Cytochalasans are a large family of fungal metabolites which inhibit actin polymerization and ultimately lead to a broad range of biological effects in different assays. Investigations into the biosynthesis of cytochalasans has revealed that the cytochrome P450 monooxygenase (P450s) tailoring enzymes possess a somewhat relaxed substrate-specificity and may accept structurally-related intermediates for oxidation, partly explaining the variety of structural variations observed in this family of molecules. In this study, we investigate a broad range of P450 enzymes via combinatorial biosynthesis to better understand their substrate scope and potential applications as biocatalysts. Genome mining enabled us to identify cryptic cytochalasan biosynthetic gene clusters (BGCs) in six different species of fungi, each with at least two P450 enzymes encoded. Comparative genomics identified a cryptic thioredoxin-like enzyme encoded in cytochalasan BGCs that co-occurs with the gene encoding a Baeyer-Villiger monooxygenase. Heterologous expression of seven P450s in Magnaporthe grisea mutant strains, lacking P450s required for pyrichalasin H biosynthesis, enabled functional characterization of three P450s, two of which were previously cryptic. The experimental results, combined with phylogenetic analysis of the P450 sequences, reveal subtle information regarding the structures of the associated cytochalasans and begins to explain why some P450s are inactive on the substrates available to them. The P450 enzymes involved in cytochalasan biosynthesis are known to be site-selective in their native host but also possess intrinsic promiscuity due to being able to modify structurally-related analogues. By investigating a diverse set of P450s from characterized and cryptic BGCs, we were able to identify that the stereochemistry of functional groups around the cytochalasan backbone is more restrictive than the size of the macrocycle when introducing the P450 enzyme to non-native substrates.
Understanding what shapes variation in organisms' capacity to utilize novel resources is essential to predicting how species will respond to environmental change. For herbivores, exposure to toxic phytochemicals in novel plants may limit persistence in new habitats. We investigated the behavioral, physiological, genetic, and microbial consequences of diet switching in two closely related species of rodent herbivores that each consume differentially toxic plants in their native habitat, and that maintain different dietary strategies (i.e., relative dietary specialist versus relative generalist). In reciprocal laboratory feeding trials, we exposed wild-caught woodrats (genus Neotoma) to toxins characteristic of either familiar or novel plant secondary compounds. We measured changes in food and water intake, locomotor activity, gut microbial composition, and gene expression across the digestive tract following feeding trials. The dietary generalist responded minimally, but the specialist responded strongly when exposed to the novel diet. This response included behavioral and genetic components including increased water intake, reduction in locomotor activity, increased differential expression of detoxification genes, and a greater shift in gut microbial composition. The dietary specialist exhibited a strong response to diet switching that corresponded with ecologically relevant shifts in behavior and physiology that would have negative fitness consequences. Although the dietary specialist had a strong genetic and microbial response to novel plant secondary compounds, this response would likely be insufficient to overcome the immediate challenge of exposure to novel dietary toxins in the wild. Our results underscore the link between feeding strategy and the capacity to shift to novel dietary resources in response to environmental change.
Xenosurveillance, which uses blood-feeding insects as biological samplers, is an emerging non-invasive approach for monitoring pathogens circulating among humans, livestock, and wildlife. However, its application to livestock-associated bacterial pathogens at human-animal-wildlife interfaces remains underexplored. We investigated whether mosquito blood meals could be used to detect tick-borne bacterial pathogens circulating in livestock in Kenya. We collected 4673 mosquitoes, belonging to Culex, Anopheles, Aedes, Mansonia, and Coquillettidia genera around livestock enclosures in Kajiado and Naivasha counties, Kenya, using CO₂-baited CDC miniature light traps. Traps were selected to maximise species diversity, and as light traps capture fewer engorged mosquitoes than resting traps, only 56 blood-fed individuals (1.2%) were collected and processed as whole-specimen homogenates and analysed for vertebrate blood-meal sources using cytochrome b sequencing. In total, 303 mosquito pools, including blood-fed individuals processed as single-mosquito pools, were screened for Anaplasma, Ehrlichia, Rickettsia, Theileria, and Babesia using PCR-high-resolution melting analysis and confirmatory sequencing. All pathogen-positive detections were exclusively from blood-fed individuals. We detected Anaplasma marginale in Culex pipiens (1/150; 0.7%) and Aedes hirsutus (2/11; 18.2%), Anaplasma sp. in Cx. pipiens (2/150; 1.4%) and Ae. hirsutus (1/11; 9.1%), and Candidatus Neoehrlichia mikurensis in Mansonia africana (2/50; 4%). Pathogen detections showed strong host concordance, where A. marginale was associated with cattle-derived blood meals and Anaplasma sp. with goat-derived blood meals, while Candidatus Neoehrlichia mikurensis was detected in Mn. africana that had fed on cattle and on a host that could not be determined. Our results provide preliminary evidence that mosquito-based xenosurveillance can detect tick-borne bacterial pathogens circulating in livestock at human-wildlife interfaces in Kenya. The strong concordance between pathogen identity and vertebrate host in blood-fed mosquitoes supports the biological plausibility of this approach. Notably, detection of Ca. Neoehrlichia mikurensis represents the first report of this zoonotic pathogen in mosquitoes in Africa, highlighting the One Health relevance of xenosurveillance in identifying settings, where pathogen circulation and cross-interface feeding coincide. Mosquito-derived sampling has potential to complement existing surveillance tools in agro-pastoral systems, where direct host sampling is difficult or costly.
Colorectal cancer (CRC) is a leading cause of cancer-related mortality, largely driven by aberrant activation of the WNT/β-catenin and RAS pathways. Despite recent therapeutic advances, effective strategies to target these oncogenic signals remain limited. A multi-step chemical library screen was performed to identify compounds capable of suppressing β-catenin and RAS signaling. Drug mechanisms and combination effects were investigated through functional assays, in vitro and in vivo experiments, and transcriptomic profiling. Survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) was conducted to evaluate the prognostic significance of candidate target genes. We identified the CDK4/6 inhibitor palbociclib as an unexpected suppressor of β-catenin signaling. Uniquely, palbociclib promoted GSK3β-mediated β-catenin degradation by dampening AKT activity, revealing a previously unrecognized mechanism of action and broadening its role beyond canonical cell-cycle inhibition. Building on this mechanism, we found that combining palbociclib with the KRASG12D-specific inhibitor MRTX1133 elicited potent and selective anti-tumor effects in vitro and in vivo. Parallel screening also revealed the ERK5 inhibitor ERK5-IN-1 as a promising combination partner: co-administration with palbociclib strongly suppressed proliferation across multiple CRC models, showed minimal toxicity in normal cells, and produced durable tumor control in vivo. Transcriptomic profiling indicated that both combinations converge on a common program of cancer cell-state reprogramming, characterized by suppression of proliferative drivers and remodeling of metabolic and mitochondrial pathways. Underscoring the clinical relevance of our findings, survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) revealed that ERK5 target genes CREB5 and NUPR1, identified in our dataset, were consistently linked to poor prognosis, thereby connecting this signaling axis to unfavorable patient outcomes. Together, these findings position palbociclib as a versatile therapeutic backbone in CRC. By simultaneously targeting cell cycle and oncogenic signaling networks, palbociclib-based combinations induce synergistic and durable responses, offering a compelling rationale for tailored therapeutic strategies in molecularly defined CRC.
The COVID-19 pandemic disproportionately affected certain populations, with intimate partner violence (IPV) survivors facing heightened risks of adverse health outcomes. This study examined whether women who experienced IPV during Ontario's COVID-19 lockdowns were more likely to report negative behavioural, psychological, and physiological health outcomes compared to women who did not experience IPV . Using a convergent mixed-methods design, a cross-sectional survey of Ontario residents and semi-structured interviews with key stakeholders were conducted. The final sample comprised 653 survey respondents who identified as women, 23% of whom reported experiencing IPV during COVID-19 lockdowns (n = 150). A total of 24 interviews were conducted, including 14 IPV survivors and 10 violence against women (VAW) service providers. Quantitative findings revealed that IPV survivors had significantly higher odds of adverse behavioural outcomes, including increased alcohol (43.3% vs. 21.9%, RRR = 3.39, p < 0.001), tobacco (15.3% vs. 8.8%, RRR = 2.16, p = 0.014), cannabis (23.8% vs. 10.4%, RRR = 3.49, p < 0.001), and illicit substance use (6.8% vs. 0.6%, RRR = 14.31, p < 0.001), as well as greater decreases in sleep quality (61.4% vs. 40.3%, RRR = 3.24, p < 0.001). They also exhibited more polarized help-seeking patterns: increased reliance on formal supports (34.7% vs. 12.9%, RRR = 4.75, p < 0.001) and higher likelihood of decreased informal support (29.5% vs. 17.3%, RRR = 2.53, p = 0.001). Logistic regression further supported that IPV survivors had over twice the odds of reporting poor mental health (aOR = 2.46, 95% CI: 1.27-4.75) and nearly twice the odds of poor physical health (aOR = 1.84, 95% CI: 1.00-3.36). Qualitative insights revealed that structural barriers, trauma, stigma, and loss of autonomy contributed to these adverse outcomes. These results underscore the bidirectional relationship between mental and physical health and the compounded vulnerabilities exacerbated by crisis conditions. Findings highlight the need to integrate IPV considerations into emergency preparedness and response planning to ensure continuity of care for IPV survivors. As public health emergencies and climate disasters become more frequent, inclusive responses must prioritize those most at risk, including IPV survivors.
Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by painful muscle stiffness and spasms. Paraneoplastic SPS associated with thymoma is rare. Here, we describe a rare case in which neurological symptoms improved after extended thymectomy. A 60-year-old woman presented with progressive painful muscle spasms and gait disturbances affecting the lower extremities. Neurological imaging revealed no structural abnormalities; however, both serum and cerebrospinal fluid were positive for anti-glutamic acid decarboxylase (GAD) antibodies, leading to a diagnosis of SPS. Despite receiving immunotherapy and symptomatic treatment, the patient's neurological symptoms persisted. Contrast-enhanced chest computed tomography revealed a small anterior mediastinal tumor suspected to be a thymoma. Subsequently, bilateral thoracoscopic extended thymectomy was performed. Histopathological examination confirmed a WHO type B1 thymoma (Masaoka stage I), and her neurological symptoms gradually improved postoperatively. Two years after surgery, she was able to walk independently and climb stairs without assistance. This case suggests that extended thymectomy may contribute to sustained neurological and functional improvement in selected patients with thymoma-associated SPS, even in the absence of normalization of the anti-GAD antibody titer.
Ophthalmic manifestations as the initial presentation of chronic myeloid leukemia (CML) are rare. This case describes a 38-year-old man who presented with unilateral severe vision loss alongside bilateral ocular findings, including intraretinal hemorrhages, vascular tortuosity, cotton wool spots, and optic disc edema. Ophthalmic imaging, particularly optical coherence tomography (OCT), revealed bilateral retinal involvement, which was more severe in the left eye despite worse vision in the right eye. Systemic evaluation revealed critical hyperleukocytosis, splenomegaly, and Philadelphia chromosome positivity, confirming CML. The subsequent MRI during remission showed no abnormality. Treatment with hydroxyurea and nilotinib rapidly normalized white blood cell counts and reached major molecular response (MMR) along with complete visual recovery and normal retina and optic nerve. This case highlights the importance of recognizing ocular signs as potential indicators of life-threatening systemic diseases such as CML, warranting prompt diagnosis and intervention. Ocular signs not only help to confirm the primary diagnosis, but also may serve as a useful adjunctive marker for monitoring treatment response.
Fungal keratitis is an uncommon condition that can occur after refractive surgery. Herein, we report a case of early postoperative Aspergillus keratitis in an immunocompetent patient following photorefractive keratectomy (PRK). We report a case of a 21-year-old white man with no past ocular or systemic diseases who underwent bilateral PRK for myopia. Seven days after surgery, he presented to his surgeon, complaining of eye redness and blurred vision that had started 3 days prior. First, empirical antibiotic therapy was initiated, and antifungal agents were subsequently added based on the direct microscopic smear examination of corneal scrapings. The polymerase chain reaction test revealed an Aspergillus corneal infection, and after 7 days of antifungal treatment, significant clinical improvement was observed. This case revealed the necessity of considering atypical microorganisms, such as fungi, in the differential diagnosis of early post-PRK keratitis and highlights the role of direct smear and polymerase chain reaction tests in diagnosis, timely treatment initiation, and subsequently favorable clinical outcomes.
The follicular fluid (FF) microenvironment plays a critical role in oocyte maturation and embryo development, reflecting local ovarian activity and systemic metabolic status. While metabolic alterations in FF have been described in different diseases, comparative analyses across different infertility-related disorders remain limited. This study aimed to characterize and compare amino acid profiles in FF from patients undergoing in vitro fertilization (IVF) with insulin resistance (IR), endometriosis (EM), thyroid dysfunction (TD) and to identify disease-specific metabolic signatures. We analyzed 171 FF samples using targeted ultra-high-performance liquid chromatography. The twenty proteogenic amino acids were quantified and analyzed using univariate and multivariate statistical analyses, including Kruskal-Wallis testing with post-hoc correction, generalized linear modeling adjusted for BMI, principal component analysis (PCA) and pathway enrichment analysis. PCA revealed that the global amino acid composition of FF was largely conserved across all groups. However, disease status had a statistically significant but moderate effect on the overall amino acid profile (PERMANOVA, R²=0.081, p = 0.001). After adjusting for BMI, IR was associated with decreased glycine and arginine levels and TD was associated with lower histidine, tryptophan and lysine concentrations. In contrast, EM was characterized by a selective increase in the histidine content. Pathway analysis revealed alterations in branched-chain amino acid (BCAA) metabolism in IR group and broader disruptions in central amino acid metabolism in TD group. Multivariate and ROC analyses indicated limited discriminative performance of individual amino acids (AUC ≤ 0.71), suggesting that metabolic alterations are subtle and distributed across multiple pathways. FF amino acid composition is tightly regulated but distinct disease-specific metabolic alterations can be detected in IR, EM and TD. These changes are independent of BMI and reflect coordinated alterations in the metabolism of different amino acids rather than strong individual biomarkers. These results show the sensitivity of the follicular environment to overall metabolic health and support the idea of using multivariable metabolic patterns to better understand reproductive dysfunction.
Interferon (IFN)-induced interstitial lung disease (ILD) is a rare but potentially fatal complication. While predominantly reported in patients with chronic hepatitis C, its occurrence during therapy for chronic hepatitis B is exceedingly rare. Although steroids are widely used empirically, the optimal therapeutic regimen remains to be elucidated. We reported a case of a middle-aged, non-smoking Asian female patient with chronic hepatitis B who received weekly subcutaneous injection of pegylated interferon-alpha (Peg-IFNα) (alternating 135 μg or 180 μg). One month after treatment initiation (following the fifth dose), she developed exertional dyspnea, dry cough, and a low-grade fever. High-resolution computed tomography revealed bilateral interlobular septal thickening with subpleural ground-glass opacities. Pulmonary function tests demonstrated a reduced diffusion capacity, however, uncommon in ILD, the patient also exhibited pulmonary hyperinflation. Serological tests did not reveal any abnormalities in white blood cell count, C-reactive protein, procalcitonin, autoantibodies, or anti-respiratory virus antibodies. Echocardiography confirmed structurally normal cardiac chambers and preserved left ventricular systolic function (ejection fraction of 71%). After excluding infectious, autoimmune, and cardiogenic causes, the IFN-induced ILD was diagnosed. After discontinuation of Peg-IFNα and initiation of methylprednisolone therapy, the patient's respiratory symptoms improved markedly within 24 h and resolved completely within a week. During follow ups, no respiratory symptom reoccurred, and chest imaging and the pulmonary function resolved gradually. In this study, we reported a female case who developed an IFN-induced ILD while monotherapy with IFN for chronic hepatitis B, and who experienced rapid clinical improvement after initiation of steroid therapy. To our knowledge, IFN-induced ILD is exceedingly rare in the context of PEG-IFNα monotherapy for chronic hepatitis B, particularly in female patients. Clinicians should maintain a high index of suspicion for IFN-induced ILD when unexplained pulmonary symptoms arise during therapy. Early recognition and appropriate steroid administration appear to be effective strategies for managing disease progression.
Combined oral contraceptives are widely used and generally considered safe. However, they have been associated with arterial thrombosis, including myocardial infarction, particularly in women with cardiovascular risk factors. This case adds to the limited literature highlighting the potential for combined oral contraceptive-induced myocardial infarction in individuals without traditional cardiovascular risk factors. A 28-year-old non-smoking Iranian woman with no significant medical history presented with 11 h of typical anginal chest pain radiating to the left arm and interscapular area. Electrocardiography revealed ST-segment elevations in leads V2-V5, and cardiac biomarkers confirmed myocardial infarction. She had been taking a second-generation combined oral contraceptive containing 150 µg levonorgestrel and 30 µg ethinyl estradiol for 13 years. Emergent coronary angiography demonstrated a thrombotic occlusion in the mid-left anterior descending artery without evidence of underlying atherosclerosis. Successful reperfusion was achieved via balloon angioplasty without stenting. The patient remained stable, was discharged on optimal medical therapy, and advised to discontinue combined oral contraceptives. At 3-month follow-up, cardiac Computed Tomography Angiography revealed a patent left anterior descending artery with no residual stenosis, and echocardiography showed improved systolic function. This case underscores the potential for thrombotic myocardial infarction in young women using combined oral contraceptives, even in the absence of conventional risk factors. It highlights the importance of considering hormonal contraceptive history in the diagnostic workup of acute coronary syndromes in young females. In addition, it demonstrates that Balloon angioplasty without stent placement may be effective in selected cases of non-atherosclerotic thrombotic occlusion.
The emergence and spread of Plasmodium falciparum resistance to artemisinin and its partner drugs pose a major challenge to malaria elimination efforts. Continuous monitoring of resistance-associated molecular markers provides valuable insights into the emergence of resistant genotypes and their geographical distribution. In this study, we investigated mutations linked to antimalarial drug resistance in the pfcrt, pfmdr1, and pfmrp1 genes among 100 P. falciparum isolates collected from southeastern Iran during 2022-2023 and compared the findings with data from the same region a decade earlier. Point mutations were genotyped using PCR-RFLP. Molecular analysis demonstrated a high prevalence (95%) of the pfcrt K76T mutation. In pfmdr1, no mutations were observed at codons 1034, 1042, or 1246; however, the N86Y and Y184F mutations were detected in 3.75% and 51.25% of isolates, respectively. Comparative analysis between the previous (2007-2010) and current (2022-2023) studies revealed a significant increase in the wild-type allele for N86Y and the mutant allele for Y184F. In pfmrp1, mutations at H191Y, S437A, I876V, and F1390I were identified in 68.75%, 85%, 78.75%, and 46.25% of isolates, respectively, while no mutation was observed at K1466R. The predominant pfmdr1 haplotype shifted from wild-type (50%) in the previous study to the single-mutation haplotype N86F184S1034N1042D1246 (50%) in the current study. Combined haplotype analysis of all three genes revealed a decrease in one major haplotype T76N86Y184S1043N1042D1246Y191A437V876F1390K1466 (from 23.5 to 3.75%) and an increase in haplotype T76N86Y184S1043N1042D1246Y191A437V876I1390K1466 (from 7 to 23.75%) over the same period. The persistence of the pfcrt K76T mutant allele despite the withdrawal of Chloroquine from the treatment policy in Iran may be attributable to the co-endemicity of P. vivax in the study area. The increasing prevalence of the N86F184S1034N1042D1246 pfmdr1 haplotype is of concern, given its reported association with reduced susceptibility to lumefantrine. Although mutant pfmrp1 alleles were detected at relatively high frequencies, current evidence does not suggest an immediate threat to the efficacy of artemether-lumefantrine in the studied population.
Rotaviruses (RVs) are important enteric pathogens of swine, contributing significantly to neonatal and post-weaning diarrhea worldwide. Although rotavirus A (RVA) is the best characterized species, much less is known about the epidemiology and genetic diversity of RVB and RVC, especially in Central Europe. This study aimed to investigate the presence and genetic diversity of RVA, RVB, and RVC in diarrheic piglets in Hungary using Nanopore third-generation sequencing. A total of 77 fecal swab samples collected from diarrheic piglets across 19 swine farms were analyzed. All three RV species were detected, RVA and RVC were each identified in 54.5% of samples, while 40.3% was RVB positive. Coinfections involving multiple RV species were frequent, highlighting the complex etiology of piglet diarrhea. Altogether, 8 RVA, 3 RVB, and 4 RVC full-genome sequences, comprising all 11 segments, were identified. Genotyping of RVA strains revealed multiple G/P genotype combinations, with G9P[23] being the most prevalent. Whole-genome analysis demonstrated a Wa-like genomic backbone of porcine origin. In RVB, three complete VP4 sequences were obtained that could not be assigned to any known P genotype, suggesting the presence of a novel lineage. Hungarian RVC strains showed high genetic diversity, including five distinct G genotypes and one potential novel P genotype, underlining evolutionary diversity of porcine RVs. This study provides a comprehensive molecular characterization of RVA, RVB, and RVC circulating in Hungarian pig populations. The high prevalence of coinfections and the detection of genetically diverse and potentially novel strains emphasize the complexity of RV epidemiology in swine. These findings highlight the need for continued surveillance to better understand their role in pig health and zoonotic risk.
Dental higher education requires teaching of critical thinking and reflective skills. Both of which are strengthened by portfolio assignments. The aim of this study was to evaluate how the implementation of a portfolio assignment in a preclinical course of dental studies affected the students' understanding of course topics and their motivation to self-reflect. Students in a preclinical course focusing on the topic of 'preventive dentistry' in the third semester of dental studies were given a newly developed portfolio assignment that they were to work on throughout the semester in relation to the internship and lecture content. At the end of the semester, the success of the portfolio assignment implementation was measured using a validated evaluation form. The form included two dichotomous items, 14 Likert scale items and two free text fields regarding "portfolio assignment in the context of dental studies", "structure and tasks", "content and knowledge gain", "requirements and scope" and "overall assessment". Students of two consecutive semesters (ntotal = 64), in which the portfolio was implemented for the first time, participated in the portfolio assignment and evaluation process. The evaluation results showed that portfolio assignments and self-reflection tasks have been underrepresented in dental studies to date. In both semesters, the portfolio assignment was rated as good to very good in > 90% of cases. The structure and tasks, as well as the repetition of course content, scope and effort, were rated positively. More than 80% of the students also agreed that the reflection tasks contributed to an increase in engagement with the course content and an awareness of the knowledge gained over the duration of the semester. In conclusion, the implementation of a portfolio assignment, including self-reflective elements, into the curriculum revealed to be a promising teaching tool that is well received by students. At the same time, portfolio assignments illustrate not only to students but also to teachers that learning and optimisation is a dynamic process that should be constantly evaluated and adapted in all semesters.
Radiotherapy (RT) for treating breast cancer can result in incidental dose deposition to the liver, leading to functional impairment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates (UHDR), has demonstrated remarkable normal tissue sparing. We investigated the hepatoprotective effects and metabolic alterations associated with FLASH-RT and conventional radiotherapy (CONV-RT) in a preclinical breast cancer model. Female BALB/c mice bearing syngeneic 4T1 breast tumors were randomized to receive a single 20 Gy fraction of either FLASH-RT (625 Gy/s) or CONV-RT (0.54 Gy/s) using a 6 MeV electron beam. Tumor kinetics and systemic toxicity were monitored for 14 days. Hepatic integrity was assessed via histology, immunohistochemistry, oxidative-stress markers, serum biochemical assays, and non-targeted UPLC-MS/MS metabolomics of liver tissue. Both modalities achieved isoeffective tumor growth delay. However, FLASH-RT induced only transient body-weight reduction followed by rapid recovery, and was associated with reduced hepatic injury markers compared with CONV-RT. Histopathological analysis revealed that FLASH-RT preserved hepatic architecture and attenuated early pro-fibrotic signaling, as reflected by reduced α-SMA and Nestin expression compared with CONV-RT. FLASH-treated mice exhibited significantly lower serum ALT/ALP levels and reduced oxidative stress (lower MDA levels and higher GSH-PX levels). Furthermore, FLASH-RT attenuated immune-mediated inflammation, as evidenced by diminished infiltration of CD8 + T cells and F4/80 + macrophages. Metabolomic profiling demonstrated that FLASH-RT preserved hepatic metabolic homeostasis, preventing the profound lipid and choline metabolism disruptions observed following CONV-RT. FLASH-RT was associated with substantial hepatic sparing by preserving structural integrity, attenuating oxidative-inflammatory signaling, and maintaining metabolic stability. These findings suggest that FLASH-RT may help expand the therapeutic window by uncoupling antitumor efficacy from collateral hepatic toxicity.
This study examines organizational racial power dynamics through a case study of the interactions between a Diversity, Equity, and Inclusion (DEI) Committee and the Board of Directors at an organization specializing in health care practitioner training. We explore how power-defined as control over resources by certain individuals while others lack such control-can be utilized constructively or destructively. Understanding the hoarding of power to maintain hierarchies, rather than fostering equitable systems, is crucial for driving proactive organizational change. Employing a case study methodology, we analyze the division of power within an organization and elucidate behaviors that led to the concentration of power, highlighting its detrimental use. We also examine how organizational leadership systematically undermined the DEI Committee's efforts to establish an accountable, transparently governed organization committed to justice, equity, diversity, and inclusion. Our analysis reveals that when existing power structures are threatened, they adapt to defend their dominance, often at the expense of the organization's mission. A failure to integrate DEI principles resulted in the loss of relationships with field experts and inflicted harm on its members, ultimately leading to the organization's collapse. Harm included symptoms of racial stress and trauma in racialized board members. In addition to exposing governance failures, this study illuminates the psychological and racial trauma experienced by affected members, linking structural exclusion to cumulative harm. This analysis is contextualized within current events, where similar patterns of dismantling equity-focused initiatives are observed at national levels. This paper offers a unique and timely perspective on advancing organizational equity, particularly relevant for diversity consultants tasked with analyzing and resolving problematic organizational dynamics. We provide guidelines for distinguishing between appropriate Board governance and detrimental power hoarding, contributing to the broader discourse on fostering equitable organizational practice. Below is a list of our various positionalities and our professional/lived experiences. These inform how we approached the present case study; through an examination of race-based power hoarding. Our various identities and life circumstances strengthened and challenged our understanding of how diversity, equity, and inclusion can be integrated within an organization. Early career co-authors consulted more senior career co-authors and all feedback was welcomed. Each author’s positionality and lived experience was valued and improved our work. The first author, Sonya Faber, PhD, MBA, is an African American scholar residing in Germany, as well as a neuroscientist and pharmaceutical professional, with a specialization in clinical development and a passionate commitment to social justice issues. NiCole T. Buchanan, Ph.D. is a Professor in the Department of Psychology at Michigan State University; her research examines how race, gender, and victimization relate to well-being and how organizations can utilize workplace best practices to reduce bias and create healthy work environments where all employees thrive. Dr. Diana Quinn, a queer mestizo Chicana with a background in Cultural Anthropology and a doctorate in Naturopathic Medicine, positions herself at the intersection of holistic health and social justice. Her extensive experience in integrative mental health care, particularly for marginalized communities, reflects a commitment to Healing Justice and transformative practices that address generational trauma and oppression. Robyn Wong-Lee is a Chinese-Canadian ciswoman and a graduate student at the University of Massachusetts Boston researching anti-Asian racism, Asian-American mental health, and resistance/activism. Daniel Zalewa is a graduate student at The University of New Haven studying Industrial Organizational Psychology with a special interest in work stress and health, particularly revolving around experiences of workplace discrimination and their impact on employee wellbeing. The senior author, Monnica Williams, PhD, is an African American woman living in Canada with expertise in racism, mental health, and anxiety-related conditions; she is a board-certified licensed clinical psychologist, tenured professor at the University of Ottawa, a major urban university, and Canada Research Chair for Mental Health Innovation and Equity. We recognize that our positionalities shape our interpretive lens, and we address this through methodological transparency and documentation of data sources.
The dietary index for gut microbiota (DI-GM) is a newly proposed metric for assessing diet quality linked to gut microbiota. However, prospective evidence is scarce on the associations between DI-GM and adverse liver outcomes. The DI-GM was calculated by averaging the intakes of 12 foods and nutrients. Elastic net regression was performed to identify metabolites associated with DI-GM and metabolic signature reflecting higher adherence to DI-GM was constructed. Cox proportional hazards regression and mediation analyses were employed to explore the potential associations and mechanisms. This prospective cohort study included 168,456 participants from the UK Biobank. Compared to participants with DI-GM scores of 0-3, those scoring ≥ 6 presented 22% lower risk of MASLD (HR = 0.78, 95% CI = 0.68-0.90). Metabolic signature for DI-GM and dietary index beneficial to gut microbiota (BDI-GM) were also inversely correlated with MASLD. Similar inverse correlations between DI-GM and BDI-GM and the risks of other chronic liver diseases were identified. Furthermore, phenotypic age, body mass index, metabolic score, inflammatory score, and metabolic signature significantly mediated the relationship between DI-GM and MASLD. No significant interactions were observed between DI-GM and polygenic risk score of hepatic steatosis, and the associations between DI-GM and adverse liver outcomes persisted regardless of genetic risk. Higher adherence to DI-GM significantly correlates with reduced risks of MASLD and other chronic liver diseases, independent of genetic susceptibility. And the apparent mediating effects of five indices highlight the role of aging, obesity, metabolic disorders, inflammation, and metabolomic alterations in the association between DI-GM and MASLD. Further research is warranted to evaluate the utility of metabolic signatures in metabolic profile monitoring and risk stratification. This large-scale cohort study first demonstrates that higher adherence to a gut microbiota-beneficial diet (DI-GM) is associated with a lower risk of MASLD and other chronic liver diseases, independent of genetic susceptibility. The estimated population attributable fractions, while derived from observational data and requiring cautious interpretation, suggest that a substantial portion of liver disease cases in the study population might be linked to suboptimal DI-GM adherence. These findings underscore the importance of integrating gut microbiome health into public health strategies for liver disease prevention, offering a practical approach to reduce disease burden at both individual and population levels. The DI-GM-associated metabolic signature represents a candidate objective biomarker meriting evaluation in future studies for its potential in early risk assessment. Mediation analyses further reveal that a diet promoting healthy gut microbiota may reduce MASLD risk by maintaining gut microbiota homeostasis, decelerating biological aging, ameliorating obesity, attenuating metabolic disorders, alleviating inflammation, and altering metabolome. Collectively, this study generates important hypotheses and provides a rationale for future interventional research to determine whether promoting DI-GM-aligned diets can effectively reduce liver disease risk at the population level.
Exclusive breastfeeding (EBF) is recommended for the first six months of life, yet only 48% of infants under six months are exclusively breastfed worldwide. Breastfeeding rates vary significantly across regions, countries, and even within cities. Brazil reports national rates of EBF of approximately 50%; however, there are notable in-country socioeconomic disparities, where EBF prevalence is lower in low-income communities compared to the wealthier communities. This study aims to: 1) investigate barriers to breastfeeding by exploring perceptions and experiences of breastfeeding in low-income communities in São Paulo, Brazil, and 2) evaluate the perceptions of a targeted social transfer program to improve EBF prevalence at six months. We conducted a semi-structured, exploratory, qualitative study in low-income communities in São Paulo, Brazil using focus group discussions (FGD) and key informant interviews (KII). Three FGDs were conducted, two with mothers and one with fathers (n = 14), alongside five KIIs with key stakeholders, including a nurse, neonatologist, social worker, and representatives from the Brazilian Ministries of Health and Social Development (n = 5), with a total sample of 19 participants. An inductive thematic analysis approach was used to develop the codebook and identify recurrent themes across transcripts. Despite the overall positive outlook on breastfeeding, FGDs and KIIs revealed several challenges, including economic, health system, and sociocultural barriers that hinder both initiation and continuation of breastfeeding. A targeted social transfer program was identified as a potential mechanism to address these barriers and support breastfeeding outcomes. The identified barriers highlight the complexity of breastfeeding in low-income settings. Strengthening the existing breastfeeding social transfer program, Auxílio Nutriz, may serve as a supportive mechanism to address identified barriers and support breastfeeding practices. Understanding these challenges is a critical step toward developing coordinated, cross-sectoral interventions that support sustained breastfeeding practices. These findings have important implications for public health policy and program design, providing an evidence base for targeted interventions aimed at reducing inequities in breastfeeding outcomes among vulnerable populations. The RCT was registered on ClinicalTrial.gov on December 6, 2023 (NCT06157697); https://clinicaltrials.gov/study/NCT06157697?term=STEBB%26rank=1.
Clinical medicine postgraduates face a heightened risk for mental health problems, particularly anxiety disorder, which is largely due to a high-pressure training environment and prevalent adverse academic events. Psychological resilience, defined as the ability to adapt to adversity, is theorized to modify the association of external stressors with mental health problems. However, limited evidence exists regarding its moderating role in this specific population, particularly using rigorous interaction analysis. In this cross-sectional study, 1182 clinical medicine postgraduates from a major Chinese medical school completed an anonymous online survey. Exposure to adverse academic events was assessed via an 8-item checklist. Anxiety symptoms were measured using the Generalized Anxiety Disorder scale (GAD-7), and psychological resilience was assessed with the Connor-Davidson Resilience Scale (CD-RISC-10). Hierarchical logistic regression was used to examine associations. The moderating role of psychological resilience was tested using the interaction contrast approach, reporting the Relative Excess Risk due to Interaction (RERI), Attributable Proportion (AP), and Synergy Index (SI). Reporting adverse academic events was strongly associated with probable anxiety disorder (OR = 3.157, 95% CI: 2.284-4.363, p < 0.001), and low psychological resilience was independently associated with higher odds (OR = 3.657, 95% CI: 2.546-5.253, p < 0.001). A significant additive interaction was observed (RERI = 5.308, 95% CI: 1.402-9.214; AP = 0.434, 95% CI: 0.218-0.650; SI = 1.897, 95% CI: 1.218-2.955). Stratified analysis revealed that the association of adverse academic events with probable anxiety disorder was substantially stronger among individuals with low resilience (OR = 12.226, 95% CI: 7.585-19.708) compared to those with high resilience (OR = 3.775, 95% CI: 2.043-6.975). Adverse academic events are positively associated with probable anxiety disorder among clinical medicine postgraduates. Psychological resilience is a potent factor that modifies this association. These findings highlight the importance of integrating resilience assessment and resilience‑building programs into postgraduate medical education to safeguard trainee mental well-being.
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, largely due to frequent metastasis to the brain and bones. Therapeutic outcomes are often limited by drug resistance, tumor heterogeneity, and the lack of effective treatment options across different stages and metastatic sites. Identifying druggable targets that are conserved between primary tumors and metastases is critical for advancing precision oncology. scRNA-seq expression profiles from primary NSCLC tumors and matched brain and bone metastases were analyzed to identify conserved and site-specific gene expression signatures. Ingenuity Pathway Analysis was used for target prioritization. Potential targets identified from scRNA-seq analysis were used for ligand screening using machine learning (ML)-based quantitative structure-activity relationship (QSAR) modeling. QSAR models were developed using ChEMBL bioactivity data and evaluated across multiple ML algorithms. Large-scale virtual screening was followed by molecular docking and molecular dynamics (MD) simulations for lead optimization. Eight candidate therapeutic targets were prioritized, among which ARPC2, PSMB4, and RAC2 were consistently overexpressed across primary, brain, and bone metastatic sites and were functionally implicated in key cancer-associated pathways. QSAR modeling demonstrated strong predictive performance, with XGBoost and Random Forest models achieving AUROC values greater than 0.97. Virtual screening of approximately 9-15 million compounds per target identified high-affinity candidates. Subsequent docking and MD simulations revealed that the ARPC2-14465616, PSMB4-74833722, and RAC2-57175325 complexes exhibited the highest structural stability and sustained intermolecular interactions. This integrative single-cell transcriptomics and ML-driven drug discovery framework identified conserved druggable targets and promising lead compounds for metastatic NSCLC. The results provide a strong foundation for experimental validation and the development of novel therapeutic strategies targeting both primary tumors and metastatic lesions.