Triplet excited state generation plays a pivotal role in photosensitizers, however the reliance on transition metals and heavy atoms can limit the utility of these systems. In this study, we demonstrate that an interplay of competing quantum effects controls the high triplet quantum yield in a prototypical boron dipyrromethene-anthracene (BD-An) donor-acceptor dyad photosensitizer, which is only captured by an accurate treatment of both inner and outer sphere reorganization energies. Our ab initio-derived model provides excellent agreement with experimentally measured spectra, triplet yields and excited state kinetic data, including the triplet lifetime. We find that rapid triplet state formation occurs primarily via high-energy triplet states through both spin-orbit coupled charge transfer and El-Sayed's rule breaking intersystem crossing, rather than direct spin-orbit coupled charge transfer to the lowest lying triplet state. Our calculations also reveal that competing effects of nuclear tunneling, electronic state recrossing, and electronic polarizability dictate the rate of non-productive ground state recombination. This study sheds light on the quantum effects driving efficient triplet formation in the BD-An system, and offers a promising simulation methodology for diverse photochemical systems.
Background: Local anaesthetics are widely used for their analgesic and anaesthetic properties in the perioperative setting, including surgical procedures to excise malignant tumours. Simultaneously, chemotherapeutic agents remain a cornerstone of cancer treatment, targeting rapidly dividing cancer cells to inhibit tumour growth. The potential interactions between these two drug classes have drawn increasing attention and there are oncological surgical contexts where their combined use could be considered. This review examines existing evidence regarding the interactions between local anaesthetics and chemotherapeutic agents, including biological mechanisms and clinical implications. Methods: A systematic search of electronic databases was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Selection criteria were designed to capture in vitro, in vivo, and clinical studies assessing interactions between local anaesthetics and a wide variety of chemotherapeutic agents. Screening and data extraction were performed independently by two reviewers. The data were synthesised using a narrative approach because of the anticipated heterogeneity of included studies. Results: Initial searches yielded 1225 relevant articles for screening, of which 43 met the inclusion criteria. The interactions between local anaesthetics and chemotherapeutic agents were diverse and multifaceted. In vitro studies frequently demonstrated altered cytotoxicity profiles when these agents were combined, with variations depending on the specific drug combination and cancer cell type. Mechanistically, some interactions were attributed to modifications in efflux pump activity, tumour suppressor gene expression, or alterations in cellular signalling pathways associated with tumour promotion. A large majority of in vitro studies report potentially beneficial effects of local anaesthetics in terms of enhancing the antineoplastic activity of chemotherapeutic agents. In animal models, the combined administration of local anaesthetics and chemotherapeutic agents showed largely beneficial effects on tumour growth, metastasis, and overall survival. Notably, no clinical study examining the possible interactions of local anaesthetics and chemotherapy on cancer outcomes has been reported. Conclusions: Reported preclinical interactions between local anaesthetics and chemotherapeutic agents are complex and encompass a spectrum of effects which are largely, although not uniformly, additive or synergistic. The clinical implications of these interactions remain unclear because of the lack of prospective trials. Nonetheless, the modulation of chemotherapy effects by local anaesthetics warrants further clinical investigation in the context of cancer surgery where they could be used together. Clinical trial registration: Open Science Framework (OSF, project link: https://osf.io/r2u4z).
Peatlands store vast amounts of carbon (C). However, land-use-driven drainage causes peat oxidation, resulting in CO2 emission. There is a growing need for ground-truthing CO2 emission and its potential drivers to better quantify long-term emission trends in peatlands. This will help improve National Inventory Reporting and ultimately aid the design and verification of mitigation measures. To investigate regional drivers of CO2 emission, we estimated C budgets using custom-made automated chamber systems measuring CO2 concentrations corrected for carbon export and import. Chamber systems were rotated among thirteen degraded peatland pastures in Friesland (the Netherlands). These peatlands varied in water table depth (WTD), drainage-irrigation management (fixed regulated ditch water level (DWL), subsurface irrigation, furrow irrigation, or dynamic regulated DWL), and soil moisture. We investigated (1) whether drainage-irrigation management and related hydrological drivers could explain variation in C budgets, (2) how nighttime ecosystem respiration (Reconight) related to hydrological drivers, and (3) how C budgets compared with estimates from Tier 1 and Tier 2 models regularly used in National Inventory Reporting. Deep-drained peatlands largely overlapped with C budgets from shallow-drained peatlands. The variation in C budgets could not be explained with drainage-irrigation measures or annual WTD, likely because of high variation between sites. Reconightincreased from 85 to 250â¯kg CO2 ha-1â¯day-1 as the WTD dropped from 0 to 50â¯cm across all sites. A deeper WTD had no apparent effect on Reconight, which could be explained by the unimodal relationship we found between Reconight and soil moisture. Finally, C budgets estimated by Tier 1 emission factors and Tier 2 national models mismatched the between-site and between-year variation found in chamber-based estimated NECBs. To conclude, our study showed that shallow WTDs greatly determine C budgets and that regional C budgets, which can be accurately measure with periodic automated chamber measurements, are instrumental for model validation.
Amphiphilic bottlebrush block copolymers (BBCPs), having a hydrophilic bottlebrush polymer (BP) linked covalently to a hydrophobic BP, were found to segregate to liquid-liquid interfaces to minimize the free energy of the system. The key parameter influencing the outcome of the experiments is the ratio between the degree of polymerization of the backbone (NBB) and that of the side-chain brushes (NSC). Specifically, a spherical, star-like configuration results when NBB < NSC, while a cylindrical, bottlebrush-like shape is preferred when NBB > NSC. Dynamic interfacial tension (γ) and fluorescence recovery after photobleaching (FRAP) measurements show that the BBCP configuration influences the areal density and in-plane diffusion at the fluid interface. The characteristic relaxation times associated with BBCP adsorption (τA) and reorganization (τR) were determined by fitting time-dependent interfacial tension measurements to a sum of two exponential relaxation functions. Both τA and τR initially increased with NBB up to 92 repeat units, due to the larger hydrodynamic radius in solution and slower in-plane diffusivity, attributed to a shorter cross-sectional diameter of the side-chains near the block junction. This trend reversed at NBB = 190, with shorter τA and τR attributed to increased segregation strength and exposure of the bare water/toluene interface due to tilting and/or wiggling of the backbone chains, respectively. The adsorption energy barrier decreased with higher NBB, due to a reduced BBCP packing density at the fluid interface. This study provides fundamental insights into macromolecular assembly at fluid interfaces, as it pertains to unique bottlebrush block architectures.
Introduction: People receiving peritoneal dialysis experience physical function decline, impairing their ability to complete everyday activities, leading to poorer quality of life. Physical factors, including cardiorespiratory fitness, muscle strength, physical activity, and sedentary behavior are associated with physical function. However, little is known about this relationship, or temporal changes of these factors in this cohort. This study aimed to explore modifiable physical factors that are associated with physical function, identify which factor has the strongest influence, and explore temporal changes. Methods: Adults receiving peritoneal dialysis underwent objective and self-reported physical function, cardiorespiratory fitness, muscle strength, physical activity and sedentary behavior assessments 3 times over a 12-month observation period (at baseline, 6 months, and 12 months). Results: Eighty-two participants underwent assessments. All modifiable physical factors were predominantly moderate to strongly associated with physical function at baseline. Cardiorespiratory fitness had the strongest and most consistent influence with every meter conferring a 0.08-unit (P < 0.01) and 0.01-unit (P < 0.05) increase in self-report and objective physical function score, respectively. Temporal changes were observed for modifiable physical factors with significant mean changes in cardiorespiratory fitness (-9.8%), quadricep strength (-5%), moderate-to-vigorous (-25.9%) and total (-16.2%) physical activity, and sedentary behavior (+7.1%). Conclusion: The results of this study indicate that cardiorespiratory fitness could be routinely monitored to detect risk of physical function decline and targeted through intervention to enhance physical function for people receiving peritoneal dialysis. Nevertheless, all factors should be considered when designing interventions to mitigate temporal changes and induce the numerous health benefits offered by being physically active.
Excessive mind wandering (MW) contributes to the development and maintenance of psychiatric disorders. Previous studies have suggested that auditory beat stimulation may represent a method enabling a reduction of MW. However, little is known about how different auditory stimulation conditions are subjectively perceived and whether this perception is in turn related to changes in subjective states, behavioral measures of attention and MW. In the present study, we therefore investigated MW under auditory beat stimulation and control conditions using experience sampling during a sustained attention to response task (SART). The subjective perception of the stimulation conditions, as well as changes in anxiety, stress and negative mood after versus before stimulation were assessed via visual-analog scales. Results showed that any auditory stimulation applied during the SART was perceived as more distracting, disturbing, uncomfortable and tiring than silence and was related to more pronounced increases of stress and negative mood. Importantly, the perception of the auditory conditions as disturbing was directly correlated with MW propensity. Additionally, distracting, disturbing and uncomfortable perceptions predicted negative mood. In turn, negative mood was inversely correlated with response accuracy for target stimuli, a behavioral indicator of MW. In summary, our data show that MW and attentional performance are affected by the adverse perception of auditory stimulation, and that this influence may be mediated by changes in mood.
A series of flume- and laboratory-based experiments defined and quantified the thresholds of sunken oil transport using No.6 heavy fuel oil mixed with kaolinite clay. When the sunken oil became mobile, the current-induced bed shear stress exceeded a threshold value specific to the oil, known as critical shear stress (CSS). The oil's CSS was evaluated as a function of water velocity, water temperature, oil condition, and sediment size. Based on experimental results, the stages of oil transport were defined and empirical relationships using the oil's kinematic viscosity (vo) and sediment size were developed to predict oil CSS at each transport stage. For vo<2 × 104 cSt, multiple thresholds of movement were observed: (1) gravity dispersion, (2) rope formation, (3) ripple formation, and (4) break-apart/resuspension. When vo> 6 × 104 cSt, transport was more likely to occur as a single event with the oil remaining intact, saltating over the bed in the direction of flow.
BACKGROUND: Black women are at an increased risk to develop uterine leiomyomas (ULMs) and to experience worse disease prognosis compared to White women. Epidemiological and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multi-omic analysis investigating molecular differences in ULMs from Black and White patients. OBJECTIVE: To identify molecular alterations within ULM tissues correlating with patient race by multi-omic analyses of ULMs collected from cohorts of Black and White women. STUDY DESIGN: We performed multi-omic analysis of ULMs from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. Our analysis also included application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, as well as sheer wave ultrasonography analyses. RESULTS: We found a greater proportion of mediator complex subunit 12 (MED12) mutant ULMs from Black women (>35% increase, Mann Whitney U p = 7E-4). MED12 mutant tumors exhibited elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in regulation of the core matrisome. Histological analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wildtype tumors. Using Sheer Wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer when compared to White patients, even when similar in size. These analyses also uncovered expression quantitative trait loci (eQTL) associated with altered allele frequencies in African and European populations that correlated with differential abundance of several proteins in ULM that are independent of MED12 mutational status, including multiple eQTL mapping to tetratricopeptide repeat protein 38. CONCLUSIONS: Our study shows that Black women have a higher prevalence of ULMs harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis in comparison with wildtype ULMs. Our study provides insights into molecular alterations underlying racial disparities in ULMs and improves our understanding of the molecular etiology underlying ULM development within these populations.
INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. METHODS: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20â mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. RESULTS: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73â µg/g (IQR: 21.94-60.65â µg/g) in skin and 33.29â µg/mL (IQR: 25.9-42.58â µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6â mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. CONCLUSION: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.
The human microbiota impacts a variety of diseases and responses to therapeutics. Due to a lack of robust in vitro models, detailed mechanistic explanations of host-microbiota interactions cannot often be recapitulated. We describe the design and development of a novel, versatile and modular in vitro system that enables indirect coculture of human epithelial cells with anaerobic bacteria for the characterization of host-microbe secreted metabolite interactions. This system was designed to compartmentalize anaerobes and human cells in separate chambers conducive to each organism's requisite cell growth conditions. Using perfusion, fluidic mixing, and automated sample collection, the cells continuously received fresh media, while in contact with their corresponding compartments conditioned supernatant. Supernatants from each chamber were collected in a cell-free time-resolved fashion. The system sustained low oxygen conditions in the anaerobic chamber, while also supporting the growth of a representative anaerobe (Bacteroides thetaiotaomicron) and a human colonic epithelial cell line (Caco-2) in the aerobic chamber. Caco-2 global gene expression changes in response to coculture with B. thetaiotaomicron was characterized using RNA sequencing. Extensive, targeted metabolomics analysis of over 150 central carbon metabolites was performed on the serially collected supernatants. We observed broad metabolite changes in host-microbe coculture, compared to respective mono-culture controls. These effects were dependent both on sampling time and the compartment probed (apical vs. basolateral). Coculturing resulted in the depletion of several important metabolites, including guanine, uridine 5'-monophosphate, asparagine, and thiamine. Additionally, while Caco-2 cells cultured alone predominantly affected the basolateral metabolite milieu, increased abundance of 2,3-dihydroxyisovalerate and thymine on the basolateral side, occurred when the cells were cocultured with B. thetaiotaomicron. Thus, our system can capture the dynamic, competitive and cooperative processes between host cells and gut microbes.
Manipulating the polarization of light at the nanoscale is key to the development of next-generation optoelectronic devices. This is typically done via waveplates using optically anisotropic crystals, with thicknesses on the order of the wavelength. Here, using a novel ultrafast electron-beam-based technique sensitive to transient near fields at THz frequencies, we observe a giant anisotropy in the linear optical response in the semimetal WTe2 and demonstrate that one can tune the THz polarization using a 50 nm thick film, acting as a broadband wave plate with thickness 3 orders of magnitude smaller than the wavelength. The observed circular deflections of the electron beam are consistent with simulations tracking the trajectory of the electron beam in the near field of the THz pulse. This finding offers a promising approach to enable atomically thin THz polarization control using anisotropic semimetals and defines new approaches for characterizing THz near-field optical response at far-subwavelength length scales.
Disordered cannabis use is linked to social problems, which could be explained by a subjective devaluation of nondrug social contexts and/or an overvaluation of cannabis-paired options relative to nondrug alternatives. To examine these hypotheses, measures to assess the subjective value of social- and/or cannabis-paired contexts were collected in people who use cannabis (n = 85) and controls (n = 98) using crowdsourcing methods. Measures included a cued concurrent choice task that presented two images (cannabis, social, social cannabis, and neutral images) paired with monetary options, hypothetical purchase tasks that included access to social parties with and without a cannabis "open bar," and the Social Anhedonia Scale (SAS). Little evidence was found to suggest that the cannabis group undervalued social contexts. People who used cannabis demonstrated a preference for social- versus neutral-cued options, and no preference for cannabis- versus social cannabis-cued options on the choice task. In addition, social party demand and SAS scores did not differ between groups. In contrast, we observed evidence for an overvaluation of cannabis context in people who use cannabis, including preference for social cannabis- versus social-cued options, and more disadvantageous choices for cannabis-cued options on the choice task, as well as more intense and inelastic demand for the social cannabis party compared to the social party. These results suggest that social problems associated with cannabis use could be at least partially explained by an overvaluation of cannabis-paired options, rather than devaluation of nondrug social-paired options, in the value calculations underlying drug use decisions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
Neuroinflammatory Diseases , Pregnanolone , Pregnanolone/pharmacology , Pregnanolone/metabolism , Humans , Animals , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Microglia/drug effects , Microglia/metabolism , Astrocytes/drug effects , Astrocytes/metabolism , GABA-A Receptor Antagonists/pharmacology
BACKGROUND: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P=3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P=0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. CONCLUSIONS: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.
Angiopoietin-Like Protein 2 , Biomarkers , Heart Failure , Proteomics , Stroke Volume , Humans , Heart Failure/urine , Heart Failure/mortality , Heart Failure/physiopathology , Male , Female , Proteomics/methods , Aged , Biomarkers/urine , Biomarkers/blood , Middle Aged , Prognosis , Mineralocorticoid Receptor Antagonists/therapeutic use , Ventricular Function, Left , Risk Factors , Risk Assessment , Proteinuria/urine , Proteinuria/diagnosis
OBJECTIVE: This study aimed to assess the impact of oral medicine (OM) practitioners on the literature regarding oral potentially malignant disorders (OPMDs), focusing on oral leukoplakia. STUDY DESIGN: Using a bibliometric approach on the Scopus database until September 1, 2022, the top 100 cited articles were analyzed for article type, subtopic, specialty contributions, author metrics, and keywords. The Bibliometrix package for R and VOSviewer were used to evaluate interactions and generate science maps. RESULTS: OM practitioners, comprising 39% of contributors, played a significant role in studies related to nomenclature and screening of OPMDs. Notably, 4 OM specialists ranked among the most prolific authors, demonstrating denser collaboration with OM co-authors compared to other cancer specialists. However, there was a scarcity of OPMD management studies authored by OM practitioners. CONCLUSIONS: Despite the paucity of OM practitioners, the findings underscored the substantial contribution of OM practitioners in developing OPMD nomenclature and classification, emphasizing the need for increased collaboration with cancer specialists to conduct comprehensive clinical trials for OPMD management. The study highlights the importance of standardized criteria in OPMDs research for better data comparison and encourages further efforts from the OM scientific community.
Bacterial meningitis, frequently caused by Streptococcus pneumoniae (pneumococcus), represents a substantial global health threat leading to long-term neurological disorders. This study focused on the cholesterol-binding toxin pneumolysin (PLY) released by pneumococci, specifically examining clinical isolates from patients with meningitis and comparing them to the PLY-reference S. pneumoniae strain D39. Clinical isolates exhibit enhanced PLY release, likely due to a significantly higher expression of the autolysin LytA. Notably, the same single amino acid (aa) D380 substitution in the PLY D4 domain present in all clinical isolates significantly enhances cholesterol binding, pore-forming activity, and cytotoxicity toward SH-SY5Y-derived neuronal cells. Scanning electron microscopy of human neuronal cells and patch clamp electrophysiological recordings on mouse brain slices confirm the enhanced neurotoxicity of the PLY variant carrying the single aa substitution. This study highlights how a single aa modification enormously alters PLY cytotoxic potential, emphasizing the importance of PLY as a major cause of the neurological sequelae associated with pneumococcal meningitis.
Ascorbate (vitamin C) limits hematopoietic stem cell (HSC) function and suppresses leukemia development by promoting the function of the Tet2 tumor suppressor. In humans, ascorbate is obtained from the diet while in mice it is synthesized in the liver. In this study, we show that deletion of the Slc23a2 ascorbate transporter severely depleted ascorbate from hematopoietic cells. Slc23a2 deficiency increased HSC reconstituting potential and self-renewal potential upon transplantation into irradiated mice. Slc23a2 deficiency also increased the reconstituting and self-renewal potential of multipotent hematopoietic progenitors (MPPs), conferring the ability to long-term reconstitute irradiated mice. Slc23a2-deficient HSCs and MPPs divided much less frequently than control HSCs and MPPs. Increased self-renewal and reconstituting potential were observed particularly in quiescent Slc23a2-deficient HSCs and MPPs. The effect of Slc23a2 deficiency on MPP self-renewal was not mediated by reduced Tet2 function. Ascorbate thus regulates quiescence and restricts self-renewal potential in HSCs and MPPs such that ascorbate depletion confers MPPs with long-term self-renewal potential.
