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Abstract Strategies to improve metabolic health include calorie restriction, time restricted eating and fasting several days per week or month. These approaches have demonstrated benefits for individuals experiencing obesity, metabolic syndrome, and prediabetes. However, their impact on established diabetes remains incompletely studied. The chronicity of type 2 diabetes (T2D) requires that interventions must be undertaken for extended periods of time, typically the entire lifetime of the individual. In this study, we examined the impact of intermittent fasting (IF), with an every-other-day protocol for a duration of 6 months in a murine model of T2D, the db/db (D) mouse on metabolism and liver steatosis. We compared D-IF mice with diabetic ad-libitum (AL; D-AL), control-IF (C-IF) and control-AL (C-AL) cohorts. We demonstrated using lipidomic, microbiome, metabolomic and liver transcriptomic studies that chronic IF improved carbohydrate utilization and glucose homeostasis without weight loss and reduced white adipose tissue inflammation and significantly impacted lipid metabolism in the liver. Microbiome studies and predicted functional analysis of gut microbiota showed that IF increased beneficial bacteria involved in sphingolipid (SL) metabolism. The metabolomic studies showed that oxidation of lipid species and ceramide levels were reduced in D-IF compared to D-AL. The liver lipidomic analysis and liver microarray confirmed a reduction in overall lipid content in D-IF mice compared to D-AL mice, especially in the feeding state as well as an overall reduction in oxidized lipids and ceramides. These studies support that long-term IF can improve glucose homeostasis and dramatically altered lipid metabolism in the absence of weight loss.

N -Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004 / MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

Background & Aims: In Latin America, genetic testing for Lynch Syndrome (LS) has been partially implemented. Traditionally, LS diagnosis relied on the Amsterdam criteria and Bethesda guidelines, collectively known as Traditional Screening (TS). However, TS may miss up to 68% of LS cases. To improve detection rates, Universal Tumor Screening (UTS) has been introduced. UTS involves screening all newly diagnosed colorectal cancer (CRC) patients for molecular markers to more effectively identify LS cases., Methods: Clinical and molecular data on 1,684 colorectal cancer (CRC) patients, collected between 1999 and 2020, were provided by 24 Latin American genetic cancer registries and centers. Germline genetic testing was not consistently performed across all cases., Results: LS screening strategies were available for 72% (1,209/1,684) of cases, with germline testing conducted in one-quarter (304/1,209) of these. Most cases (78%, n=943) underwent UTS, primarily in Argentina, Chile, and Uruguay, while 22% (266/1,209) were screened through TS. UTS identified deficient mismatch repair (dMMR) tumors in 29% (272/943) of cases. The rate of LS confirmed by sequencing was higher with UTS (53.3%, 65/122) compared to TS (47.8%, 87/182), though the difference was not statistically significant (P value = 0.175)., Conclusions: UTS is widely implemented in Latin America; however, the low detection rate of LS demonstrated in this study raises concerns about the routine use of germline genetic testing in our region. Our study provides real-world outcomes that highlight disparities in screening uptake and counseling referrals, illustrating the challenges that Latin American countries face in hereditary cancer syndrome screening. These results contribute to the rationale for designing effective screening strategies for LS, which may also be applicable to other hereditary cancer syndromes, ultimately., (Copyright © 2025. Published by Elsevier Inc.)

Purpose of Review: This review assesses the role of wearable technologies in pain management, emphasizing their capability to transcend subjective pain evaluations with objective functional outcome tracking. We explore the types and veracity of health metrics wearable devices track, illustrating how this technological evolution can significantly enhance patient care in the context of chronic pain prevention and management., Recent Findings: The advancements in modular wearable technology offer new avenues to track a variety of health outcomes, including aerobic capacity, physical activity, stress, and sleep quality. This provides objective measurements that can aid in the management of chronic conditions and can offer a more comprehensive assessment of a patient's pain and function. Although the initial approach to pain management that emphasized pain as the fifth vital sign had unintended devastating consequences, leveraging wearable technology for objective outcomes tracking presents an opportunity to optimize pain management strategies. Wearable technologies capture functional metrics that provide insight into many aspects of the biopsychosocial model of pain. Utilizing function as the key performance indicator has the potential to improve treatment outcomes and, ultimately, patient care., Competing Interests: Compliance with Ethical Standards. Competing Interests: Competing interests: CLR is a consultant for Augmend Health and section editor at Current Pain and Headache Reports. Human and Animal Rights and Informed Consent: All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines)., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

3,3'-Diindolylmethane (DIM), a naturally occurring bis-indole found in cruciferous vegetables and produced in small amounts in the normal flora of the human gut, has demonstrated neuroprotective benefits in models of CNS hypoxia and stroke. In the CNS, DIM modulates the activation of the aryl hydrocarbon receptor (AhR) and inhibits its pro-inflammatory effects. Although capable of crossing the blood brain barrier, DIM's bioavailability is limited by its low solubility. Dispersed BR4044 provides a nanoscale high-solubility DIM suspension with the potential for treating traumatic brain injury (TBI). The present study aimed to determine whether BR4044 treatment could reduce pathology and improve behavioral recovery following moderate TBI. Male Sprague Dawley rats received moderate fluid percussion injury or sham surgery followed by vehicle or BR4044 treatment in the acute recovery period. TBI BR4044 animals showed significantly reduced cortical and hippocampal edema and lower levels of serum-derived extracellular vesicles compared to TBI Vehicle animals. BR4044 treatment of TBI animals preserved sensorimotor function and associative fear memory. Cortical contusion size and neuronal loss in the parietal cortex and CA3 region of the hippocampus were also significantly reduced with BR4044 treatment. BR4044 also decreased microbleeding and nuclear AhR at the contusion site. This translational study demonstrates that BR4044 ameliorates pathology and improves neurological outcomes following TBI by reducing brain edema, lowering acute extracellular vesicle release, modulating AhR, preserving cortical and hippocampal neurons, reducing red blood cell (RBC) extravasation into the injured brain, and promoting behavioral recovery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Coleen M. Atkins reports financial support was provided by Boulder BioScience, LLC. Michael A. Zeligs reports a relationship with Boulder BioScience, LLC that includes: board membership and equity or stocks. Irwin C. Jacobs reports a relationship with Boulder BioScience, LLC that includes: consulting and advisory. Michael A. Zeligs has patents pending to Boulder BioScience, LLC. Michael A. Zeligs has patents issued to Boulder BioScience, LLC. Irwin C. Jacobs has patents pending to Boulder BioScience, LLC. Irwin C. Jacobs has patents issued to Boulder BioScience, LLC. Michael A. Zeligs and Irwin C. Jacobs are co-inventors of the BR4044 pending and issued patents assigned to Boulder BioScience, LLC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Definitive hematopoietic stem and progenitor cells (HSPCs) arise from a small number of hemogenic endothelial cells (HECs) within the developing embryo. Understanding the origin and ontogeny of HSPCs is of considerable interest and potential therapeutic value. It has been proposed that the murine placenta contains HECs that differentiate into HSPCs. However, during human gestation HSPCs arise in the aorta considerably earlier than when they can first be detected in the placenta, suggesting that the placenta may primarily serve as a niche. We found that the Runx1 transcription factor, which is required to generate HSPCs from HECs, is not expressed by mouse placental ECs. To definitively determine whether the mouse placenta is a site of HSPC emergence, we performed lineage tracing experiments with a Hoxa13Cre allele that specifically labels ECs in the placenta and umbilical cord (UC), but not in the yolk sac or embryo. Immunostaining revealed Hoxa13Cre lineage-traced HECs and HSPCs in the UC, a known site of HECs, but not the placenta. Consistent with these findings, ECs harvested from the E10.5 aorta and UC, but not the placenta, gave rise to hematopoietic cells ex vivo, while colony forming assays using E14.5 fetal liver revealed only 2% of HSPCs arose from Hoxa13-expressing precursors. In contrast, the pan-EC Cdh5-CreERT2 allele labeled most HSPCs in the mouse placenta. Lastly, we found that RUNX1 and other HEC genes were not expressed in first-trimester human placenta villous ECs, suggesting that human placenta is not hemogenic. Our findings demonstrate that the placenta functions as a site for expansion of HSPCs that arise within the embryo proper and is not a primary site of HSPC emergence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: Competing interests: TTS reports consultation fees from Tillotts Pharma, Nouscom and Mehiläinen, being a co-owner and CEO of Healthfund Finland Ltd, and a position in the Clinical Advisory Board and a minor shareholder of Lynsight Ltd.

Factor H (FH) is a crucial complement regulator that prevents complement-mediated injury to healthy cells and tissues. This regulatory function can be disrupted by Factor H autoantibodies (FHAA), which then leads to diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 Glomerulopathy (C3G). In pediatric aHUS, the FHAA incidence is ~10-15%, although in the Indian population, it rises to ~50%. The specific regions of FH targeted by FHAAs correlate with the pathogenic mechanism of the associated disease. In aHUS, FHAAs target the C-terminus, thereby impacting FH ability to recognize cell surfaces. In C3G, in contrast, FHAAs often target the N-terminus, generating an acquired functional FH deficiency. Detection and monitoring FHAAs are decisive for effectively treating patients. Current FHAA analysis normally identify free FHAAs that bind surface-bound FH using ELISA techniques. These methods require well-equipped laboratories and qualified staff, and do not measure FH-FHAA complexes, which can make it difficult to correlate titers with clinical outcomes. The visually-based immunochromatographic test (ICT) described herein allows for quick detection and quantification of IgG and IgM FH-FHAA complexes in human EDTA-plasma or serum. This ICT offers improved detection of FHAAs compared to ELISA as demonstrated by cases where the ICT identifies FH-FHAA complexes in samples that tested negative with the free FHAA ELISA. Importantly, the ICT indirectly informs on the amount of FH that is complexed with FHAAs, thus assessing the significance of the FHAA in disrupting the regulatory function of FH. Overall, this novel assay offers a simple, fast, cost-effective, and, likely, more clinically relevant alternative for diagnosing FHAAs in at-risk populations., Competing Interests: Authors IC and JP-P were employed in Secugen S. L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Rodríguez de Córdoba, Reparaz, Sanchez, Pinto, Juana Lopez, Martin Merinero, Calvete, Perez-Perez, Jellison, Zhang, Smith, Moreno and Dominguez.)

Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Informed consent: Not applicable. Competing interests: T.T.S. reports consultation fees from Mehiläinen, Nouscom, Orion Pharma, Amgen, and Tillots Pharma, being a co-owner and CEO of Healthfund Finland Ltd., and a position in the Clinical Advisory Board and as a minor shareholder of Lynsight Ltd. M.D.V. is advisor of Nouscom. Other authors declare that they have no conflicts of interest. All other authours declare no conflict of interest relevant to the current paper., (© 2025. The Author(s).)

Introduction: Infective thoracic aortic aneurysms are uncommon, especially presenting with haemoptysis., Case Presentation: We report the case of an 81-year-old male who presented with fever and pleuritic chest pain and was initially misdiagnosed with community-acquired pneumonia. A CT scan later  revealed a saccular, ruptured thoracic aortic aneurysm. Despite antibiotic therapy, the patient developed haemoptysis, necessitating thoracic endovascular aortic repair (TEVAR). Post-procedure, the patient showed significant clinical improvement and was discharged in stable condition 45 days later., Conclusions: Infected thoracic aortic aneurysms presenting as haemoptysis are exceptionally rare but life-threatening. Early clinical suspicion (manifested by haemoptysis, fever and thoracic pain) is essential, particularly in patients with risk factors such as immunosuppression or previous infections. This case emphasizes the importance of prompt diagnosis and intervention, along with the use of appropriate imaging techniques to reduce morbidity and mortality associated with this rare yet severe condition.

Inflammatory environments induce the generation of dysfunctional IFNγ + T-bet + FOXP3 + Th1-like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1-like Tregs are not well understood. Sphingosine-1-phosphate (S1P) signalling molecules are upregulated in Th1-like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1-like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1-like Tregs in vitro. Finally, these results are validated in in vivo-generated Th1-like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1-like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1-like Tregs., (© 2024 The Author(s). Immunology published by John Wiley & Sons Ltd.)