, samples of altered arachnoid tissue were collected from five patients and subjected to Hematoxylin-Eosin staining and immunohistochemistry for S100 and CD2 Results In a long-term follow-up, 80% of patients operated by DMV remains pain free. Analysis of biopsies revealed chronic fibrosis (n=4), hyperplasia of neurothelial cells (n=3), dystrophic calcifications (n=1). Immunohistochemistry was positive for S100 (n=3) and CD20 (n=3) inflammatory markers. Conclusion Chronic inflammation in the arachnoid tissue involved in paroxysmal TN with CCP could be a contributor to the pathophysiology of this variant of the disease.

Multimodal, PSMA-Targeted, PAMAM Dendrimer-Drug Conjugates for Treatment of Prostate Cancer: Preclinical Evaluation.

Introduction: Prostate cancer (PC) is the second most common cancer and the fifth most frequent cause of cancer death among men. Prostate-specific membrane antigen (PSMA) expression is associated with aggressive PC, with expression in over 90% of patients with metastatic disease. Those characteristics have led to its use for PC diagnosis and therapies with radiopharmaceuticals, antibody-drug conjugates, and nanoparticles. Despite these advancements, none of the current therapeutics are curative and show some degree of toxicity. Here we present the synthesis and preclinical evaluation of a multimodal, PSMA-targeted dendrimer-drug conjugate (PT-DDC), synthesized using poly(amidoamine) (PAMAM) dendrimers. PT-DDC was designed to enable imaging of drug delivery, providing valuable insights to understand and enhance therapeutic response. Methods: The PT-DDC was synthesized through consecutive conjugation of generation-4 PAMAM dendrimers with maytansinoid-1 (DM1) a highly potent antimitotic agent, Cy5 infrared dye for optical imaging, 2,2',2"-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA) chelator for radiolabeling with copper-64 and positron emission tomography tomography/computed tomography (PET/CT), lysine-urea-glutamate (KEU) PSMA-targeting moiety and the remaining terminal primary amines were capped with butane-1,2-diol. Non-targeted control dendrimer-drug conjugate (Ctrl-DDC) was formulated without conjugation of KEU. PT-DDC and Ctrl-DDC were characterized using high-performance liquid chromatography, matrix assisted laser desorption ionization mass spectrometry and dynamic light scattering. In vitro and in vivo evaluation of PT-DDC and Ctrl-DDC were carried out in isogenic human prostate cancer PSMA+ PC3 PIP and PSMA- PC3 flu cell lines, and in mice bearing the corresponding xenografts. Results: PT-DDC was stable in 1×PBS and human blood plasma and required glutathione for DM1 release. Optical, PET/CT and biodistribution studies confirmed the in vivo PSMA-specificity of PT-DDC. PT-DDC demonstrated dose-dependent accumulation and cytotoxicity in PSMA+ PC3 PIP cells, and also showed growth inhibition of the corresponding tumors. PT-DDC did not accumulate in PSMA- PC3 flu tumors and did not inhibit their growth. Ctrl-DDC did not show PSMA specificity. Conclusion: In this study, we synthesized a multimodal theranostic agent capable of delivering DM1 and a radionuclide to PSMA+ tumors. This approach holds promise for enhancing image-guided treatment of aggressive, metastatic subtypes of prostate cancer.

The role of hydraulic conductivity in the Pine Island Glacier's subglacial water distribution.

Global climate warming leads to ever-increasing glacier mass loss. Pine Island Glacier in Antarctica is one of the largest contributors to global sea level rise (SLR). One of the biggest uncertainties in the assessment of glacier contribution to SLR at present are subglacial hydrology processes which are less well known than other ice dynamical processes. We use the Glacier Drainage System (GlaDS) model which couples both distributed and channelized components to simulate the basal hydrology of Pine Island Glacier with basal sliding and meltwater production taken from a full-Stokes Elmer/Ice model fitting observed surface velocities. We find ≈100 km long Rothlisberger channels up to 26 m in diameter extending up glacier from the grounding line along the main trunk of Pine Island Glacier delivering 51 m3 s-1 of fresh water to the grounding line. Channelization occurs at high water pressure because of high basal melt rates (maximum of 1 m a-1) caused by high rates of shear heating in regions with fast ice flow (>1000 m a-1). We simulate a shallow "swamp" of 0.8 m water depth where flow transitions from a distributed system into the channels. We performed a set of 38 sensitivity experiments varying sheet and channel conductivity over 4 orders of magnitude. We find a threshold behavior in distributed sheet conductivity above which basal water pressures are unaffected by changing channel conductivities. Our findings suggest a strong need to better understand controls on basal water conductivity through the distributed system. This issue is critical to improve model-based predictive capability for the Pine Island Glacier and, more generally, the Antarctic Ice Sheet.

A new schedule of one week on/one week off temozolomide as second-line treatment of advanced neuroendocrine carcinomas (TENEC-TRIAL): a multicenter, open-label, single-arm, phase II trial.

BACKGROUND: There is no consensus on the second-line treatment of patients with progressive high-grade neuroendocrine neoplasms (NENs G3) and large-cell lung neuroendocrine carcinoma. These patients generally have poor performance status and low tolerance to combination therapy. In this trial, we aim to evaluate the efficacy and safety of temozolomide given every other week in patients with advanced platinum-pretreated NENs G3. PATIENTS AND METHODS: This trial is an open-label, non-randomized, phase II trial. Patients with platinum-pretreated metastatic neuroendocrine carcinoma were treated with 75 mg/m2/day of temozolomide for 7 days, followed by 7 days of no treatment (regimen one week on/one week off). The primary endpoint was the overall response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and tolerability. This study is registered with ClinicalTrials.gov, NCT04122911. RESULTS: From 2017 to 2020, 38 patients were enrolled. Among the patients with determined Ki67, 12 out of 36 (33.3%) had a Ki67 index <55% and the remaining 24 out of 36 (66.6%) had an index ≥55%. Overall response rate was 18% (7/38), including one complete response and six partial responses. The median PFS was 5.86 months [95% confidence interval (CI) 4.8 months-not applicable) and the median OS was 12.1 months (95% CI 5.6-20.4 months). The 1-year PFS rate was 37%. No statistically significant difference in median PFS [hazard ratio 1.3 (95% CI 0.6-2.8); P = 0.44] and median OS [hazard ratio 1.1 (95% CI 0.5-2.4); P = 0.77] was observed among patients with Ki67 <55% versus ≥55%. Only G1-G2 adverse events were registered, the most common being G1 nausea, diarrhea and abdominal pain. CONCLUSION: One week on/one week off temozolomide shows promising activity in patients with poorly differentiated NEN. The good safety profile confirmed the possibility of using this scheme in patients with poor performance status.

A Review on Carbon Nanotubes Family of Nanomaterials and Their Health Field.

The use of carbon nanotubes (CNTs), which are nanometric materials, in pathogen detection, protection of environments, food safety, and in the diagnosis and treatment of diseases, as efficient drug delivery systems, is relevant for the improvement and advancement of pharmacological profiles of many molecules employed in therapeutics and in tissue bioengineering. It has contributed to the advancement of science due to the development of new tools and devices in the field of medicine. CNTs have versatile mechanical, physical, and chemical properties, in addition to their great potential for association with other materials to contribute to applications in different fields of medicine. As, for example, photothermal therapy, due to the ability to convert infrared light into heat, in tissue engineering, due to the mechanical resistance, flexibility, elasticity, and low density, in addition to many other possible applications, and as biomarkers, where the electronic and optics properties enable the transduction of their signals. This review aims to describe the state of the art and the perspectives and challenges of applying CNTs in the medical field. A systematic search was carried out in the indexes Medline, Lilacs, SciELO, and Web of Science using the descriptors "carbon nanotubes", "tissue regeneration", "electrical interface (biosensors and chemical sensors)", "photosensitizers", "photothermal", "drug delivery", "biocompatibility" and "nanotechnology", and "Prodrug design" and appropriately grouped. The literature reviewed showed great applicability, but more studies are needed regarding the biocompatibility of CNTs. The data obtained point to the need for standardized studies on the applications and interactions of these nanostructures with biological systems.

Bridge: A New Algorithm for Rooting Orthologous Genes in Large-Scale Evolutionary Analyses.

Orthology information has been used for searching patterns in high-dimensional data, allowing transferring functional information between species. The key concept behind this strategy is that orthologous genes share ancestry to some extent. While reconstructing the history of a single gene is feasible with the existing computational resources, the reconstruction of entire biological systems remains challenging. In this study, we present Bridge, a new algorithm designed to infer the evolutionary root of orthologous genes in large-scale evolutionary analyses. The Bridge algorithm infers the evolutionary root of a given gene based on the distribution of its orthologs in a species tree. The Bridge algorithm is implemented in R and can be used either to assess genetic changes across the evolutionary history of orthologous groups or to infer the onset of specific traits in a biological system.

Effects of silver diamine fluoride on demineralization protection after a secondary acid challenge.

OBJECTIVE: This investigation describes the effects of 5% sodium fluoride varnish and 38% silver diamine fluoride on demineralization protection of human enamel lesions of three different severities after a secondary acid challenge. STUDY DESIGN: Specimens underwent color and enamel surface microhardness change measurements after demineralization and treatment events. Transverse microradiography was conducted following the secondary demineralization. RESULTS: After treatments, enamel surface microhardness change showed that 24-hour lesions treated with fluoride varnish had less rehardening than 24-hour lesions treated with silver diamine fluoride (p<0.05), whereas 144-hour lesions from both treatment groups showed a beneficial decrease in surface microhardness change that was markedly better in samples treated with silver diamine fluoride (p<0.05). After the secondary demineralization, 24- and 144-hour lesions treated with silver diamine fluoride showed a sustained beneficial decrease in enamel surface microhardness change when compared to fluoride varnish-treated samples of the corresponding lesion severity (p<0.05). Transverse microradiography showed no difference between fluoride varnish- and silver diamine fluoride-treated samples of any corresponding lesion severity, indicating that remineralization in both fluoride varnish- and silver diamine fluoride-treated samples was proportional to each other after a secondary acid challenge. CONCLUSIONS: Using silver diamine fluoride may have comparable benefits to fluoride varnish in mineral loss prevention.

Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects.

Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.

Anorectic effect of COR659 in a rat model of overeating.

COR659 is a new compound, the action of which is exerted via a dual mechanism: positive allosteric modulation of the GABAB receptor; antagonism or inverse agonism at the cannabinoid CB1 receptor. Recent lines of experimental evidence have indicated that COR659 potently and effectively reduced operant self-administration of and reinstatement of seeking behaviour for a chocolate-flavoured beverage. The present study was designed to assess whether the ability of COR659 to diminish these addictive-like, food-motivated behaviours extended to a rat model of overeating palatable food. To this end, rats were habituated to feed on a standard rat chow for 3 h/day; every 4 days, the 3-hour chow-feeding session was followed by a 1-hour feeding session with highly palatable, calorie-rich Danish butter cookies. Even though satiated, rats overconsumed cookies. COR659 (0, 2.5, 5, and 10 mg/kg, i.p.) was administered before the start of the cookie-feeding session. Treatment with all 3 doses of COR659 produced a substantial decrease in intake of cookies and calories from cookies. These results extend the anorectic profile of COR659 to overconsumption of a highly palatable food and intake of large amounts of unnecessary calories.

Automated Sample Preparation for Mass Spectrometry-Based Clinical Proteomics.

Mass spectrometry (MS)-based proteomics is a rapidly maturing discipline, thus gaining momentum for routine molecular profiling of clinical specimens to improve disease classification, diagnostics, and therapy development. Yet, hurdles need to be overcome to enhance reproducibility in preanalytical sample processing, especially in large, quantity-limited sample cohorts. Therefore, automated sonication and single-pot solid-phase-enhanced sample preparation (autoSP3) was developed as a streamlined workflow that integrates all tasks from tissue lysis and protein extraction, protein cleanup, and proteolysis. It enables the concurrent processing of 96 clinical samples of any type (fresh-frozen or FFPE tissue, liquid biopsies, or cells) on an automated liquid handling platform, which can be directly interfaced to LC-MS for proteome analysis of clinical specimens with high sensitivity, high reproducibility, and short turn-around times.

In vitro toxicity and lung cancer risk: Atmospheric particulate matter from a city in southeastern Brazil impacted by biomass burning.

The effects of PM10 on human health were investigated using samples collected in São Carlos city (São Paulo state), by the determination of the concentrations of PAHs and derivatives, together with evaluations of cytotoxicity and the formation of ROS in in vitro tests. In 2016, the mean concentrations of PM10, ΣPAHs, Σoxy-PAHs, Σnitro-PAHs, Σsaccharides, and Σions were 21.12 ± 9.90 µg m-3, 1.47 ± 1.70 ng m-3, 0.37 ± 0.31 ng m-3, 0.84 ng m-3, 119.91 ± 62.14 ng m-3, and 5.66 ± 4.52 µg m-3, respectively. The PM10 concentrations did not exceed the limit thresholds set by national legislation, however, the annual lung cancer risk calculated was 2.59 ± 1.22 cases per 100,000 people, in the dry season, which accounts for the annual risk (April to September). Moreover, the carcinogenic activities of the PAHs mixture were more than 1000-fold higher in the dry season (dry season: BaPeq = 0.30 ng m-3; wet season BaPeq = 0.02 ng m-3). The concentrations of most analytes were also higher during the dry season, as had already been demonstrated in the same city. This was due to reductions in precipitation, relative humidity and air temperature, and increased biomass burning, which was the main source of PM10 in the city in 2016 (contribution rate of more than 50%). Toxicological results also showed the negative impacts of PM10, exposure to PM10 extracts for 72 h reduced the viability of A549 and MRC5 cells, and the formation of ROS was observed. The cellular responses obtained using combined and individual extracts of PM10 differed and were sometimes associated with specific compounds. These demonstrate the importance of monitoring PM toxicity using different approaches and the main anthropogenic sources' contribution. Therefore, to improve air quality and human health, existing legislation needs to be modified to incorporate these tests.

The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy.

HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent proviruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with t1/2 of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4+ T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART.

Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.

spongEffects: ceRNA modules offer patient-specific insights into the miRNA regulatory landscape.

MOTIVATION: Cancer is one of the leading causes of death worldwide. Despite significant improvements in prevention and treatment, mortality remains high for many cancer types. Hence, innovative methods that use molecular data to stratify patients and identify biomarkers are needed. Promising biomarkers can also be inferred from competing endogenous RNA (ceRNA) networks that capture the gene-miRNA gene regulatory landscape. Thus far, the role of these biomarkers could only be studied globally but not in a sample-specific manner. To mitigate this, we introduce spongEffects, a novel method that infers subnetworks (or modules) from ceRNA networks and calculates patient- or sample-specific scores related to their regulatory activity. RESULTS: We show how spongEffects can be used for downstream interpretation and machine learning tasks such as tumor classification and for identifying subtype-specific regulatory interactions. In a concrete example of breast cancer subtype classification, we prioritize modules impacting the biology of the different subtypes. In summary, spongEffects prioritizes ceRNA modules as biomarkers and offers insights into the miRNA regulatory landscape. Notably, these module scores can be inferred from gene expression data alone and can thus be applied to cohorts where miRNA expression information is lacking. AVAILABILITY AND IMPLEMENTATION: https://bioconductor.org/packages/devel/bioc/html/SPONGE.html.

Immunomodulatory effects of different strains of Lactococcus lactis in DSS-induced colitis.

Inflammatory bowel diseases (IBD) are gastrointestinal disorders characterized by a breakdown in intestinal homeostasis by inflammatory immune responses to luminal antigens. Novel strategies for ameliorating IBD have been proposed in many studies using animal models. Our group has demonstrated that administration of Lactococcus lactis NCDO 2118 can improve clinical parameters of colitis induced by oral administration of dextran sulphate sodium (DSS). However, it is not clear whether other strains of L. lactis can yield the same effect. The objective of present study was to analyze the effects of three different L. lactis strains (NCDO2118, IL1403 and MG1363) in the development of DSS-induced colitis in C57BL/6 mice. Acute colitis was induced in C57/BL6 mice by the administration of 2% DSS during 7 consecutive days. Body weight loss and shortening of colon length were observed in DSS-treated mice, and none of L. lactis strains had an impact in these clinical signs of colitis. On the other hand, all strains improved the global macroscopical disease index and prevented goblet cells depletion as well as the increase of intestinal permeability. TNF-α production was reduced in gut mucosa of L. lactis DSS-treated mice indicating a modulation of a critical pro-inflammatory response by all strains tested. However, only L. lactis NCDO2118 and MG1363 induced a higher frequency of CD11c+CD11b-CD103+ tolerogenic dendritic cells in lymphoid organs of mice at steady state. We conclude that all tested strains of L. lactis improved the clinical scores and parameters of colitis, which confirm their anti-inflammatory properties in this model of colitis.

Hsp65-producing Lactococcus lactis inhibits experimental autoimmune encephalomyelitis by preventing cell migration into spinal cord.

Multiple sclerosis is an autoimmune disease that affects the central nervous system. Because of its complexity and the difficulty to treat, searching for immunoregulatory responses that reduce the clinical signs of disease by non-aggressive mechanisms and without adverse effects is a scientific challenge. Herein we propose a protocol of oral tolerance induction that prevented and controlled MOG-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The genetically modified strain HSP65-producing Lactococcus lactis was orally administered for 5 consecutive days either before or during disease development in mice. Both protocols of feeding HSP65 resulted in significant reduction in the clinical score of EAE. Frequencies of LAP+CD4+Foxp3- regulatory T cells were higher in spleens and inguinal lymph nodes of fed mice. In addition, intravital microscopy showed that adherence of leukocytes to venules in the spinal cord was reduced in orally treated mice. Oral treatment with HSP65-producing L.lactis prevented leukocytes to leave the secondary lymphoid organs, therefore they could not reach the central nervous system. Despite the inhibition of pathological immune response that drive EAE development, activated T cells were at normal frequencies suggesting that oral tolerance did not induce general immunosuppression, but it led to specific control of pathogenic T cells. Our results indicate a novel therapeutic strategy to prevent and control autoimmune diseases such as multiple sclerosis.

Towards a unified vision on animal navigation.

The study of animal navigation is a complex and fertile field of research: Several questions regarding how animals relate to external stimuli, integrating them to perform their everyday movement routine, have been or are being addressed in different organisms and taxa, both from the behavioural and the neuronal activity point of view. Several invertebrate model organisms are the object of studies aimed at unravelling how they navigate and their ability to precisely return to a starting point and also how navigational information is communicated to conspecifics when precise social structures are present. Also, vertebrates are studied because of the interest in their orientation abilities while migrating, homing over impressive distances and studying exploration, orientation and space recognition. Last, research on the navigation capabilities of humans pursues a better understanding of the neural architecture involved in these processes in the remarkable effort to find answers and possible solutions to impairments, lesions and diseases. However, an 'all-inclusive' vision of navigation still appears to be in its embryonic state: A better perspective could (and should) shift from a paradigm where single research teams are centred on studying navigation in a single genus or species towards a more comprehensive evolutionary-centred view, searching systematically for behavioural analogies, and possibly for homologies in neural architecture between different taxa. In this review, we introduce examples of relevant topics in animal navigation from distinct animal groups, highlighting the similar approaches of those studies, and why, in our opinion, this research field could profit from a 'new' perspective.

Effects of silver diamine fluoride on demineralization protection after a secondary acid challenge

Abstract Objective This investigation describes the effects of 5% sodium fluoride varnish and 38% silver diamine fluoride on demineralization protection of human enamel lesions of three different severities after a secondary acid challenge. Study design Specimens underwent color and enamel surface microhardness change measurements after demineralization and treatment events. Transverse microradiography was conducted following the secondary demineralization. Results After treatments, enamel surface microhardness change showed that 24-hour lesions treated with fluoride varnish had less rehardening than 24-hour lesions treated with silver diamine fluoride (p<0.05), whereas 144-hour lesions from both treatment groups showed a beneficial decrease in surface microhardness change that was markedly better in samples treated with silver diamine fluoride (p<0.05). After the secondary demineralization, 24- and 144-hour lesions treated with silver diamine fluoride showed a sustained beneficial decrease in enamel surface microhardness change when compared to fluoride varnish-treated samples of the corresponding lesion severity (p<0.05). Transverse microradiography showed no difference between fluoride varnish- and silver diamine fluoride-treated samples of any corresponding lesion severity, indicating that remineralization in both fluoride varnish- and silver diamine fluoride-treated samples was proportional to each other after a secondary acid challenge. Conclusions Using silver diamine fluoride may have comparable benefits to fluoride varnish in mineral loss prevention.

Structural Chirality of Polar Skyrmions Probed by Resonant Elastic X-Ray Scattering.

An escalating challenge in condensed-matter research is the characterization of emergent order-parameter nanostructures such as ferroelectric and ferromagnetic skyrmions. Their small length scales coupled with complex, three-dimensional polarization or spin structures makes them demanding to trace out fully. Resonant elastic x-ray scattering (REXS) has emerged as a technique to study chirality in spin textures such as skyrmions and domain walls. It has, however, been used to a considerably lesser extent to study analogous features in ferroelectrics. Here, we present a framework for modeling REXS from an arbitrary arrangement of charge quadrupole moments, which can be applied to nanostructures in materials such as ferroelectrics. With this, we demonstrate how extended reciprocal space scans using REXS with circularly polarized x rays can probe the three-dimensional structure and chirality of polar skyrmions. Measurements, bolstered by quantitative scattering calculations, show that polar skyrmions of mixed chirality coexist, and that REXS allows valuation of relative fractions of right- and left-handed skyrmions. Our quantitative analysis of the structure and chirality of polar skyrmions highlights the capability of REXS for establishing complex topological structures toward future application exploits.