Search

The complex effects of combined CDki/SPyADI application on arginine-auxotrophic glioblastoma multiforme cells. CDki/SPyADI combination therapy impairs cell proliferation, invasiveness, gene expression, induces mitochondrial impairment, and vacuole formation. Abemaciclib-SPyADI-treatment suppresses DNA repair, dinaciclib-SpyADI-treatment enhances γ-H2AX accumulation and activates the stress sensor GADD45 and β-catenin antagonist AXIN2. Both CDKi/SpyADI combinations significantly boost cell death.

Here, the authors show brightening of dark excitons by strong coupling between cavity photons and high energy, spin-allowed, bright excitons in monolayer WSe2. In this regime, the commonly observed photoluminescence quenching stemming from the fast relaxation to the dark ground state is prevented.

Dog vaccination is an effective rabies prevention measure, but widespread vaccination campaigns are challenging in settings like India with large free-roaming dog populations. Here, the authors describe a One Health campaign in Goa state which led to a large reduction of cases in dogs and elimination in humans.

The transition to a low-carbon energy source from coal has become imperative to mitigating the escalating climate change crisis. This study aims to investigate the organic-rich shale core samples of the Limpopo-Area Karoo Basin, retrieved from the borehole at depth 480–580 m. These samples were subjected to petrographic, mineralogical, morphological, and kerogen-type analysis to investigate potentials for shale gas generation. The petrographic analysis reveals maceral group mainly comprised of vitrinite group with some liptinite and inertinite and mineral compositions. The preponderance of pyrite framboids (1.6–12%) indicate redox of FeS2 as a precursor to methane gas generation in anoxic condition. The x-ray diffractometer (XRD) reveals the presence of quartz, albite, microcline, dolomite, pyrite and clay minerals which alluded to the mineral composition indicated by the petrographic analysis. The clay mineral component consists of montmorillonite, illite, chlorite, and mixed layered illite/smectite (I/S) in the Madzaringwe samples. The representative scanning electron microscopy-Energy Dispersive X-ray (SEM-EDX) images of the studied shales depict a combination of organic-matter, groundmass mineral, micro-fracture pore structures reflecting polyframboidal pyrite and carbonate dissolution morphology. The total organic carbon (TOC) contents averaging at 47 wt%, indicating an excellent source rock. The Rock-Eval 6 programmed pyrolysis samples showed S2 value (15.25–16.47 mg HC/g rock) with an average of 15.69 mg HC/g rock and Hydrogen index (HI) (34.0–37.0 mg HC/g TOC) indicating a Type-III Kerogen dominance prone to gas generation. The shale showed Tmax values (464–470 °C) averaging at 467.2 °C, yielding a thermally mature condensate wet-gas. This study reveals that the Permian carbonaceous rock tends to generate gas which can be hosted mainly by the organic matter pore structures, inorganic and micro-fracture pore structures.

Summary: Recent research suggests that mindfulness, compassion, and self-compassion relate to inner transformative qualities/capacities and intermediary factors that can support increased pro-environmental behavior and attitudes across individual, collective, organizational, and system levels. However, current insights focus on the individual level, are restricted to certain sustainability fields, and wider experimental evidence is scarce and contradictory. Our pilot study addresses this gap and tests the aforementioned proposition in the context of an intervention: an EU Climate Leadership Program for high-level decision-makers. The intervention was found to have significant effects on transformative qualities/capacities, intermediary factors, and pro-environmental behaviors and engagement across all levels. The picture is, however, more complex for pro-environmental attitudes. With due limitations (e.g., small sample size), this preliminary evidence confirms the feasibility and potential of mindfulness- and compassion-based interventions to foster inner-outer transformation for sustainability and climate action. Aspects that should be taken into account in larger confirmatory trials are discussed.

Adding a topological theta term to the action of N=1 D=4 super Yang–Mills theory modifies its Nicolai map. For the BPS value of the theta angle a chiral version of the map emerges, which allows for a considerable simplification compared to the non-chiral formulation. We exhibit these improvements to all orders in perturbation theory and compute the map to fourth order in the coupling on the Laudau-gauge hypersurface. The second-order contribution vanishes, and antisymmetrizations are more manifest. All checks are verified to third order.

Canine-mediated rabies kills tens of thousands of people annually in lesser-developed communities of Asia, Africa, and the Americas, primarily through bites from infected dogs. Multiple rabies outbreaks have been associated with human deaths in Nigeria. However, the lack of quality data on human rabies hinders advocacy and resource allocation for effective prevention and control. We obtained 20 years of dog bite surveillance data across 19 major hospitals in Abuja, incorporating modifiable and environmental covariates. To overcome the challenge of missing information, we used a Bayesian approach with expert-solicited prior information to jointly model missing covariate data and the additive effects of the covariates on the predicted probability of human death after rabies virus exposure. Only 1155 cases of dog bites were recorded throughout the study period, out of which 4.2% (N = 49) died of rabies. The odds for risk of human death were predicted to decrease among individuals who were bitten by owned dogs compared to those bitten by free-roaming dogs. Similarly, there was a predicted decrease in the probability of human death among victims bitten by vaccinated dogs compared to those bitten by unvaccinated dogs. The odds for the risk of human death after bitten individuals received rabies prophylaxis were predicted to decrease compared to no prophylaxis. We demonstrate the practical application of a regularised Bayesian approach to model sparse dog bite surveillance data to uncover risk factors for human rabies, with broader applications in other endemic rabies settings with similar profiles. The low reporting observed in this study underscores the need for community engagement and investment in surveillance to increase data availability. Better data on bite cases will help to estimate the burden of rabies in Nigeria and would be important to plan effective prevention and control of this disease.

Abstract We offer a novel perspective on N $$ \mathcal{N} $$ = 4 supersymmetric Yang-Mills (SYM) theory through the framework of the Nicolai map, a transformation of the bosonic fields that allows one to compute quantum correlators in terms of a free, purely bosonic functional measure. Generally, any Nicolai map is obtained through a path-ordered exponential of the so-called coupling flow operator. The latter can be canonically constructed in any gauge using an N $$ \mathcal{N} $$ = 1 off-shell superfield formulation of N $$ \mathcal{N} $$ = 4 SYM, or alternatively through dimensional reduction of the result from N $$ \mathcal{N} $$ = 1 D = 10 SYM, in which case we need to restrict to the Landau gauge. We propose a general theory of the N $$ \mathcal{N} $$ = 4 coupling flow operator, arguing that it exhibits an ambiguity in form of an R-symmetry freedom given by the Lie algebra su $$ \mathfrak{su} $$ (4). This theory incorporates our two construction approaches as special points in su $$ \mathfrak{su} $$ (4) and defines a broad class of Nicolai maps for N $$ \mathcal{N} $$ = 4 SYM.

Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin N-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds.

To obtain reliable data that allow health authorities to re-evaluate recommendations for oral vitamin D uptake, we conducted a meta-analysis to investigate the impact of supplementation on serum 25-hydroxyvitamin D (25(OH)D) levels in healthy adults in Europe. Of the publications identified (n = 4005) in our literature search (PUBMED, through 2 January 2022), 49 primary studies (7320 subjects, 73 study arms) were eligible for inclusion in our meta-analysis. The risk of bias was assessed using the Cochrane RoB tool based on seven categories, according to which each study is rated using three grades, and overall was rated as rather low. The median duration of intervention was 136.78 days (range, 1088 days); the mean weighted baseline 25(OH)D concentration and mean age were 33.01 vs. 33.84 nmol/L and 46.8 vs. 44.8 years in the vitamin D and placebo groups, respectively. Using random-effects models, 25(OH)D levels were increased by 36.28 nmol/L (95% CI 31.97–40.59) in the vitamin D group compared to the placebo, with a relative serum increment of 1.77 nmol/L per 2.5 μg of vitamin D daily. Notably, the relative serum 25(OH)D increment was affected by various factors, including the dosage and baseline serum 25(OH)D concentration, decreasing with increasing vitamin D doses and with increasing baseline serum levels. We estimate that supplementation in all healthy adults in Europe with appr. 25 μg of vitamin D (1000 IU) daily would raise serum 25(OH)D levels in 95% of the population to ≥50 nmol/L. Our work provides health authorities with reliable data that can help to re-evaluate recommendations for oral vitamin D supplementation.

IntroductionScientific discoveries over the past few decades have provided significant insight into the abuse liability and negative health consequences associated with tobacco and nicotine-containing products. While many of these advances have led to the development of policies and laws that regulate access to and formulations of these products, further research is critical to guide future regulatory efforts, especially as novel nicotine-containing products are introduced and selectively marketed to vulnerable populations.DiscussionIn this narrative review, we provide an overview of the scientific findings that have impacted regulatory policy and discuss considerations for further translation of science into policy decisions. We propose that open, bidirectional communication between scientists and policy makers is essential to develop transformative preventive- and intervention-focused policies and programs to reduce appeal, abuse liability, and toxicity of the products.ConclusionsThrough these types of interactions, collaborative efforts to inform and modify policy have the potential to significantly decrease the use of tobacco and alternative nicotine products and thus enhance health outcomes for individuals.ImplicationsThis work addresses current topics in the nicotine and tobacco research field to emphasize the importance of basic science research and provide examples of how it can be utilized to inform public policy. In addition to relaying current thoughts on the topic from experts in the field, the article encourages continued efforts and communication between basic scientists and policy officials.

RationaleThe ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure.ObjectiveThe current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis.MethodsAdult male rats with ad libitum access to powdered standard rodent chow self-administered intravenous infusions of nicotine (60 μg/kg/infusion or saline control) in daily 1-h sessions in the last hour of the light cycle. Indirect calorimetry measured respiratory exchange ratio (RER), energy expenditure, motor activity, and food and water consumption for 22.5 h between select self-administration sessions.ResultsSelf-administered nicotine suppressed weight gain and reduced the percent of body fat without altering the percent of lean mass, as measured by Echo MRI. Nicotine reduced RER, indicating increased fat utilization; this effect was observed prior to weight suppression. Moreover, nicotine intake did not affect motor activity or energy expenditure. Daily food intake was not altered by nicotine self-administration; however, a trend in suppression of meal size, a transient suppression of water intake, and an increase in meal frequency was observed.ConclusionThese data provide evidence that self-administered nicotine suppresses body weight via increased fat metabolism, independent of significant changes in feeding, activity, or energy expenditure.

Here, the authors show that the interaction between microcavity photons and excitons in an atomically thin WSe2 results in a hybridized regime of strong light-matter coupling. Coherence build-up is accompanied by a threshold-like behaviour of the emitted light intensity, which is a fingerprint of a polariton laser effect.

Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput chemical screens with patient-derived models of cancer to identify new potential therapeutic targets for CRC. However, this pipeline is limited by (1) the use of cell lines that do not appropriately recapitulate the tumor microenvironment, and (2) the use of patient-derived xenografts (PDXs), which are time-consuming and costly for validation of drug efficacy. To overcome these limitations, we have turned to patient-derived organoids. Organoids are increasingly being accepted as a “standard” preclinical model that recapitulates tumor microenvironment cross-talk in a rapid, cost-effective platform. In the present work, we employed a library of natural products, intermediates, and drug-like compounds for which full synthesis has been demonstrated. Using this compound library, we performed a high-throughput screen on multiple low-passage cancer cell lines to identify potential treatments. The top candidate, psymberin, was further validated, with a focus on CRC cell lines and organoids. Mechanistic and genomics analyses pinpointed protein translation inhibition as a mechanism of action of psymberin. These findings suggest the potential of psymberin as a novel therapy for the treatment of CRC.

Background: Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives: The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design: Randomized double blind placebo control, monocenter study. Methods: In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results: Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion: The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration: ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors ; URL: https://clinicaltrials.gov/ct2/show/NCT02753738 .

Abstract Background Patients in Germany are free to seek care from any office-based physician and can always ask for multiple opinions on a diagnosis or treatment. The high density of physicians and the freedom to choose among them without referrals have led to a need for better coordination between the multiple health professionals treating any given patient. The objectives of this study are to (1) identify informal networks of physicians who treat the same patient population, (2) provide these physicians with feedback on their network and patients, using routine data and (3) give the physicians the opportunity to meet one another in facilitated network meetings. Methods The Accountable Care Deutschland (ACD) study is a prospective, non-blinded, cluster-randomised trial comprising a process and economic evaluation of informal networks among 12,525 GPs and office-based specialists and their 1.9 million patients. The units of allocation are the informal networks, which will be randomised either to the intervention (feedback and facilitated meetings) or control group (usual care). The informal networks will be generated by identifying connections between office-based physicians using complete datasets from the Regional Associations of Statutory Health Insurance (SHI) Physicians in Hamburg, Schleswig Holstein, North Rhine and Westphalia Lip, as well as data from three large statutory health insurers in Germany. The physicians will (a) receive feedback on selected indicators of their own treatment activity and that of the colleagues in their network and (b) will be invited to voluntary, facilitated network meetings by their Regional Association of SHI physicians. The primary outcome will be ambulatory-care-sensitive hospitalisations at baseline, at the end of the 2-year intervention period, and at six months and at 12 months after the end of the intervention period. Data will be analysed using the intention-to-treat principle. A pilot study preceded the ACD study. Discussion Cochrane reviews show that feedback can improve everyday medical practice by shedding light on previously unknown relationships. Providing physicians with information on how they are connected with their colleagues and what the outcomes are of care delivered within their informal networks can help them make these improvements, as well as strengthen their awareness of possible discontinuities in the care they provide. Trial registration German Clinical Trials Register DRKS00020884 . Registered on 25 March 2020—retrospectively registered.

Ultrashort circularly polarised light pulses from free-electron lasers offer a route for exploring chiral molecules and their dynamics, but remain challenging to harness. Here, X-ray pump-probe experiments enable a site-specific photoelectron circular dichroism measurement on a dissociating chiral molecule.

Imagining sustainable food futures is key to effectively transforming food systems. Yet even transdisciplinary approaches struggle to open up complex and highly segregated food policy governance for co-production and can fail to critically interrogate assumptions, worldviews, and values. In this Perspective we argue that transdisciplinary processes concerned with sustainable food system transformation need to meaningufully engage with critical food futures, and can do so through the use of soft scenario methods to learn about, play with, and experiment in futures. Specifically, soft scenarios contribute in four ways: 1) questioning widely held assumptions about the future; 2) being inclusive to multiple perspectives and worldviews; 3) fostering receptiveness to unimaginable futures; 4) developing futures literacy. Based on insights from a 5-year transdisciplinary action research project on sustainable food transformation across Asia, we demonstrate how these processes play out in narratives, serious games and interactive art featuring soft scenarios. We conclude by discussing the potential for collaboration between transdisciplinary and futures researchers, especially for transforming food systems.

Although gains and losses are an integral part of human development, the experience of change and readjustment that often comes with major life events may be particularly influential for an individual's subjective aging experience and awareness of age-related change (AARC). Thus, this study focused on the role of life events in the domains of family and health for an individual's awareness of age-related gains and losses. Specifically, we differentiated between the experience of specific life events (e.g., entering a new romantic relationship; hospital stay) and the cumulative experience of multiple life events. Furthermore, we differentiated between life events experienced at an expected time in life and life events experienced relatively early or relatively late compared to established social norms. Data came from the Innovation Sample of the German Socio-Economic Panel (SOEP-IS) and consisted of 1,612 participants aged 16 to 93 years (M = 54.1; SD = 18.2). Life events were assessed annually and retrospectively for the last 2 years. Propensity score matching provided evidence for an association of specific family life events and a higher awareness of age-related gains, as well as specific health life events and a higher awareness of age-related losses. Results furthermore indicated that the cumulative experience of family life events was associated with a higher awareness of age-related gains. Conversely, the cumulative experience of health events was associated with higher awareness of both age-related losses and age-related gains. Moreover, it was not only life events happening at an expected age, but also those happening relatively early and particularly those happening late in life, which were associated with AARC. In summary, life events and the change they may bring seem to be reflected in individuals' awareness of age-related losses and awareness of age-related gains.