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The lateral septum (LS) is a midline, subcortical structure that is a critical regulator of social behaviors. Mouse studies have identified molecularly distinct neuronal populations within the LS, which control specific facets of social behavior. Despite its known molecular heterogeneity in the mouse and critical role in regulating social behavior, comprehensive molecular profiling of the human LS has not been performed. Here, we conducted single-nucleus RNA sequencing (snRNA-seq) to generate transcriptomic profiles of the human LS and compared human LS profiles to recently collected mouse LS snRNA-seq datasets. Our analyses identified TRPC4 as a conserved molecular marker of the mouse and human LS, while FREM2 is enriched only in the human LS. We also identify a distinct neuronal cell type marked by OPRM1 , the gene encoding the μ-opioid receptor. Together, these results highlight transcriptional heterogeneity of the human LS and identify robust marker genes for the human LS., Competing Interests: Co-author J.E.K. is a consultant on a data monitoring committee for an antipsychotic drug trial for Merck & Co., Inc., (© 2025 The Authors.)

Background: Early posttransplant cytomegalovirus (CMV) infections in CMV seronegative solid organ transplant recipients (SOTR) with CMV seronegative donors (D-/R-) are often attributed transfusion-transmitted CMV. The prevalence of false-negative donor CMV serology in D-/R- SOTR with early CMV infections has not been explored., Methods: We determined the frequency and characteristics of CMV DNAemia that occurred within 90 days of transplant among adult SOTR classified as D-/R- who underwent a first SOT at a single center between February 25, 2014 and February 25, 2024. Repeat donor CMV antibody testing was performed on stored donor sera if possible., Results: Thirteen of 737 (1.8%) D-/R- SOTR from 12 donors developed CMV DNAemia within 90 days of transplant (median time to DNAemia: 28 days, interquartile range 23-42 days). Five (38%) recipients experienced CMV disease either before (n = 2) or after (n = 3) CMV DNAemia was identified, and five (38%) developed CMV antiviral resistance mutations during their course. Repeat CMV antibody testing was performed on sera from four donors to five recipients and was positive in three (75%) tested donors., Conclusions: Early CMV infections in D-/R- SOTR are uncommon but associated with high morbidity. CMV transmission from organ donors with false negative CMV serology is an important source of early CMV infections in D-/R- SOTR. Clinicians should suspect and promptly report early CMV infections in D-/R- SOTR as potential donor-derived processes, regardless of donor and/or recipient transfusion histories. Reporting such cases is essential to promote broader investigations that may identify suboptimal donor CMV screening assays., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Coccidioidomycosis is a fungal infection that poses a serious risk when transmitted through organ transplantation. We analyzed cases reported to the Organ Procurement and Transplantation Network ad hoc Disease Transmission Advisory Committee from 2013 to 2022., Methods: Donors and/or recipients who had positive Coccidioides immitis/posadasii serology, pathology, and/or culture were included in this study. Cases adjudicated as 'proven' or 'probable' were analyzed for donor infection risk factors, the timing of infection, transmission by organ type, clinical manifestations, and recipient outcomes. Patient and facility identifiers were removed prior to review., Results: During this time period, 73 potential instances of Coccidioides donor disease transmission events were reported. Among them, infection was transmitted from seven deceased donors to eight recipients. All seven deceased donors had prior infection or exposure to regions where coccidioidomycosis is endemic. Of 20 individuals receiving organs from these donors, eight developed infection, resulting in a 40% transmission rate. The median time to diagnosis post-transplant was 39 days. Disseminated disease occurred in six recipients, five of whom died from the infection. Notably, none of the recipients who received prophylactic antifungal treatment died from the infection., Conclusion: Despite its rarity, donor-derived Coccidioides infection is a serious concern, particularly due to the high mortality rate in the early post-transplant period. To mitigate these risks, a thorough assessment of donor exposure history, coupled with donor serology and bronchoalveolar lavage cultures, can effectively guide post-transplant antifungal prophylaxis. Prompt reporting is crucial to prevent Coccidioides infections among other recipients., (© 2024 Wiley Periodicals LLC.)

Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs) 1,2 , partly because there are immunosuppressive myeloid cells in tumours 3,4 . However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1 hi -TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8 + T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1 hi -TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1 hi -TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1 hi -TAM-mediated immunosuppression in CD8 + T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1 hi -TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1 hi -TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy., Competing Interests: Competing interests: L.F. has received research support from Roche/Genentech, Abbvie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen and Merck; has served on the scientific advisory boards of Actym, Astra Zeneca, Bioatla, Bristol Myers Squibb, Daiichi Sankyo, Immunogenesis, Innovent, Merck, Merck KGA, Nutcracker, RAPT, Senti, Sutro and Roche/Genentech; and reports ownership interest in Actym, BioAtla, ImmunoGenesis, Nutcracker, RAPT, Senti and Therapaint. R.A.M. is an employee of Corvus Pharmaceuticals. E.M.V.A. has received research support from Novartis, BMS and Sanofi, and served on the scientific advisory boards of Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics and Serinus Bio. The remaining authors declare no competing interests., (© 2024. The Author(s).)

This work was performed to generate the data needed to set epidemiological cut-off values for minimal inhibitory concentrations (MICs) of 10 antimicrobial agents against Vibrio parahaemolyticus determined using standardised broth microdilution protocols. Eight laboratories performed broth microdilution tests with incubation at 35°C for 16 to 20 h, and 7 also performed tests on the same isolates with incubation at 28°C for 24 to 28 h. Data were analysed by the ECOFFinder and normalised resistance interpretation algorithms. The cut-off values calculated for ceftazidime, florfenicol and trimethoprim/sulfamethoxazole, 1, 1 and 0.25/4.75 µg ml-1, respectively, were the same when calculated from data obtained at both temperatures. The cut-off values calculated from data obtained at 35°C and from data obtained at 28°C were 0.25 and 0.5 µg ml-1 for enrofloxacin, 2 and 4 µg ml-1 for gentamicin, 0.5 and 1 µg ml-1 for oxolinic acid and 2 and 1 µg ml-1 for oxytetracycline, respectively. The influence of incubation temperature on MIC values was investigated by comparing MICs obtained at 35 and 28°C for a specific antimicrobial agent with a particular isolate by an individual laboratory. Results showed that 56% of 1473 of these paired MIC values were identical, while 38% differed from one another by not more than 1 dilution step. The data generated in this work will be submitted to the Clinical and Laboratory Standards Institute for consideration in their setting of internationally agreed epidemiological cut-off values for V. parahaemolyticus that are essential for interpreting antimicrobial susceptibility testing data of this species.

Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging mice. These included both sexes of GHRKO and Snell Dwarf mutant mice, and in females only of PAPPA KO mice. P65 is also lower in both sexes of mice treated with rapamycin, canagliflozin, meclizine, or acarbose, and in mice undergoing caloric restriction. Two drugs that extend lifespan of male mice, i.e. 17α-estradiol and astaxanthin, however, did not produce lower levels of p65. We also measured other canonical NF-κB signaling regulators, including the activators IKKα and IKKβ and the inhibitor IκB-α. We found that those regulators do not consistently change in a direction that would lead to of NF-κB inhibition. In contrast, we found that NCoR1, an HDAC3 cofactor and a transcription co-repressor that regulates p65 activity, was also downregulated in many of these mouse models. Finally, we report downregulation of three p65 target proteins that regulate the metabolic and inflammatory states of the liver (HNF4α, IL-1β, and CRP) in multiple slow-aging mouse models. Together, these data suggest that NF-κB signaling, might be inhibited in liver of multiple varieties of slow aging mice. This establishes p65 as a potential target for novel longevity interventions., Competing Interests: Declarations. Competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

The hippocampus contains many unique cell types, which serve the structure's specialized functions, including learning, memory and cognition. These cells have distinct spatial organization, morphology, physiology, and connectivity, highlighting the importance of transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus in ten adult neurotypical donors to define molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and inferring their expression in the SRT data. We identified NMF patterns that captured transcriptional variation across neuronal cell types and indicated that the response of excitatory and inhibitory postsynaptic specializations were prioritized in different SRT spatial domains. We used the NMF and label transfer approach to leverage existing rodent datasets, identifying patterns of activity-dependent transcription and subpopulations of dentate gyrus granule cells in our SRT dataset that may be predisposed to participate in learning and memory ensembles. Finally, we characterized the spatial organization of NMF patterns corresponding to non- cornu ammonis pyramidal neurons and identified snRNA-seq clusters mapping to distinct regions of the retrohippocampus, to three subiculum layers, and to a population of presubiculum neurons. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications., Competing Interests: Conflict of Interest: Co-Author Erik Nelson is now a full-time employee at GSK, which is unrelated to the contents of this manuscript. His contributions to this manuscript were made while previously enrolled as a student at Johns Hopkins University and performing research at Lieber Institute for Brain Development (LIBD). Co-Author Joel E. Kleinman is a consultant on a Data Monitoring Committee for an antipsychotic drug trial for Merck & Co., Inc. All other authors have no declared conflicts of interests.

Background: Heart failure with preserved ejection fraction (HFpEF) currently accounts for more than half of patients with HF, with limited approved evidence-based therapies. HFpEF is a complex multifactorial disease associated with hypertension, obesity, diabetes, and renal dysfunction. In addition to our limited understanding of HFpEF pathophysiology, the development of new therapies is partially hindered by the existing translationally relevant preclinical HFpEF models., Methods and Results: Here, we report the development of a novel 2-hit HFpEF male mouse model through adding hypertensive stress from the activation of the renin-angiotensin-aldosterone system with adeno-associated viral-renin (AAV-renin), to the metabolic syndrome nonalcoholic steatohepatitis (MSNASH, formerly FATZO) mouse (MSNASH+AAV-renin). To further demonstrate model translatability, MSNASH+AAV-renin mice were then treated with approved HFpEF therapies sacubitril/valsartan or a combination of sacubitril/valsartan and empagliflozin. We found that the MSNASH+AAV-renin mouse model demonstrates clinically relevant features of human HFpEF, including preserved ejection fraction, cardiac hypertrophy, left atrial enlargement, diastolic dysfunction, elevated natriuretic peptides, inflammation, and low exercise capacity. We also demonstrate that treatment with approved HFpEF therapies sacubitril/valsartan and the combination of sacubitril/valsartan with empagliflozin improves the cardiac phenotypes of HFpEF in this model., Conclusions: The MSNASH+AAV-renin model faithfully represents a severe cardiometabolic HFpEF phenogroup that can be used as a new tool for HFpEF preclinical research and drug discovery.

Restricting the intake of protein or the branched-chain amino acid isoleucine promotes healthspan and extends lifespan in young or adult mice. However, their effects when initiated in aged animals are unknown. Here we investigate the consequences of consuming a diet with 67% reduction of all amino acids (low AA) or of isoleucine alone (low Ile), in male and female C57BL/6J.Nia mice starting at 20 months of age. Both dietary regimens effectively promote overall metabolic health without reducing calorie intake. Both low AA and low Ile diets improve aspects of frailty and slow multiple molecular indicators of aging rate; however, the low Ile diet reduces grip strength in both sexes and has mixed, sexually dimorphic effects on the heart. These results demonstrate that low AA and low Ile diets can promote aspects of healthy aging in aged mice and suggest that similar interventions might promote healthy aging in older adults., Competing Interests: Competing interests: D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Invasive primary surgical site infections (IP-SSI) are a severe complication of liver transplant surgery. Identification of risk factors for IP-SSI is critical to IP-SSI prevention., Methods: All adult single liver transplants performed at Duke University Hospital in the period 2015-2020 were reviewed for IP-SSI occurring within 90 d of transplant. Risks for IP-SSI were identified using least absolute shrinkage and selection operator variable selection procedure. A 2-sided P value of <0.05 was considered statistically significant., Results: IP-SSI were identified in 34/470 (7.2%) adult single liver transplants. Repeat transplantation, spilt liver, Roux-en-Y biliary anastomosis, anastomotic leak, and post-transplant renal replacement therapy were positively associated with IP-SSI. IP-SSI were associated with increased length of index transplant hospitalization (24.5 versus 10.0 d, P  < 0.01) and 1-y all-cause mortality (14.7% versus 4.1%, P  = 0.02). Gram positive bacteria were the main pathogens (51.7%), followed by Gram negative bacteria (24.1%) and Candida (24.1%). Multidrug resistance bacteria increased over time (27.3% in 2015 versus 66.7% in 2020, P  = 0.17)., Conclusions: In the setting of routine antimicrobial prophylaxis and an overall low rate of IP-SSI, surgical factors were the main determinants of IP-SSI among adult liver transplant recipients. IP-SSI had a negative impact on the length of index transplant hospitalization and 1-y mortality. While the surgical factors associated with an increased risk of IP-SSI are not easily modifiable, their impact may be best contained by close clinical monitoring and tailored antimicrobial therapy., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Visium is a widely-used spatially-resolved transcriptomics assay available from 10x Genomics. Standard Visium capture areas (6.5mm by 6.5mm) limit the survey of larger tissue structures, but combining overlapping images and associated gene expression data allow for more complex study designs. Current software can handle nested or partial image overlaps, but is designed for merging up to two capture areas, and cannot account for some technical scenarios related to capture area alignment., Results: We generated Visium data from a postmortem human tissue sample such that two capture areas were partially overlapping and a third one was adjacent. We developed the R/Bioconductor package visiumStitched, which facilitates stitching the images together with Fiji (ImageJ), and constructing SpatialExperiment R objects with the stitched images and gene expression data. visiumStitched constructs an artificial hexagonal array grid which allows seamless downstream analyses such as spatially-aware clustering without discarding data from overlapping spots. Data stitched with visiumStitched can then be interactively visualized with spatialLIBD., Conclusions: visiumStitched provides a simple, but flexible framework to handle various multi-capture area study design scenarios. Specifically, it resolves a data processing step without disrupting analysis workflows and without discarding data from overlapping spots. visiumStitched relies on affine transformations by Fiji, which have limitations and are less accurate when aligning against an atlas or other situations. visiumStitched provides an easy-to-use solution which expands possibilities for designing multi-capture area study designs., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Oxidative metabolism declines with aging in humans leading to multiple metabolic ailments and subsequent inflammation. In mice, there is evidence of age-related suppression of fatty acid oxidation and oxidative phosphorylation in the liver, heart, and muscles. Many interventions that extend healthy lifespan of mice have been developed, including genetic, pharmacological, and dietary interventions. In this article, we review the literature on oxidative metabolism changes in response to those interventions. We also discuss the molecular pathways that mediate those changes, and their potential as targets for future longevity interventions., Competing Interests: Declaration of Competing Interest The authors 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 © 2024 Elsevier Inc. All rights reserved.)

Background: Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation., Aim: To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy., Methods: The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted., Results: From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis., Conclusion: HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

Parasitic infections in dairy cattle reduce herd immunity, milk production, and conception rates. This leads to higher production costs, compromised animal welfare, and increased interest in extralabel drug use. The extralabel use of anthelmintics poses food safety risks for consumers since appropriate withdrawal intervals in milk have yet to be established. Although topical eprinomectin has no milk withdrawal time, more research is needed to determine the residues present in milk after subcutaneous administration. This study aimed to characterize the pharmacokinetics of injectable eprinomectin in dry dairy cows. We hypothesized that, when given at the labeled dose, eprinomectin residues in dry dairy cattle would be below the FDA milk tolerance at the onset of lactation. Plasma was collected daily from 13 mature dairy cattle for 7 days postadministration, followed by periodic samples for 90 days. After calving, milk was collected daily until 90 days. Eprinomectin concentrations were measured using HPLC-fluorescence detection. The maximum eprinomectin concentration in plasma and milk was approximately 36 ng/mL 43 h after administration and 3 ng/mL at the onset of lactation, respectively. The low eprinomectin levels in milk collected from these lactating dairy cattle suggest that administering eprinomectin at dry-off is unlikely to result in violative residues. However, subcutaneous eprinomectin in lactating dairy cattle would be hard to justify unless there is evidence that the approved topical formulation is clinically ineffective., (© 2024 The Author(s). Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.)

The amygdaloid complex mediates learning, memory, and emotions. Understanding the cellular and anatomical features that are specialized in the amygdala of primates versus other vertebrates requires a systematic, anatomically-resolved molecular analysis of constituent cell populations. We analyzed five nuclear subdivisions of the primate amygdala with single-nucleus RNA sequencing in macaques, baboons, and humans to examine gene expression profiles for excitatory and inhibitory neurons and confirmed our results with single-molecule FISH analysis. We identified distinct subtypes of FOXP2 + interneurons in the intercalated cell masses and protein-kinase C-δ interneurons in the central nucleus. We also establish that glutamatergic, pyramidal-like neurons are transcriptionally specialized within the basal, lateral, or accessory basal nuclei. Understanding the molecular heterogeneity of anatomically-resolved amygdalar neuron types provides a cellular framework for improving existing models of how amygdalar neural circuits contribute to cognition and mental health in humans by using nonhuman primates as a translational bridge., Competing Interests: CONFLICT OF INTEREST No conflicts of interest to declare.

Purine stretches, sequences of adenine (A) and guanine (G) in DNA, play critical roles in binding regulatory protein factors and influence gene expression by affecting DNA folding. This study investigates the relationship between purine stretches and cancer development, considering the aromaticity of purines, quantified by methods like Hückel's rule and NICS calculations, and the importance of the flanking sequence context. A pronounced avoidance of long purine stretches by typical cancer mutations was observed in public data on the intergenic regions of cancer patients, suggesting a role of intergenic sequences in chromatin reorganization and gene regulation. A statistically significant shortening of purine stretches in cancerous tumors ( p value < 0.0001) was found. The insights into the aromatic nature of purines and their stacking energies explain the role of purine stretches in DNA structure, contributing to their role in cancer progression. This research lays the groundwork for understanding the nature of purine stretches, emphasizing their importance in gene regulation and chromatin restructuring, and offers potential avenues for novel cancer therapies and insights into cancer etiology.

Here, we present a case of a healthy young man with an initial presentation concerning for infectious encephalitis later found on neuroimaging to have extensive intracranial lesions. Pathological analysis of these lesions was consistent with a bacterial intraparenchymal abscess; however, cultures were negative for a causative organism. Results of gene sequencing from an abscess sample were consistent with Streptococcus intermedius infection. Streptococcus intermedius , a β-hemolytic gram-positive species of the Streptococcus anginosus group (SAG), is known to possess several virulence factors that promote abscess formation., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Miller et al.)

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and metabolic homeostasis. Recent studies have shown that a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are affected by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control., (© 2024. The Author(s).)

Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH&#95;Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH&#95;Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Dietary restriction (DR) and hypoxia (low oxygen) extend lifespan in Caenorhabditis elegans through the induction of a convergent downstream longevity gene, fmo-2. Flavin-containing monooxygenases (FMOs) are highly conserved xenobiotic-metabolizing enzymes with a clear role in promoting longevity in nematodes and a plausible similar role in mammals. This makes them an attractive potential target of small molecule drugs to stimulate the health-promoting effects of longevity pathways. Here, we utilize an fmo-2 fluorescent transcriptional reporter in C. elegans to screen a set of 80 compounds previously shown to improve stress resistance in mouse fibroblasts. Our data show that 19 compounds significantly induce fmo-2, and 10 of the compounds induce fmo-2 more than twofold. Interestingly, 9 of the 10 high fmo-2 inducers also extend lifespan in C. elegans. Two of these drugs, mitochondrial respiration chain complex inhibitors, interact with the hypoxia pathway to induce fmo-2, whereas two dopamine receptor type 2 (DRD2) antagonists interact with the DR pathway to induce fmo-2, indicating that dopamine signaling is involved in DR-mediated fmo-2 induction. Together, our data identify nine drugs that each (1) increase stress resistance in mouse fibroblasts, (2) induce fmo-2 in C. elegans, and (3) extend nematode lifespan, some through known longevity pathways. These results define fmo-2 induction as a viable approach to identifying and understanding mechanisms of putative longevity compounds., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background: Adequate skill levels of gross motor capacity affect activities of daily living, participation in recreational activities and general physical activity levels of youths (7-21 years). Most studies of typically developing youths have reported significant negative relationships between gross motor capacity and body mass index. The latter findings are especially of concern for youths with intellectual disabilities in that it has been estimated that 61% of children and 66% of adolescents were classified as overweight/obese. Therefore, the purpose of this study was to determine the strength of the relationship between body mass index and gross motor capacity among youths with mild to moderate intellectual disability (ID)., Methods: Components of the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) were used for designated aspects of gross motor capacity: six items for upper limb coordination (ULC); seven items for balance (BAL); six items for bilateral coordination (BLC); and one item for agility (A-2). Participants consisted of 654 youths (438 men), ages 8-21 years with ID. Participants were divided into pre-puberty and post-puberty men (post ≥12 years) and women (post ≥10 years of age). Body mass index (BMI, kg/m 2 ) was determined by height and weight measurements on the day of testing. A Kendall's tau correlation coefficient (τ) was used to determine the strength of the relationship between body mass index and gross motor capacity (BOT-2 test scores)., Results: The τ values for both pre-puberty and post-puberty for all BAL, BLC, A-2 tests and for three of the six ULC tests were negligible to very weak (τ = 0 to ±0.19). Higher τ values were seen for pre-puberty youths in three of the ULC tests, but they fell within the weak range (τ < 0.24). When combining all pre-puberty and post-puberty participants, τ values were in the negligible to very weak range for all tests., Conclusion: The strength of relationship between body mass index and gross motor capacity as measured by the BOT-2 subtest item scores used in this study is very weak and suggests that they are not clinically relevant., (© 2024 John Wiley & Sons and MENCAP.)

The lateral septum (LS) is a midline, subcortical structure, which regulates social behaviors that are frequently impaired in neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Mouse studies have identified neuronal populations within the LS that express a variety of molecular markers, including vasopressin receptor, oxytocin receptor, and corticotropin releasing hormone receptor, which control specific facets of social behavior. Despite its critical role in regulating social behavior and notable gene expression patterns, comprehensive molecular profiling of the human LS has not been performed. Here, we conducted single nucleus RNA-sequencing (snRNA-seq) to generate the first transcriptomic profiles of the human LS using postmortem human brain tissue samples from 3 neurotypical donors. Our analysis identified 5 transcriptionally distinct neuronal cell types within the human LS that are enriched for TRPC4 , the gene encoding Trp-related protein 4. Differential expression analysis revealed a distinct LS neuronal cell type that is enriched for OPRM1 , the gene encoding the μ-opioid receptor. Leveraging recently generated mouse LS snRNA-seq datasets, we conducted a cross-species analysis. Our results demonstrate that TRPC4 enrichment in the LS is highly conserved between human and mouse, while FREM2, which encodes FRAS1 related extracellular matrix protein 2, is enriched only in the human LS. Together, these results highlight transcriptional heterogeneity of the human LS, and identify robust marker genes for the human LS., Competing Interests: CONFLICT OF INTEREST The authors do not report any conflict of interest.

Despite the blockbuster popularity of drugs that act on catecholamine receptors, catecholamine dynamics in human health and disease remain an incomplete picture. Recent advances in fluorescent sensors have enabled unprecedented access to catecholamine dynamics in preclinical animal models, but the requirements of these technologies limit translational value for clinical diagnostics. Here, we present a flexible and convenient tool for fluorescent catecholamine detection by functionalizing optical fibers with single-walled carbon nanotube (SWNT)-based near-infrared catecholamine sensors (nIRCats), a form factor that has potential for more convenient and less invasive clinical translation. We show that these near-infrared functionalized (nIRF) fibers respond to dopamine in a biologically-relevant concentration range (10nM through 1 μM) with a mean ΔF/F0 of 0.022 through 0.411, with no statistically significant effect on signal magnitude after 16-hour exposure to human blood plasma. We further demonstrate the utility of these fibers in as little as 10 μL volumes of clinically relevant biofluids up to 24 weeks after preparation, with a ΔF/F0 of up to 0.059 through 1.127 for 10 nM through 1 μM dopamine. We also introduce a compact, mobile dual-near-infrared fiber photometry rig and demonstrate its success detecting dopamine with 0.005 ΔF/F0 in acute brain slices with nIRF fibers. Together, this fiber-based tool and photometry rig expand the toolbox of catecholamine detection technologies to a broader range of applications.

We evaluated use of maribavir (MBV) for treatment of 15 episodes of refractory/resistant cytomegalovirus infection in 13 solid organ transplant recipients. Treatment failure due to treatment-emergent MBV resistance or early virological recurrence after MBV discontinuation occurred in 7 (47%) episodes. Sustained viral clearance was achieved in 6 (40%) episodes., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium., Methods: We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging., Results: Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance., Conclusions: Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes., (© 2024. The Author(s).)

This study identified 26 late invasive primary surgical site infection (IP-SSI) within 4-12 months of transplantation among 2073 SOT recipients at Duke University Hospital over the period 2015-2019. Thoracic organ transplants accounted for 25 late IP-SSI. Surveillance for late IP-SSI should be maintained for at least one year following transplant.

The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we investigated age-associated changes in transcriptome-wide spatial gene expression in the human dentate gyrus across the lifespan. Genes associated with neurogenesis and the extracellular matrix were enriched in infants, while gene markers of inhibitory neurons and cell proliferation showed increases and decreases in post-infancy, respectively. While we did not find evidence for neural proliferation post-infancy, we did identify molecular signatures supporting protracted maturation of granule cells. We also identified a wide-spread hippocampal aging signature and an age-associated increase in genes related to neuroinflammation. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.

The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics., (© 2023. The Author(s).)

Purpose: To determine if there is a homogeneity of scores for youth with intellectual disability (ID) with and without Down syndrome (DS) in 19 test items of motor competence from the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition (BOT-2). Homogeneity was defined as the means for each of the 19 test items scores by sex and the presence or absence of DS sharing the same population mean., Method: Participants were 622 youth with ID aged 6 to 21 years. Items for bilateral coordination, balance, and upper limb coordination were examined using the BOT-2., Results: For all 19 BOT-2 items, means between youth with and without DS did not differ from the population mean., Conclusion: These results potentiate the development of expected BOT-2 motor competence scores for youth with ID independent of the presence of DS for clinical practice., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in writing of the manuscript; and in the decision to publish the results., (Copyright © 2024 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species. To investigate the effect of long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro , the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.

Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks., Competing Interests: Andrew S. Barbas: scientific advisory board for BioMedInnovations.

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging., (© 2023. The Author(s).)