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This study explored the interplay between the ligand–surface chemistry of colloidal CsPbBr3 nanowires (NWs) and their optical properties. The ligand equilibrium was probed using nuclear magnetic resonance spectroscopy, and by perturbing the equilibrium via dilution, the gradual removal of ligands from the CsPbBr3 surface was observed. This removal was correlated with an increase in the surface defect density, as suggested by a broadening of the photoluminescence (PL) spectrum, a decrease in the PL quantum yield (PLQY), and quenching of the PL decay. These results highlight similar surface binding between the traditional CsPbBr3 quantum dots and our NWs, thereby expanding the scope of well-established ligand chemistry to a relatively unexplored nanocrystal morphology. By controlling the dilution factor, it was revealed that CsPbBr3 NWs achieve a PLQY of 72% ± 2% and a relatively long average PL lifetime of 400 ± 10 ns, without relying on additional surface passivation techniques, such as ligand exchange. [ABSTRACT FROM AUTHOR]

Key governing bodies (e.g., Association for Applied Sport Psychology) recognize that graduate programs must prepare multiculturally competent practitioners. Students and recent graduates of sport psychology master's degree programs (N = 107, Mage = 26.32, SD = 5.19) reported moderate levels of feeling safe, valued, and comfortable within their program; low to moderate levels of multicultural training integration; and low to moderate satisfaction with their multicultural training. Students of Color (n = 42) compared to White students (n = 63) reported less satisfaction with their multicultural training; felt less safe, comfortable, and valued; and perceived less multicultural integration. Furthermore, perceptions of multicultural training integration and of feeling safe, comfortable, and valued were significantly related to satisfaction with their multicultural training. Training programs are advised to improve integration of multicultural training, invest in program climate to help students feel safe and valued, and ensure continuing education of faculty members. [ABSTRACT FROM AUTHOR]

This qualitative study used an inclusive and participatory research approach to examine the perspectives of people with intellectual and developmental disabilities (IDD) on instrumental supports. Instrumental supports include concrete and direct ways people assist others in solving a problem or accomplishing a task, including helping to access and navigate formal supports and services. Natural supporters play essential roles in setting up and maintaining formal supports for individuals with IDD. Family members that provide instrumental support are responsible for integrating the formal and informal supports for the best mix of supports based on the person with IDD's needs and preferences. This study examined the instrumental support people with IDD received from and gave to their families related to physical support, healthy living, financial support, and navigating formal services. Thirty virtual interviews were conducted using the dyadic interview method with 10 adults with IDD and 10 family members who they chose. Findings showed that people with IDD received natural supports from their family in numerous areas including physical help, support to be healthy, and financial support. Also, families helped with formal supports by navigating the system of services for people with IDD. In addition to receiving support from their families, people with IDD also provided some reciprocal support to their families, specifically in the areas of physical help and healthy living. Implications for practice and policy are shared along with directions for future research. [ABSTRACT FROM AUTHOR]

Neuroinflammation immediately follows the onset of ischemic stroke in the middle cerebral artery. During this process, microglial cells are activated in and recruited to the penumbra. Microglial cells can be activated into two different phenotypes: M1, which can worsen brain injury; or M2, which can aid in long-term recovery. In this study, we contribute a summary of experimental data on microglial cell counts in the penumbra following ischemic stroke induced by middle cerebral artery occlusion (MCAO) in mice and compile available data sets into a single set suitable for time series analysis. Further, we formulate a mathematical model of microglial cells in the penumbra during ischemic stroke due to MCAO. Through use of global sensitivity analysis and Markov Chain Monte Carlo (MCMC)-based parameter estimation, we analyze the effects of the model parameters on the number of M1 and M2 cells in the penumbra and fit identifiable parameters to the compiled experimental data set. We utilize results from MCMC parameter estimation to ascertain uncertainty bounds and forward predictions for the number of M1 and M2 microglial cells over time. Results demonstrate the significance of parameters related to M1 and M2 activation on the number of M1 and M2 microglial cells. Simulations further suggest that potential outliers in the observed data may be omitted and forecast predictions suggest a lingering inflammatory response. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource‐intensive process. DR is the process of identifying alternative clinical applications for pre‐approved drugs as a low‐risk and low‐cost strategy. Computational approaches are crucial during the early hypothesis‐generating stage of DR. However, 'large‐scale' data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research. Experimental Approach: We introduce a novel computational workflow (combining free‐accessible computational platforms) to provide 'proof‐of‐concept' of the pre‐approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease‐ and drug‐target pathway identification) and retrospective literature and drug‐like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease‐approved drug with literature‐attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD). Key Results: Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO‐B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5‐HT levels (MAO‐B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition). Conclusion and Implications: The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low‐risk and low‐cost DR computational tool providing a bird's‐eye view for exploring alternative clinical applications of pre‐approved drugs. [ABSTRACT FROM AUTHOR]

Retroviruses can be detected by the innate immune sensor cyclic GMP-AMP synthase (cGAS), which recognizes reverse-transcribed DNA and activates an antiviral response. However, the extent to which HIV-1 shields its genome from cGAS recognition remains unclear. To study this process in mechanistic detail, we reconstituted reverse transcription, genome release, and innate immune sensing of HIV-1 in a cell-free system. We found that wild-type HIV-1 capsids protect viral genomes from cGAS even after completing reverse transcription. Viral DNA could be "deprotected" by thermal stress, capsid mutations, or reduced concentrations of inositol hexakisphosphate (IP6) that destabilize the capsid. Strikingly, the capsid inhibitor lenacapavir also disrupted viral cores and dramatically potentiated cGAS activity, both in vitro and in cellular infections. Our results provide biochemical evidence that the HIV-1 capsid lattice conceals the genome from cGAS and that chemical or physical disruption of the viral core can expose HIV-1 DNA and activate innate immune signaling. Author summary: Human Immunodeficiency Virus type 1 (HIV-1) remains a global health threat. Drug therapies can help manage HIV-1 infection and prevent its spread, but without treatment, the immune system fails to control the virus. In part, this is because HIV-1 is thought to avoid detection by immune cells during entry. Once inside a target cell, the virus copies its RNA genome into double-stranded DNA within a viral protein shell called the capsid. In this study, we developed a novel cell-free method to study how the HIV-1 capsid shields viral DNA from detection. We found that the capsid normally functions as a molecular cloak that hides the viral DNA from innate immune sensors. We also identified experimental conditions and drug treatments that can "break" the capsid and allow the viral DNA to be detected, both in vitro and in cells. We anticipate that future work using cell-free systems will reveal how host factors regulate innate detection of HIV-1, possibly guiding new therapeutic strategies that block infection and engage antiviral immune responses simultaneously. [ABSTRACT FROM AUTHOR]

Severe tricuspid regurgitation (TR) often causes substantial impairment in patient-reported health status (ie, symptoms, physical and social function, and quality of life), which may improve with transcatheter tricuspid valve replacement (TTVR). The authors performed an in-depth analysis of health status of patients enrolled in the TRISCEND (Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy using a Novel Device) II pivotal trial to help quantify the benefit of intervention to patients. The TRISCEND II pivotal trial randomized 400 patients with symptomatic and severe or greater TR 2:1 to TTVR with the EVOQUE tricuspid valve replacement system plus optimal medical therapy (OMT) or OMT alone. Health status was assessed with the Kansas City Cardiomyopathy Questionnaire and the 36-Item Short Form Health Survey. Changes in health status over 1 year were compared between treatment groups using mixed-effects repeated-measures models. The analysis cohort included 392 patients, of whom 259 underwent attempted TTVR and 133 received OMT alone (mean age 79.2 ± 7.6 years, 75.5% women, 56.1% with massive or torrential TR). Patients had substantially impaired health status at baseline (mean Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS] 52.1 ± 22.8; mean 36-Item Short Form Health Survey physical component summary score 35.2 ± 8.4). TTVR+OMT patients reported significantly greater improvement in both disease-specific and generic health status at each follow-up time point. Mean between-group differences in the KCCQ-OS favored TTVR+OMT at each time point: 11.8 points (95% CI: 7.4-16.3 points) at 30 days, 20.8 points (95% CI: 16.1-25.5 points) at 6 months, and 17.8 points (95% CI: 13.0-22.5 points) at 1 year. In subgroup analyses, TTVR+OMT improved health status to a greater extent among patients with torrential or massive TR vs severe TR (treatment effect 23.3 vs 22.6 vs 11.3; interaction P = 0.049). At 1 year, 64.6% of TTVR+OMT patients were alive and well (KCCQ-OS ≥60 points and no decline of ≥10 points from baseline) compared with 31.0% with OMT alone. Compared with OMT alone, treatment of patients with symptomatic and severe or greater TR with TTVR+OMT resulted in substantial improvement in patients' symptoms, function, and quality of life. These benefits were evident 30 days after TTVR, continued to increase through 6 months, and remained durable through 1 year. (TRISCEND II Pivotal Trial [Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy using a Novel Device]; NCT04482062) [Display omitted] [ABSTRACT FROM AUTHOR]

It is well known that comprehenders assume that pronouns are more likely to refer to recently mentioned referents than less-recent referents; for example, in Ana ordered a croissant with her latte. Liz ordered a cappuccino. She grabbed a table by the window, people are more likely to assign she to Liz than Ana. Why does this bias occur? Is it just recency, or do apparent recency effects stem from some other cognitive mechanism? We consider three proposals about what underlies the recency bias: (1) recent things tend to be topical; (2) recent things tend to be attended by the speaker and listener; and (3) recent things tend to be predictable. For each we test whether they modulate the recency bias in a series of five experiments. Results confirm that recency is a strong constraint for pronoun comprehension, and this bias can be modulated by pointing, but not significantly by gazing or discourse topicality. Pointing is known to modulate the addressee’s attention, but we also saw that it strongly affected measures of predictability. However, recency itself was not associated with predictability. In sum, the strongest effects on pronoun comprehension were the most proximal signals: recent mention in subject position and social signals about the speaker’s meaning. Although recency is associated with topicality, attention, and predictability, it cannot be reduced to any one dimension. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNAB6 and mtDNANZB, where mtDNANZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNAB6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNANZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNANZB mice exhibited strikingly impaired tumor growth while mtDNAB6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNANZB Teff cells increased mitochondrial gene expression while activation of mtDNANZB Treg cells impaired mitochondrial gene expression and resulted in mtDNANZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNANZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine high-grade glioma (HGG) is a deadly disease in dogs, with limited treatment options. Involving the host immune system in the fight against HGG through immunotherapy has improved outcomes in many dogs, with a notable exception in the French bulldog breed. We hypothesized that French bulldog HGG responds differently to immunotherapy than other breeds, and that this response difference is attributable to differences in transcriptomic landscapes in the breed compared to other breeds. We performed bulk RNA sequencing (RNASeq) on tumors pre-treatment and post-treatment and examined the differentially expressed genes (DEGs) between the two timepoints in both French bulldogs and in our comparison group of boxers and Boston terriers. We then analyzed the differences in DEGs between French bulldogs and boxers and Boston terriers, and performed gene set enrichment analysis (GSEA) to categorize the observed changes by gene function. We confirmed that when compared to boxers and Boston terriers, the transcriptomes of French bulldog tumors change in significantly different ways following immunotherapy treatment, with many DEGs mapping to tumor-promoting pathways and immune pathways. This study highlights important breed-associated differences in HGG transcriptomes, which may guide patient-centered immunotherapy treatment to improve patient outcomes. Canine high-grade glioma (HGG) is among the deadliest and most treatment-resistant forms of canine cancer. Successful, widespread treatment is challenged by heterogeneity in tumor cells and the tumor microenvironment and tumor evolution following treatment. Immunotherapy is theoretically a strong novel therapy, since HGG-generated immunosuppression is a substantial malignancy mechanism. Immunotherapy has improved survival times overall, but has been associated with extremely poor outcomes in French bulldogs. Given this breed-specific observation, we hypothesized that within the French bulldog breed, there are key transcriptomic differences when compared to other breeds, and that their tumors change differently in response to immunotherapy. Using bulk RNA sequencing, French bulldog tumors were confirmed to differ substantially from boxer and Boston terrier tumors, with only 15.9% overlap in significant differentially expressed genes (DEGs). In upregulated DEGs, the magnitude of changes in expression post-treatment compared to pre-treatment was markedly greater in French bulldogs. Gene set enrichment analysis confirmed that following treatment, French bulldog tumors showed enrichment of key immune-associated pathways previously correlated with poor prognosis. Overall, this study confirmed that French bulldog HGG transcriptomes differ from boxer and Boston terrier transcriptomes, further refining description of the canine glioma transcriptome and providing important information to guide novel therapy development, both for specific dog breeds and for possible correlative variants of human glioblastoma. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cognitive functions are a crucial part of daily living, especially for adults with Down syndrome (DS) who have a high likelihood of developing Alzheimer's disease in adulthood. In addition, adults with DS move slower and are not meeting the standard aerobic activity guidelines each week. The aim of this study was to examine if Assisted Cycle Therapy (ACT) would improve cognitive planning as measured by the Tower of London (TOL), set switching as measured by the modified Wisconsin Card Sorting Test, and spatial memory as measured by the Corsi Block Test in adults with DS as compared to self-paced cycling. Methods: Twenty-four participants were randomly assigned to one of two interventions over eight weeks. (1) Thirteen older adults with DS completed the ACT intervention, which is stationary cycling with the assistance of a motor to maintain a cadence at least 35% greater than voluntary cycling. (2) Eleven older adults with DS completed voluntary cycling (VC). Results: Our results showed that cognitive planning as measured by total correct score in the TOL showed improvement for both ACT and VC after 8 weeks of exercise, F(1, 22) = 6.22, p = 0.021. There were no significant differences for spatial memory or set switching. Conclusions: We concluded that cycling exercise has a positive impact on cognitive function, especially problem solving in older adults with DS. Our results are discussed with respect to upregulation of neurotrophic factors that increase functioning in the prefrontal cortex that accompanies exercise and leads to improvements in cognitive planning which is essential to many activities of daily living and quality of life for older adults with DS. [ABSTRACT FROM AUTHOR]

Background: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients. Objective: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs). Methods: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10–<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment. Results: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset. Conclusion: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months. [ABSTRACT FROM AUTHOR]

Black mothers are highly capable of supporting their children by creating homeplaces, or spaces where children are shielded from the challenges of the outside world, by leveraging their strengths-based assets to support their children’s positive development. When confronted with a barrage of viral videos of police brutality and other negative news media, Black women caregivers may engage in more activities and conversations to help their children cope with the outside world. This study investigates how Black women caregivers safeguard their children from experiencing vicarious trauma as a result of viewing negative news media. Utilizing consensual qualitative analysis, interviews with 12 Black women caregivers revealed a dynamic process termed ‘homeplace fortification’. This process involved caregivers heightened emotional responses to negative news, prompting caregivers to make deliberate decisions to engage their children – either by discussing the news or limiting their exposure. Both approaches serve to protect and support Black children’s health and wellbeing. This study advances the field of family psychology by demonstrating how Black women caregivers use homeplace fortification to bolster their children’s mental health in the face of negative news media, emphasizing Black women caregiver’s strengths in being attuned and responsive to their children’s emotional needs. [ABSTRACT FROM AUTHOR]

Background: The Veterans Affairs Nebraska Western Iowa Health Care System (VA‐NWIHCS) uses teleoncology and remote systemic cancer therapy services to expand care to veterans in rural Nebraska via remote sites in Lincoln and Grand Island. This study compares clinical outcomes in patients receiving care at these remote sites to those at the primary site in Omaha. Methods: Data were retrospectively reviewed for 151 patients who received first‐line systemic therapy at VA sites in Omaha, Lincoln, or Grand Island between January 1, 2018, and December 31, 2020. This included patient demographics, malignancy type and stage, survival, systemic therapy received, treatment intent and toxicities, missed or delayed cycles, and frequency of hospitalizations or emergency department visits. SAS version 9.4 was used for analysis. Results: The study population included 108 patients who received their systemic therapy in Omaha, whereas 43 received therapy at the remote sites. The demographic of both populations was predominantly male with a median age of 69 years and Eastern Cooperative Oncology Group Performance Status of 0 to 1. The two groups were comparable in terms of comorbidities. Both populations had a similar distribution of cancer types, proportion of patients with stage IV disease, and treatment with curative intent. There was no difference in 1‐ and 2‐year survival, systemic therapy‐related toxicity classification and prevalence, number of delayed/missed cycles, and hospitalization/emergency department visits. Conclusion: Evaluated outcomes in patients treated in Omaha versus remote sites via teleoncology under the same providers were similar. Effective oncology care, including systemic therapy, can be provided via teleoncology, and this model can help mitigate issues with access to care. Disparities in the delivery of high‐quality, cancer‐directed systemic therapy arise from a variety of factors including patient proximity to treatment centers. Use of teleoncology and remote systemic therapy administration can help to alleviate these barriers to cancer‐directed therapies. [ABSTRACT FROM AUTHOR]

Historians have long debated to what extent there was a shift in the sacrament of penance marked by the injunction at the Fourth Lateran Council (1215) for all Christians to make annual confession. It has long been suggested that in the early Middle Ages confession was primarily a collective ritual and only became individualized and interiorized in the later Middle Ages, though early medievalists have recently presented evidence challenging this view. However, the debate has hitherto paid little attention to the variety of lived experiences and social contexts of "confession," the act or acts that preceded the bestowal of penance. Reconsideration of these aspects might help to readdress some of the issues regarding continuity and change and to explore productively an important area of religious experience for the Christian laity. [ABSTRACT FROM AUTHOR]

Introduction: The ability to detect pathogenic bacteria before the onsets of severe respiratory symptoms and to differentiate bacterial infection allows to improve patient-tailored treatment leading to a significant reduction in illness severity, comorbidity as well as antibiotic resistance. As such, this study refines the application of the non-invasive Secondary Electrospray Ionization-High Resolution Mass Spectrometry (SESI-HRMS) methodology for real-time and early detection of human respiratory bacterial pathogens in the respiratory tract of a mouse infection model. Methods: A real-time analysis of changes in volatile metabolites excreted by mice undergoing a lung infection by Staphylococcus aureus or Streptococcus pneumoniae were evaluated using a SESI-HRMS instrument. The infection status was confirmed using classical CFU enumeration and tissue histology. The detected VOCs were analyzed using a pre- and post-processing algorithm along with ANOVA and RASCA statistical evaluation methods. Results: Characteristic changes in the VOCs emitted from the mice were detected as early as 4–6 h post-inoculation. Additionally, by using each mouse as its own baseline, we mimicked the inherent variation within biological organism and reported significant variations in 25 volatile organic compounds (VOCs) during the course of a lung bacterial infection. Conclusion: the non-invasive SESI-HRMS enables real-time detection of infection specific VOCs. However, further refinement of this technology is necessary to improve clinical patient management, treatment, and facilitate decisions regarding antibiotic use due to early infection detection. [ABSTRACT FROM AUTHOR]

Exposure to reactive oxygen species (ROS) can induce DNA-protein crosslinks (DPCs), unusually bulky DNA lesions that block replication and transcription and play a role in aging, cancer, cardiovascular disease, and neurodegenerative disorders. Repair of DPCs depends on the coordinated efforts of proteases and DNA repair enzymes to cleave the protein component of the lesion to smaller DNA-peptide crosslinks which can be processed by tyrosyl-DNA phosphodiesterases 1 and 2, nucleotide excision and homologous recombination repair pathways. DNA-dependent metalloprotease SPRTN plays a role in DPC repair, and SPRTN-deficient mice exhibit an accelerated aging phenotype and develop liver cancer early in life. We investigated the role of the SPRTN enzyme in the repair of DPCs produced by a free radical mechanism. Sprtn-deficient MEF cells treated with ionizing radiation had higher levels of total DPCs and exhibited greater sensitivity upon exposure to hydrogen peroxide and other crosslinking agents including cisplatin, phosphoramide mustard, and 1,2,3,4-diepoxybutane. Using a sensitive and accurate nanoLC-ESI+-MS/MS assay, we specifically measured the radical-induced crosslinking of thymidine in DNA crosslinking of thymidine in DNA to tyrosine in proteins (dT-Tyr) in the tissues of SPRTN hypomorphic (SprtnH/H) and wild type mice. Genomic DNA isolated from the tissues of SPRTN hypomorphic (SprtnH/H) mice exhibited higher levels of dT-Tyr in the liver, brain, heart, and kidney than wild-type animals. Overall, our results are consistent with the understanding that SPRTN has a role in maintaining genomic integrity upon exposure to ionizing radiation and endogenous reactive oxygen species. [ABSTRACT FROM AUTHOR]

This study evaluates the transportability of clayey-silt natural gas hydrate (NGH) solid particles during solid fluidization in horizontal tubing, a crucial step in recovering marine NGH. Non-uniform solid particle distribution in horizontal flows can cause unstable operations and financial losses. Thus, assessing transportability is necessary to avoid these issues and harness the potential of NGH as an alternative energy source. This study introduces a model based on each phase's two-layer approach and momentum balance equation, considers potential hydrates (re)formation, and overcomes previous models' limitations. Moreover, it assumes that the critical settling velocity marks the moment when the lower bed of solid particles stagnates, thereby leading to the disappearance of frictional pressure in the lower bed. The proposed model is evaluated and compared with existing models using a laboratory dataset and the South China Sea offshore field dataset and found to provide the highest prediction accuracy and precision. Moreover, it reveals that the tubing diameter, solid particle diameter, and solid particle concentration are the major influential parameters affecting the solid particle conveyance. Consequently, the proposed model is suitable for evaluating the transportability of those solid particles in horizontal tubing, making it ideal for assessing their transportability in pipelines. [ABSTRACT FROM AUTHOR]

Background: Limited access to the comprehensive assessment of disorders of the upper aerodigestive tract is a barrier to care in rural health facilities. Assessment of the full aerodigestive tract requires a variety of specialists. The inability to access the necessary specialists can result in misdiagnosis, underdiagnosis, and increased associated mortality. Currently, no single differential diagnostic exam comprehensively assesses all functions of the upper aerodigestive tract to bridge this gap. The purpose of this study is to investigate the feasibility and safety of a novel procedure called ADS that can bridge this gap. Methods: Results from 18,464 ADS procedures were retrospectively analyzed for feasibility, safety and comfort. Results: 96.8% of ADS procedures were successfully completed without complication, confirming the efficacy of the procedure. Conclusions: ADS is a single procedure for the assessment of physiological functions of the upper aerodigestive tract, including swallow, voice, respiration, and cough while also screening for impaired gastric retention and obstructive sleep apnea, which may pose additional urgent and emergent airway threats. ADS may improve health outcomes in underserved populations, e.g., those in a rural community, referred to by other health professionals due to complaints of aerodigestive symptoms and signs. [ABSTRACT FROM AUTHOR]

Simple Summary: Atypical scrapie (AS) is a disease of sheep and goats. Currently, when AS is detected on a farm in Great Britain (GB), all animals that exit the flock through natural death or slaughter are tested for AS for a period of 2 years following detection of the initial case, as used to be performed within the European Union (EU), in order to provide support as to whether AS can transmit directly between sheep. The aim of this study was to determine how many AS animals would be missed if this testing was also stopped in positive flocks in GB and hence determine the value of continuing with this surveillance programme. Our model estimated approximately one undetected AS case every three years if additional testing was stopped in detected flocks. In comparison, around 10 AS cases are detected per year through other active surveillance streams. Our model estimates suggest that stopping the intensive monitoring of AS would have relatively little impact on AS surveillance and that continuing it would provide limited evidence as to whether AS is contagious. Atypical scrapie (AS) is a transmissible spongiform encephalopathy (TSE) that affects sheep and goats. Low within-flock incidence suggests that AS is not transmissible between animals, and testing of all animals that exit positive flocks for two years following detection (i.e., intensified monitoring) used to be carried out in the EU to provide data to test this. This intensified monitoring stopped in 2021 but continues in Great Britain (GB). The aim of this study was to predict the number of AS cases missed if this monitoring were also stopped in GB, using a combination of statistical and transmission modelling. The number of AS cases estimated to be missed if the intensified monitoring was stopped was low relative to the number of AS cases detected in other active surveillance streams (e.g., fallen stock and abattoir surveys), at approximately 1 case every 3 years (0.34 per year, 95% CI: 0.18–0.54) compared to 10 per year (95% CI: 4–17) in the active surveillance stream. This suggests that stopping the intensive monitoring of AS would have relatively little impact on AS surveillance and on the power of the available AS data to infer whether AS is contagious. [ABSTRACT FROM AUTHOR]

AbstractHow do cultural legacies expand our understanding of the causes and longevity of the war? Is this Putin’s or Russia’s war? While Russia and Ukraine share many cultural traditions, this article takes just one—the Cossack legacy—and uses it to gauge popular support for the war. Whereas in Russia one branch of the Cossack revival movement has become institutionalised as a paramilitary movement, in Ukraine its legacy has become foundational to a civic conception of nationhood. The theory is evaluated using contestations of the Cossack legacy by Russians and Ukrainians. [ABSTRACT FROM AUTHOR]

South African towns and cities face substantial challenges, owing largely to the pace of economic growth to date and continued migration of people from rural areas. The widely accepted push–pull theory of migration assumes that migration is a functional and inevitable outcome of spatial inequality. Economic drivers are frequently used to explain population movements in South Africa, given that the country’s biggest socio-economic challenges include high unemployment, stark inequality and persistent poverty. This study empirically investigates the theoretical perspective of the push–pull model from an economic and settlement-based standpoint. It establishes a settlement-level perspective of the relationship between economic performance and working-age population change in South Africa between the 2001 and 2011 Censuses. Fine-resolution downscaled economic and population datasets are used, applying spatial GIS-based methods and techniques, together with statistical correlation analyses, to explore and quantify the relationship. Population change in the working-age population is found to have a positive statistically significant association with economic performance at settlement level. The relationship is multifaceted, given the complexity of South Africa’s economic and development landscape, with considerable variability between different economically profiled settlement types, and different demographic groups based on age, gender, employment status and skills level. [ABSTRACT FROM AUTHOR]

Outbreaks of highly pathogenic avian influenza virus in wild animals highlight the need for disease surveillance in wild birds to improve our understanding of their role as reservoirs and dispersers, and potential threats to domestic poultry and wild bird populations. Surveillance for avian influenza varies in its approach, objectives, and coordination with other monitoring efforts. For waterfowl, a common host to avian influenza viruses, banding represents a concerted effort of capturing and marking thousands of individuals annually to estimate survival and harvest rates, but users of these data have generally taken a conservative approach to remove any banded birds from analyses that had a sample taken for disease surveillance during capture. We tested for differences in survival and encounter probabilities of blue‐winged teal (Spatula discors) marked (n = 21,702 teal) and sampled for disease surveillance (n = 4,216) during the nonbreeding season in Louisiana, USA, from 2016 to 2023. Although we found no consistent effect of collecting biological samples on survival probability, including an additional test showing no detectable effects of sampling for disease surveillance with oropharyngeal and cloacal swabs versus sampling with swabs and a syringe‐drawn blood sample, wide 95% credible intervals on the posterior survival estimates (mean 0.36 difference between upper and lower values across all year‐sex‐sampling groups; 0.44 for sampling type groups) indicated low statistical power to detect an effect. Seber recovery probability during the first interval following sampling was lower among birds sampled using swabs only, but we assume this stems from low sample sizes rather than an effect of collecting biological samples. Because recovery probabilities can vary as a function of individual covariates, we also examined direct recovery probabilities and observed no meaningful effect of disease surveillance sampling type but strong effects of capture date, suggesting the effect on Seber recovery probability may have been due to heterogeneity in exposure to natural and harvest mortality risks. Although we suggest that aligning disease surveillance sample collection efforts with landscape‐scale waterfowl banding efforts may have little effect on observed demographic rates, additional studies with larger sample sizes are likely needed to provide the statistical power necessary to formally conclude no effect of biological sampling on survival probabilities. [ABSTRACT FROM AUTHOR]

Plants use physical barriers and chemical compounds to defend themselves against natural enemies. For instance, tough leaves are considered to be better defended than soft leaves, part of a spectrum of defences defined by functional traits such as leaf chemistry, lifespan, toughness and leaf mass per area (LMA). Plants with longer lifespans, which invest more in leaf tissue and higher LMA, typically feature robust constitutive defences (e.g. toughness, thickness and dense cell walls). In contrast, plants with lower LMA and more leaf nutrients often invest more in induced defences. Leaf traits represent an environmental filter for foliar endophytic fungi (FEF), which may play an additional role in plant defence. Our overarching assumption is that FEF alter leaf fate by interacting directly or indirectly with leaf traits, thus shaping successive FEF colonization, development of leaf traits and response to plant enemies. To evaluate this hypothesis, we inoculated seedlings of seven tropical tree species, which varied in leaf traits, with natural and diverse endophyte communities. We characterized leaves by low FEF load (E‐low) and high FEF load (E‐high) based on culturing and culture‐free amplicon sequencing. We measured leaf removal by leaf‐cutter ants and leaf necrosis due to a generalist fungal pathogen. Across the experiment, we observed greater leaf removal from the E‐low treatment compared to the E‐high treatment, but no difference in pathogen damage. Dimensionality reduction of leaf functional traits (i.e. LMA, toughness, thickness and anthocyanin levels) revealed relationships among traits and distinct host species characteristics. All leaf functional traits had significant correlations with FEF community composition. In turn, indicator species analyses revealed functional traits and taxonomic identities of FEF associated with high and low leaf damage by natural enemies. Our findings highlight the complex dynamics of plant‐herbivore‐pathogen relationships and underscore the importance of endophytes as a potentially low‐cost, preemptive defence strategy for plants, especially during early growth stages. These insights shed light on the nuanced role of endophytes in plant ecology. Further, they open avenues for future research, particularly in exploring strategic resource allocation in plants and the specific contributions of endophytes to plant resilience. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

External comparator (EC) studies are increasingly being used to generate evidence that supports the evaluation of emerging pharmacological treatments for regulatory and health technology assessment (HTA) purposes. However, the reliability of evidence generated from EC studies can vary. In this paper, we outline how an existing framework for causal inference, the target trial emulation (TTE) framework, can be appropriately applied to improve the design and analysis of EC studies. Applying the TTE framework involves specifying the protocol of an ideal target trial which would answer the causal question of interest, then emulating its key elements under real-world (RW) settings. We describe each component of the original TTE framework and explain how it can be applied to EC studies, supplemented with practical recommendations. We also highlight special considerations and limitations in applying the TTE framework to EC studies. We describe how the TTE framework can be applied to improve the clarity, transparency, and reliability of evidence generated from EC studies. [ABSTRACT FROM AUTHOR]

The article discusses the emergence of remote sanctions-busting as a result of new technologies and changes in global business practices accelerated by the COVID-19 pandemic. It highlights how North Korea adapted to generate revenue for its nuclear weapons and ballistic missile programs through remote IT labor schemes during the pandemic. The text explores the challenges faced by policymakers in enforcing sanctions effectively in a world where evasion activities are increasingly conducted remotely, emphasizing the need for enhanced identity management, international cooperation, and awareness within emerging high-tech sectors to address these evolving tactics. [Extracted from the article]

The article focuses on the history of the U.S. Space Force and its origins in the U.S. Air Force, highlighting the importance of both people and artifacts in shaping its development. Topics include the historical significance of military space artifacts, the role of the National Museum of the U.S. Air Force in preserving this history, and how non-technological factors have influenced technological advancements in space policy.

This paper introduces a measure for zigzagging strength and a minimal zigzagging direction. Based on this, a new nonlinear conjugate gradient (CG) method is proposed that works with line searches not satisfying the Wolfe condition. Global convergence to a stationary point is proved for differentiable objective functions with Lipschitz continuous gradient, and global linear convergence if this stationary point is a strong local minimizer. For approximating a stationary point, an O (ε - 2) complexity bound is derived for the number of function and gradient evaluations. This bound improves to O (log ε - 1) for objective functions having a strong minimizer and no other stationary points. For strictly convex quadratic functions in n variables, the new method terminates in at most n iterations. Numerical results on the unconstrained CUTEst test problems suggest that the new method is competitive with the best nonlinear state-of-the-art CG methods proposed in the literature. [ABSTRACT FROM AUTHOR]

Much of empirical research on public opinion is dominated by a focus on individual-level determinants of support for, or opposition to, the European Union, missing the heterogeneity that lies within and between societies. Our article aims to understand whether national publics are increasingly heterogeneous in their opinions towards Europe, and if so, how this heterogeneity manifests itself. To do so, we rely on a Eurobarometer trend file containing data on the 28 member states between 1994 and 2019. The results show that the degree of popular dissensus over European Union integration has gone deeper since the Maastricht Treaty and reached a peak during the years of the Great Recession (2010 to 2013). The study also demonstrates that the public opinion dynamics triggering heterogeneity vary across clusters of European Union member states. [ABSTRACT FROM AUTHOR]

Simple Summary: We provide the first (preliminary) characterization of an immune-related gene (MHC-DAB) in trouts from Albania, an area harboring ecologically and genetically rich Salmonid diversity, including endemisms valuable for conservation. By genotyping 36 trout samples, we revealed generally high sequence/allelic polymorphism and remarkable distinctiveness (34 different sequences in total, most of which were exclusive to a taxon or population), also finding expected signals of historical positive selection. Interestingly, samples of lacustrine Belvica trout (Salmo ohridanus) showed contrasting results compared to other examined trout (S. trutta complex and S. letnica). Further investigations will provide a deeper understanding of the evolutionary mechanisms yielding the observed pattern of MHC-DAB diversity. Beyond evolutionary genetics, our outcomes offer useful information (namely immune-related adaptive genetic diversity) for conservation programs aimed at preserving the long-term viability of threatened wild populations. Due to their involvement in pathogen-mediated immune responses, the hypervariable genes of the Major Histocompatibility Complex (MHC) have become a paradigm for investigating the evolution and maintenance of genetic (adaptive) diversity, contextually providing insight into the viability of wild populations, which is meaningful for conservation. Here, we provide the first preliminary characterization of MHC polymorphism and evolution in trouts from Albania, a known hotspot of Salmonid diversity harboring ecologically and phylogenetically distinct native (threatened) taxa. Overall, 36 trout—including Lake Ohrid-endemic Salmo ohridanus and S. letnica, and both riverine and lacustrine native brown trout (the S. trutta complex) from the Drin-Skadar drainage—were genotyped at the MHC-DAB locus through next-generation amplicon sequencing. We identified 34 alleles (including 30 novel alleles), unveiling remarkable population/taxon MHC-DAB distinctiveness. Despite apparent functional (supertype) similarity, S. letnica and the S. trutta complex showed MHC-typical high sequence/allele diversity and evidence of global/codon-specific positive selection, particularly at antigen-binding sites. Conversely, deep-water-adapted S. ohridanus revealed unexpectedly reduced allelic/supertype diversity and relaxed selection. Evolution by reticulation and signals of trans-species polymorphism emerged from sequence genealogies. Further investigations and increased sampling will provide a deeper understanding of the evolutionary mechanisms yielding the observed pattern of MHC diversity across Albanian trout taxa and populations. [ABSTRACT FROM AUTHOR]

The doctoral comprehensive exam is a common benchmark in counselor education doctoral programs. The current study examined policies and procedures for comprehensive exams in CACREP‐accredited counselor education doctoral programs. Using conventional qualitative content analysis, researchers analyzed CACREP‐accredited doctoral program student handbooks to determine common practices for conducting comprehensive exams. [ABSTRACT FROM AUTHOR]

This special issue aims to take steps towards the internationalisation of scholarship on women's television by drawing together articles on different national contexts of television and detailing the experiences of women in various national and historical television ecologies and economies. This is, of course, merely a step, since no one issue can attend to the breadth of women's experiences in the many national television organisations and roles. Scholarship in anglophone, Global North and Western countries has been enabled because of the confluence of various factors including: fairly stable employment prospects for academics comparable, for example, to Global South scholars; the availability of funding for such scholars to undertake travel to conferences and network with scholars; the availability of research on the topic of women's media histories because it is in English language and universities have the library resources. Therefore, the history of women's work in these national contexts has begun to be told but there is a pressing need for attention to, and recognition of, scholarship beyond the limited context of anglophone territories. [ABSTRACT FROM AUTHOR]

This perspective article highlights the significance of systems-theoretical approaches within family business research. Extant systems-theoretical literature in the field of family business research is reviewed to outline potential research gaps and avenues. The article highlights the fundamental differences between organisational decision communication and intimate family communication. At the same time, it shows that both organisations and families as addressable social systems that may be characterised by the specific ways in which these systems refer to and manage expectations represented by the function systems of society. The article demonstrates how the key family business research areas of boundary management, succession planning, and family-business paradoxes could benefit from leveraging systems theory. [ABSTRACT FROM AUTHOR]

This article briefly summarizes clinically relevant new aspects of the recently published German, Austrian, and Swiss Onkopedia guideline for the treatment of locally advanced rectal cancer. Main aspects comprise (i) the use of total neoadjuvant therapy for rectal cancers with high-risk features, (ii) treatment with neoadjuvant chemotherapy for patients with a low risk for local recurrence, (iii) immunotherapy using dostarlimab in patients with MSI high/dMMR rectal cancer, as well as (iv) the implementation of organ sparing treatment concepts. The availability of several evidence-based treatment options requires intensive discussion within the multidisciplinary team as well as dedicated information for patients about treatment goals, options, and risks of individual treatment approaches. [ABSTRACT FROM AUTHOR]

This paper builds upon the research of Arnold et al. (2024), further exploring factors which increase or decrease the likelihood of trainee psychologists choosing to work in the Intellectual Disability speciality on qualifying. This research was conducted in light of difficulties in the recruitment of psychologists in ID services despite the expansion of clinical psychology trainee cohorts. A qualitative design was used, whereby data was analysed via qualitative content analysis. Results demonstrate that support, interests, social inequalities, and career development (amongst other factors) are important in determining likeliness to work in ID services. These findings add to the quantitative findings of Arnold et al. (2024). On comparing results of these two studies, contradictions were noted, and thus further research is recommended to explore explicit and implicit attitudes. Recommendations are made for doctoral programmes, ID services and the BPS's Faculty for People with Intellectual Disabilities. [ABSTRACT FROM AUTHOR]

Despite the expansion of clinical psychology training programmes, recruitment into Intellectual Disability (ID) services remains a problem. This research explores the factors which increase the likelihood of trainee psychologists choosing to work in the ID specialty on qualifying. A multivariate linear regression was used to analyse quantitative data collected from a wider project. Results suggest that the mean attitude score is associated with a higher likeliness to work in ID services, as self-reported by participants. Experience in ID services gained prior to training and having a core ID placement during training may also be relevant factors, although these covariates did not reach statistical significance in regression analysis. [ABSTRACT FROM AUTHOR]

Background: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study was designed to determine the effects of a best‐practice hearing intervention on cognitive decline among community‐dwelling older adults. Here, we conducted a secondary analysis of the ACHIEVE Study to investigate the effect of hearing intervention on self‐reported communicative function. Methods: The ACHIEVE Study is a parallel‐group, unmasked, randomized controlled trial of adults aged 70–84 years with untreated mild‐to‐moderate hearing loss and without substantial cognitive impairment. Participants were randomly assigned (1:1) to a hearing intervention (audiological counseling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed semiannually for 3 years. Self‐reported communicative function was measured with the Hearing Handicap Inventory—Elderly Screening version (HHIE‐S, range 0–40, higher scores indicate greater impairment). Effect of hearing intervention versus control on HHIE‐S was analyzed through an intention‐to‐treat model controlling for known covariates. Results: HHIE‐S improved after 6‐months with hearing intervention compared to control, and continued to be better through 3‐year follow‐up. We estimated a difference of −8.9 (95% CI: −10.4, −7.5) points between intervention and control groups in change in HHIE‐S score from baseline to 6 months, −9.3 (95% CI: −10.8, −7.9) to Year 1, −8.4 (95% CI: −9.8, −6.9) to Year 2, and − 9.5 (95% CI: −11.0, −8.0) to Year 3. Other prespecified sensitivity analyses that varied analytical parameters did not change the observed results. Conclusions: Hearing intervention improved self‐reported communicative function compared to a control intervention within 6 months and with effects sustained through 3 years. These findings suggest that clinical recommendations for older adults with hearing loss should encourage hearing intervention that could benefit communicative function and potentially have positive downstream effects on other aspects of health. [ABSTRACT FROM AUTHOR]

Vanillin, an aromatic aldehyde, is one of the most popular flavors worldwide, extensively used in the food, cosmetics, pharmaceutical, and agrochemical industries. Despite its widespread use, less than 1% of the total vanillin production is natural, with the majority being synthesized chemically. While chemical synthesis can help to meet the growing demand for vanillin, a strong market trend has rapidly developed for products created from natural ingredients, including natural vanillin. Given the labor-intensive process of extracting vanillin from vanilla pods, there is a critical need for new metabolic engineering platforms to support the biotechnological production of nature-identical vanillin. This review highlights the significance of vanillin in various markets, its diverse applications, and the current state of bio-engineered production using both prokaryotic and eukaryotic biological systems. Although recent advancements have demonstrated successful vanillin production through biocatalytic approaches, our focus was to provide a current and innovative overview of vanillin bioengineering across various host systems with special consideration placed on microalgae, which are emerging as promising platforms for vanillin production through metabolic engineering. The use of these systems to support the biotechnological production of vanillin, while leveraging the photosynthetic capabilities of microalgae to capture CO2 and convert it into biomass, can significantly reduce the overall carbon footprint. [ABSTRACT FROM AUTHOR]

Background: Flow limitations in the iliac arteries (FLIA) is a sport-related vascular condition increasingly recognised as an occupational risk for professional cyclists and other endurance athletes. Surgical reconstruction is the definitive treatment for athletes wishing to continue competition. However, less information has been published regarding conservative management options and return-to-sport (RTS) guidelines. Objective: Our aim was to review the existing literature on conservative treatment of FLIA, identify knowledge gaps and propose an RTS framework for athletes returning to competition. Methods: A comprehensive literature review was performed using the Ovid-MEDLINE, PubMed, Embase and PEDro databases for publications relevant to conservative management of FLIA. A scoping review was conducted following PRISMA-ScR guidelines. Original, peer-reviewed publications in English describing conservative or postoperative management for athletes with FLIA were included. Additional grey literature and clinical expertise were consulted to inform RTS guidelines. Results: Overall, 62 studies were included in this review. In total, 11 categories of conservative modalities were extracted and presented qualitatively in terms of the information source (discussion or results statements) and perspective of the authors (positive, negative or mixed). We have proposed RTS guidelines covering pre-operative preparation and postoperative rehabilitation based on the available literature, clinical experience, and drawing from other areas of sports medicine research. Conclusion: There is insufficient literature evaluating the effectiveness of conservative management options for FLIA to establish best practices. Considering the importance of RTS for competitive athletes, we proposed practical guidelines to help with clinician and patient decision making. Future consensus should be sought for RTS best practices. [ABSTRACT FROM AUTHOR]

Comet 67P/Churyumov–Gerasimenko (hereafter 67P) was the primary target of ESA's Rosetta mission. Hyperspectral images acquired by the Mapping channel of the Visible and InfraRed Thermal Imaging Spectrometer aboard Rosetta can be used to derive physical and compositional surface properties by detailed spectrophotometric analyses. This calls for a precise spatial co-registration between measurements and geometry information. In this work, we improve the wavelength-dependent co-registration and also the spatial consistency of the radiometric calibration. This is accomplished by applying a feature-based image matching method comparing measured 67P nucleus images from the entire mission to corresponding photometric simulations. The derived geometric distortions suggest previously unaccounted optical aberrations of the instrument, in conjunction with non-systematic spacecraft pointing and perspective errors, and discrepancies between the true nucleus shape at data acquisition time and the used digital shape model. [ABSTRACT FROM AUTHOR]

This article considers Turkey as an archetypal example of the semi-periphery, neither entirely beholden to international rules and norms nor free to set them. We focus on three leading export sectors – textiles and garments, automotives and infrastructure – and analyze how the Turkish state and associated industrial firms have worked to navigate the complicated demands of cost-competitiveness while increasing the production of value-added goods. We find that the Turkish state and firms have adopted a mix of strategies for integrating with export markets, combining neoliberal adherence to the rules and norms of Western markets through global value chains with neomercantilist efforts to direct cross-border trade and investment toward the Balkans, Middle East, and Central Asia. Although neoliberalism and neomercantilism are traditionally treated as opposing approaches to international economic integration, we find that, for semi-peripheral countries like Turkey, these strategies are not contradictory but rather complementary, as they reduce exposure to the volatility and dependence upon Western markets. While the success of these efforts varies across industries and types of firms, we suggest that such dualistic approaches may be a key strategy for semi-peripheral countries seeking to minimize their dependence on Western markets while exerting economic influence in their near abroad. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation. Methods: Liver tissue samples were collected during 2008–2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53). Results: CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression. Conclusions: These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC. TRANSLATIONAL RELEVANCE: The tumor immune microenvironment (TIME) plays a critical role in the immune response In many cancers, including intrahepatic cholangiocarcinoma (ICC). Molecular subtyping of the ICC microenvironment already revealed inter-tumoral heterogeneity with variant profiles of immune cell infiltrates. A recent study created an in-depth immune cell atlas of the TIME in biliary tract cancers and could demonstrate the relevance of specific immune cell subpopulations on patient outcome. We are able to provide a distinctive characterization of TIME, separating tumor epithelial- and stroma areas, in a large and representative ICC cohort using digitalized image analysis on tissue microarrays (TMA) as well as multiplex imaging mass cytometry (IMC). The study was designed for identification of immune cell prognosticators allocating institutional ICC patients into a discovery (2008–15) and a validation (2010–19) cohort. Immune cell subpopulations were correlated with clinicopathological characteristics and patient outcome. Our results highlight: i. The important role of CD4+ T cell infiltration in ICC patients; ii. ICC tumors with high density of immune cells associated with PD-L1 expression identifies a subset of patients with variant tumor biology; iii. Stimulation of STAT1 pathway may be a relevant target to turn "cold" into "hot" tumors. [ABSTRACT FROM AUTHOR]

A Pro‐Gly‐typed cyclopeptide, cyclosenegalin A, was firstly isolated from Annona senegalensis and Annona scleroderma. In this study, we reported synthesis the cycloheptapeptide with a combination of solid‐ and solution‐phase synthetic methods. This study also compared the effectiveness of β‐turn inducer type I and II in cyclosenegalin A to facilitate the cyclization process. The synthesis of cyclosenegalin A were prepared using two different sequences of linear peptides for cyclization. First sequence employed β‐turn type I inducer (Ser‐Ala‐Val‐Thr) as turning point and second sequence employed β‐turn type II inducer (Thr‐Pro‐Gly‐Leu). The successful cyclization was obtained using the linear sequence of NH2‐Ala‐Val‐Thr‐Pro‐Gly‐Leu‐Ser‐OH with β‐turn type II. The final product was obtained in 8.2 % yield with PyBOP/DIEA act as coupling agent. The synthetic cyclosenegalin A were characterized with HR‐ToFMS, 1H NMR, 13C NMR, HSQC, HMBC, TOCSY, and ROESY. The synthetic product was also evaluated for its antimicrobial activity. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol consumption despite negative consequences is a core symptom of Alcohol Use Disorder. In animal models, this is studied by pairing aversive stimuli with alcohol access, and continuation of drinking under these conditions is known as aversion resistance. Previously, we found that female mice are more aversion resistant than males. Corticotropin releasing hormone (Crh) and the Crh receptor 1 (Crhr1) regulate stress-induced reinstatement, alcohol dependence, and binge-like drinking. However, the role of the Crh system in aversion resistance has not been assessed. Objectives: We aimed to identify sex differences in the Crh system during quinine-adulterated alcohol intake. Methods: We used two-bottle choice and adulterated the alcohol solution with quinine. Next, we measured Crh and Crhr1 levels in brain tissue using real-time polymerase chain reaction (RT-qPCR) and RNAscope in situ hybridization. We then infused a Crhr1 antagonist into the medial prefrontal cortex (mPFC) prior to quinine-alcohol intake. Results: After quinine-alcohol consumption, females exhibited increased mPFC Crhr1 mRNA levels as measured by RT-qPCR. This was confirmed with greater anatomical specificity using RNAscope, with females exhibiting an increased number of Crhr1 + cells in the dorsomedial PFC and the ventromedial PFC. mPFC Crhr1 antagonist treatment reduced quinine-alcohol consumption in females but did not impact consumption in males. Quinine-free alcohol intake was unaffected by Crhr1 antagonist treatment. Conclusions: Our findings suggest that Crhr1 in mPFC plays a role in aversion resistant alcohol intake in females. Future experiments will examine the sources of Crh innervation to the mPFC and their distinct roles in alcohol seeking. [ABSTRACT FROM AUTHOR]

This article explores how relationships between policy actors at different scales, and their changing character over time, shape the production of spatial imaginaries and their use in transport infrastructure planning. Based on research on the planning of a major rail project in Northern England between 2011 and 2022, the article illustrates how spatial imaginaries reflect interactions between national, sub-national, regional and local institutions. Drawing on a programme of interviews with policy actors, the research highlights the tensions manifested in planning for transport infrastructure about which places are prioritized in policy, and the institutional influences shaping these decisions. The article develops understanding of how inter-scalar politics influences the production of spatial imaginaries and how these imaginaries are in turn utilized in support of transport infrastructure plans by policy actors at different spatial scales. [ABSTRACT FROM AUTHOR]

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering. To address the limitation, we developed N -(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WD C LDNRIGRRQ C VKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as P H -cDR5 (high valence), P M -cDR5 (medium valence) and P L -cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells P M -cDR5 exhibited an IC50 of 94 pM, while P H -cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC 50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Rheumatoid arthritis can be classified according to ACPA and RF status. ACPA status may be associated with other pathophysiological differences, e.g., the cytokines driving inflammation. Obesity influences the course of RA, likely involving leptin; the exact mechanisms are not completely understood. This study investigates BMI influence on RA cytokine profiles and the possibility of predicting ACPA status and disease activity measured by Power-Doppler sonography (PDS). Methods: Patients were examined using a multi-biomarker disease assay and PDS examination of wrists and MCP and PIP joints and stratified according to ACPA status and BMI, using prediction precision to determine BMI cutoff. Analysis was performed using elastic net regularization of logistic and multiple regression. We then attempted to predict ACPA status/PDS activity based on a bootstrap approach. Results: A total of 120 measurements from 95 patients were performed. ACPA status prediction peaked at BMI 26 kg/m2, with AUC 0.82. PDS activity prediction had a mean average error of < 1.6 PDS points for all groups. In obese patients, cytokine profiles appear to align in ACPA-positive and -negative patients, with leptin playing a greater role in predicting PDS activity, but with some remaining differences. Conclusion: When stratified according to BMI, cytokine patterns can predict ACPA status and PDS activity in RA with a high degree of precision. This indicates that studies into the pathophysiology of RA should take BMI into account, to differentiate between disease- and obesity-associated phenomena. The underlying pathological processes of ACPA-negative and -positive RA appear different. Multi-cytokine evaluations may provide a deeper understanding of disease processes. Key Points • A multi-cytokine approach combined with ultrasonography and modern mathematical methods can contribute to a deeper understanding of the relationship between systemic and joint inflammation. • BMI influences cytokine profiles in rheumatoid arthritis and appears to "override" disease-specific processes. • Using cytokines only, and adjusting for BMI, it is possible to predict the ACPA status and joint inflammation with considerable precision. [ABSTRACT FROM AUTHOR]

The mechanisms of non-financial defined contribution pension schemes (NDCs) are close to those of a fully funded defined contribution plan but under a pay-as-you-go framework. Of particular interest is how the accumulated capital of a deceased person is used, when the death occurs prior to retirement. At the moment, Sweden is the only NDC country that distributes this capital, called survivor dividend (SD). Without a distribution of the SD, the scheme would accumulate a reserve with no clear purpose. This paper aims to analyse to what extent the SD kept by most NDCs can be used to improve pension adequacy giving low-income pensioners the financial support they need. We develop theoretical models to achieve the financial equilibrium of the scheme depending on how the SD is distributed among all socio-economic groups and the use of different mortality tables (unisex versus group-specific). Our results indicate that the survivor dividend can be used to set up a minimum pension that benefit 66.54 $ \% $ % of the pensioners increasing the average annual pension by 8.68%. [ABSTRACT FROM AUTHOR]