Research square最新文献

{"title":"Reinfection with a Bacterial Pathogen Augments Heterogeneity in Host Disease Responses.","authors":"Jesse Garrett-Larsen, Anna Pérez-Umphrey, Arietta Fleming-Davies, James Adelman, Lauren Childs, Steven Geary, Kate Langwig, Dana Hawley","doi":"10.21203/rs.3.rs-6856045/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6856045/v1","url":null,"abstract":"<p><p>Individual responses to infection are often highly heterogeneous within host populations, with key consequences for transmission dynamics and pathogen evolution. Because re-exposure to pathogens is ubiquitous, understanding how priming exposures to a given pathogen alter inter-individual heterogeneity in immune responses and transmission-relevant traits is critical. Recent work in house finches ( <i>Haemorhous mexicanus</i> ) found that priming exposures to the bacterial pathogen <i>Mycoplasma gallisepticum</i> augment population-level heterogeneity in susceptibility to infection. However, it remains unclear whether priming exposures exacerbate heterogeneity in both underlying immune responses and transmission-relevant traits during reinfection. Using wild-caught, pathogen-naïve house finches, we experimentally tested whether priming with a low or high dose of <i>Mycoplasma gallisepticum</i> affects population-level heterogeneity in antibody responses, pathogen loads, and disease responses upon reinfection. We find that any prior exposure results in more heterogeneous antibody responses, and more variable pathogen loads upon reinfection. Further, the detected patterns in antibody variability with prior exposure match previously documented patterns of population-level heterogeneity in susceptibility upon secondary challenge, suggesting that variability in antibody responses within a population can be a relevant proxy for heterogeneity in susceptibility. Overall, we show that prior exposure to pathogens contributes to subsequent heterogeneity in transmission-relevant traits, with implications for downstream infection dynamics.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world Diagnostic Value of Integrating Oral and Ocular Dryness Testing in Suspected Sjögren's Disease.","authors":"Brandon M Law, Eman Seyal, Jesse Akaa, David O'Dea, Thao Nguyen, Rahmatullah W Rahmati","doi":"10.21203/rs.3.rs-7011813/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-7011813/v1","url":null,"abstract":"<p><p><b>Background</b> : Sjögren's disease is an autoimmune condition requiring a systemic evaluation that integrates serologic, histopathologic, and glandular assessments for diagnosis. Current 2016 ACR/EULAR classification criteria includes anti-Ro serology, labial salivary gland biopsy (LSGB), and measures of oral/ocular dryness. However, oral/ocular dryness evaluations are rarely performed by rheumatologists during routine clinical care. Thus, the real-world diagnostic value of contemporaneous oral/ocular dryness testing remains poorly understood. <b>Objective</b> : To evaluate the incremental value of contemporaneous testing of oral/ocular dryness (Schirmer's test and unstimulated whole salivary flow) in meeting classification criteria for subjects evaluated with suspected Sjögren's disease. <b>Methods</b> : 73 subjects referred for suspected Sjögren's disease were evaluated. Correlations between LSGB results and dryness tests, as well as LSGB results and anti-Ro serology, were evaluated. 31 subjects completed testing of oral/ocular dryness (Schirmer's test and unstimulated whole salivary flow), anti-Ro serology, and LSGB. Diagnostic pathways were analyzed to assess the contributions of non-invasive tests (serologies and oral/ocular dryness tests) and invasive testing (LSGB) in meeting the threshold for classification criteria. <b>Results</b> : A significant association ( <i>p</i> -value = 0.0263) was observed between LSGB positivity and positive Schirmer's testing. No significant association was observed between LSGB positivity and anti-Ro positivity, or between LSGB positivity and low unstimulated whole salivary flow. Among those classified, 81% (30/37) met classification independently of LSGB results. Of those who completed testing, 22 met classification criteria for Sjögren's disease, among whom 68% (15/22) fulfilled criteria independently of LSGB results. Of these 15 subjects, 8 (53%) had negative LSGB with a focus score < 1. While a positive LSGB was mandatory to confirm classification for seronegative subjects, only 11.8% (2/17) of anti-Ro-positive subjects required LSGB for classification. <b>Conclusion</b> : Objective oral/ocular dryness testing, though rarely performed in routine rheumatologic care, is a valuable complement to serology and biopsy in diagnosing Sjögren's disease. While LSGB is essential for confirming classification in anti-Ro-negative subjects, it adds only modest value to meeting classification criteria in anti-Ro-positive subjects relative to contemporaneous glandular dryness testing. These findings support integrating objective dryness measures into routine diagnostic workflows to reduce reliance on invasive biopsies and improve diagnostic accuracy, especially in seropositive populations.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ORF3a is a key driver of maternal SARS-CoV-2 infection-associated placental dysfunction.","authors":"Indira Mysorekar, Deepak Kumar, Eliza McColl, Rowan Karvas, Brittany Jones, Long Tran, Emily Diveley, Sukanta Jash, Surendra Sharma, Jeannie Kelly, Thorold Theunissen","doi":"10.21203/rs.3.rs-6857689/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6857689/v1","url":null,"abstract":"<p><p>SARS-CoV-2 infection during pregnancy is associated with an increased risk of pre-eclampsia (PE), a hypertensive disorder, but the molecular mechanisms remain poorly understood. Here, we identify ORF3a, a SARS-CoV-2 accessory protein, as a key factor in placental dysfunction, driving autophagy dysregulation, trophoblast maturation impairment, protein aggregation and placental barrier disruption- processes linked to PE. We detect ORF3a in placentas from women infected with SARS-CoV-2 along with increased protein aggregation and disrupted tight junctions in ORF3a + regions. In placental cell lines, ORF3a impairs syncytiotrophoblast maturation and induces protein aggregation. Mechanistically, ORF3a binds to ZO-1 via its PDZ-binding motif (SVPL), and deletion of this domain from ORF3a abrogates its effect on trophoblast barrier integrity. In human trophoblast cells engineered with an LC3-GFP-mCherry reporter, ORF3a induces autophagosome accumulation, and shifts autophagy toward a secretory pathway with elevated levels of CD63 + extracellular vesicles and disrupted ZO-1 localization, all of which are recapitulated by live infection with the SARS-CoV-2 Delta variant. These ORF3a-dependent changes are fully recapitulated in 3D stem-cell-derived trophoblast organoids (SC-TOs). Together, our findings define a molecular mechanism by which SARS-CoV-2 infection compromises placental syncytial integrity. Targeting ORF3a may provide a therapeutic strategy to mitigate PE-like placental dysfunction in SARS-CoV-2-infected pregnancies.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High connectivity and low differentiation of Plasmodium falciparum parasite populations in a setting with high seasonal migration.","authors":"Endashaw Esayas, William Louie, Isobel Routledge, Maxwell Murphy, Nigatu Negash Demeke, Faith De Amaral, Andrés Aranda-Díaz, Bryan Greenhouse, Fikregabrail Aberra Kassa, Tedros Nigusse, Muluken Assefa, Temesgen Ashine, Asefaw Getachew, Henry Ntuku, Lemu Golassa, Endalamaw Gadisa, Adam Bennett, Jennifer L Smith","doi":"10.21203/rs.3.rs-6771360/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6771360/v1","url":null,"abstract":"<p><p>Seasonal movement of less-immune people from low- to high- transmission regions increases malaria risk and may introduce parasite strains to both areas. This study examined Plasmodium falciparum genetic diversity and connectivity between low-transmission highlands and endemic lowlands in Ethiopia to assess the contribution of seasonal agricultural migration in sustaining transmission. P. falciparum qPCR-positive dried blood spots collected from highland health facilities and lowland agricultural worksites were sequenced using multiplexed amplicon sequencing. Complexity of infection (COI) and infection pairwise relatedness were estimated and used for clustering analysis. Lowland populations (seasonal workers and local residents) had higher COI and polyclonal infection rates (mean COI 2.62, 60%, n=581) than highland residents (mean COI 2.00, 42%, n=599). Similar expected heterozygosity (He ≈0.4) was observed, and P. falciparum infections from worksites showed high genetic connectivity between highland and lowland populations, with extensive parasite sharing, including 27 identical clusters in highland cases and 12 in seasonal workers. Integrating parasite genomic data with epidemiological information revealed strong connectivity and low genetic differentiation between these regions linked by seasonal migration. These findings highlight how agricultural mobility likely drives parasite diversity and gene flow, implicating its role in sustaining malaria transmission.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glymphatic System Impairment in Type II Diabetes Mellitus Adults.","authors":"Bhaswati Roy, Veronica Lubera, Kamal R Singh, Anshita Singh, Megan Carrier, Sarah E Choi, Matthew J Freeby, Rajesh Kumar","doi":"10.21203/rs.3.rs-6467065/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6467065/v1","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is associated with multiple systemic complications, including cognitive decline and increased risk of neurodegenerative diseases. The glymphatic system, a brain waste clearance pathway, can be impaired from sleep disturbances common in T2DM, has not been examined. Therefore, the aim was to evaluate glymphatic system in T2DM subjects using diffusion tensor imaging along the perivascular space (DTI-ALPS) index. A total of 78 T2DM adults and 106 healthy controls underwent for brain MRI. Sleep issues were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), and cognition with the Montreal Cognitive Assessment (MoCA). Group differences in DTI-ALPS, sleep metrics, and MoCA scores were assessed with analysis of covariance (covariates, age, sex, and BMI). T2DM patients exhibited higher PSQI (p = 0.03) and ESS (p = 0.004), reflecting poorer sleep quality and increased daytime sleepiness. MoCA scores were significantly lower in T2DM adults (p = 0.001), with impairments emerged in visuospatial skills, attention, and language. Also, significantly reduced DTI-ALPS values appeared in T2DM over controls (p = 0.003). T2DM adults show impaired glymphatic function along with poor sleep quality and day-time issues. The findings indicate that glymphatic dysfunction potentially-driven by metabolic, vascular, and sleep-related disturbances may exacerbate cognitive deficits in T2DM adults.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmarking the Builders: A Comparative Analysis of PRosettaC and AlphaFold3 for Predicting PROTAC Ternary Complexes.","authors":"Joseph M Schulz, Sarah I Schürer, Robert C Reynolds, Stephan C Schürer","doi":"10.21203/rs.3.rs-6866610/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6866610/v1","url":null,"abstract":"<p><p>Targeted protein degradation via PROTACs offers a promising therapeutic strategy, yet accurate modeling of ternary complexes remains a critical challenge in degrader design. In this study, we systematically benchmark two leading structure prediction tools, AlphaFold3 and PRosettaC, against a curated dataset of 36 crystallographically resolved ternary complexes. Using DockQ as a quantitative interface scoring metric, we assess the structural fidelity of predicted complexes under both scaffold-inclusive and stripped configurations. Our results demonstrate that AlphaFold3's performance is often inflated by accessory proteins such as Elongin B/C or DDB1, which contribute to overall interface area but not degrader-specific binding. PRosettaC, on the other hand, leverages chemically defined anchor points to yield more geometrically accurate models in select systems, though it frequently fails when linker sampling is insufficient or misaligned. To overcome the limitations of static benchmarking, we introduce a dynamic evaluation strategy using molecular dynamics simulations of the crystal structures. This frame-resolved analysis reveals that several PRosettaC models, while poorly aligned to the static crystal conformation, transiently achieve high DockQ alignment with specific frames along the MD trajectory. These findings underscore the importance of incorporating protein flexibility into benchmarking workflows and suggest that transient conformational compatibility may be overlooked in conventional evaluations. By combining constraint-based modeling with dynamic frame matching, this study provides a more nuanced framework for assessing ternary complex predictions and informs the selection of <i>in silico</i> tools for rational PROTAC development.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of a clinical decision support algorithm (CDSA) on reducing unnecessary antibiotic prescriptions for upper respiratory tract infections among ambulatory HIV-infected adults in Mozambique: a cluster randomized controlled trial.","authors":"Candido Faiela, Moon Troy D, Gustavo Amorim, Mohsin Sidat, Esperança Sevene","doi":"10.21203/rs.3.rs-6972996/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6972996/v1","url":null,"abstract":"<p><p><b>Background:</b> Antibiotics are widely overprescribed to treat upper respiratory tract infections (URTIs), even though viruses cause most URTIs. We evaluated the effectiveness of a clinical decision support algorithm (CDSA)- based intervention in reducing antibiotic prescriptions among ambulatory HIV-infected adult patients with acute URTI symptoms. <b>Methods:</b> Between June and September 2024, we conducted a multicenter, two-arm parallel, cluster-randomized controlled trial in six primary healthcare facilities in Mozambique. The intervention included applying the CDSA, educating and supervising clinicians, and conducting prescription audits. We used Pearson's chi-square test and relative risk to assess the effectiveness of the intervention in reducing antibiotic prescribing. <b>Results:</b> Three hundred seventy-nine (97.9%) HIV-infected adult patients with URTI symptoms were recruited, 182 (48%) in the intervention arm and 197 (52%) in the control. Most were females (75.5%) and single (57%). Most appeared with common cold and flu-like symptoms. Participants in the intervention arm were less likely to receive an antibiotic prescription (RR 0.41, 95% CI: 0.31 - 0.55) and develop a complication (RR 0.44, 95% CI: 0.16 - 1.20) than those not exposed. The antibiotic prescribing rate was 23.1% for the intervention and 56.3% for the control. The intervention was associated with a significant reduction in antibiotic prescribing by 33.2% (p < 0.001) and a non-significant decrease in incidence of complications by 3.7% (p = 0.096). In both arms, most patients (78%) recovered completely within five days. Amoxicillin (47.8%), azithromycin (21.9%), and phenoxymethylpenicillin (14.1%) were the most prescribed antibiotics. <b>Conclusions:</b> Our CDSA, coupled with education and audits with feedback, effectively reduced antibiotic usage. Furthermore, withholding antibiotics for URTIs did not increase the incidence of complications. The intervention worked in our six sites, but larger studies must be performed with our CDSA across Mozambique to see if these findings also hold up elsewhere. <b>Trial registration:</b> ISRCTN, ISRCTN88272350. Registered 16 May 2024, https://www.isrctn.com/ISRCTN88272350.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enkephalinergic Neurons in Barrington's Nucleus Gate Sex-Specific Control of Micturition.","authors":"Anne Verstegen, Nataliya Klymko, Andrea Sartori, Mihoko Leon, Cassandra Seifert, Richard Lee, John Mathai","doi":"10.21203/rs.3.rs-6940959/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6940959/v1","url":null,"abstract":"<p><p>Lower urinary tract (LUT) control is a vital physiological function governed by a complex interplay between neural circuits and muscle activity. This regulation depends on brainstem circuits, with Barrington's nucleus (Bar) acting as a central hub. Here, we construct a transcriptional atlas of Bar, uncovering its neuronal diversity and extensively characterize a distinct excitatory population expressing proenkephalin (Bar-Penk). Using in vivo calcium imaging and optogenetics, we demonstrate that Bar-Penk neurons selectively activate during voiding and specifically facilitate external urethral sphincter (EUS) relaxation. Chemogenetic activation of these neurons elicits an aberrant micturition phenotype in male but not female mice, whereas conditional ablation impairs voluntary scent-marking behavior. Moreover, anatomical tracing reveals that Bar-Penk neurons project to spinal regions critical for LUT control and receive convergent input from areas involved in visceromotor regulation and behavioral state processing. These findings position Bar-Penk as a specialized brainstem population that integrates internal states and environmental cues to orchestrate context-dependent urinary behaviors in a sex-specific manner.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of Perfluoroalkyl substances (PFAS) with terminal ductal lobular unit involution of the normal breast.","authors":"Katherine W Reeves, Youssef Oulhote, Philippe Grandjean, Flemming Nielsen","doi":"10.21203/rs.3.rs-6829962/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6829962/v1","url":null,"abstract":"<p><p>Background Per- and polyfluoroalkyl substances (PFAS) may be carcinogenic, and animal studies demonstrate their harmful effects on mammary gland development. Terminal ductal lobular units (TDLUs) are the structures that produce milk following childbirth, and involution of TDLUs normally occurs with aging. Most breast cancers arise from TDLUs, and a greater degree of TDLU involution is associated with lower breast cancer risk. We estimated associations between PFAS concentrations and TDLU involution in normal breast tissue samples. Methods Concentrations of seven PFAS were measured in serum provided by a subset of 263 healthy volunteer participants from the Susan G. Komen for the Cure Tissue Bank (KTB) who were postmenopausal, not currently using hormone therapy, and had available TDLU measurements. Bayesian kernel machine regression and quantile-G computation were used to estimate covariate-adjusted associations between the PFAS mixture and measures of TDLU involution (presence of TDLUs, number of observed TDLUs, and median TDLU span) within this population and with stratification on parity and breastfeeding history. Results Distributions of PFAS were similar between participants with (N = 106) and without (N = 157) observed TDLUs. No strong, statistically significant associations were observed between individual PFAS and presence of observed TDLUs. The overall effect of the PFAS mixture suggested an inverted U-shaped association with odds of observed TDLUs, although this was not statistically significant. Among the subgroup of parous women, stratified analyses suggested a positive association between the PFAS mixture and observed TDLUs among those who had ever breastfed, but a slightly negative association among those who had never breastfed. Conclusions Overall, our analysis does not support meaningful effects of PFAS on TDLU involution, although we note that these findings are not applicable to premenopausal women or to postmenopausal women using hormone therapy.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CEST MRI Affirms HIV-1-Associated Neurometabolic Impairments in a Humanized Mouse Model.","authors":"Gabriel C Gauthier, Micah Summerlin, Balasrinivasa R Sajja, Mariano G Uberti, Emma G Foster, Manjeet Kumar, Matthew Thiele, Santhi Gorantla, Aditya N Bade, Yutong Liu","doi":"10.21203/rs.3.rs-6821484/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6821484/v1","url":null,"abstract":"<p><p>Purpose Human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND) persist in people living with HIV-1 (PLWH) despite antiretroviral therapy (ART), driven by unresolved neuroinflammation and metabolic dysfunction. This study evaluates chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) detection of HIV-1-induced neurometabolic impairments and ART-mediated improvements in a humanized mouse model. Methods HIV-1-infected CD34-NSG mice (n = 14) underwent CEST MRI to quantify metabolic profiles in the cortex, hippocampus, hypothalamus, piriform cortex, and thalamus at three timepoints: pre-infection (Week 0), 6 weeks-post-infection (WPI), and after 6 weeks of ART- or vehicle-treatment (12 WPI). CEST contrasts were analyzed at 2 ppm (creatine), 3 ppm (glutamate), and - 3.5 ppm (nuclear Overhauser effect, NOE). Neuroinflammation and infection were confirmed using immunohistology and qPCR. Results At 6 WPI, HIV-1-infection reduced creatine in the cortex (p = 0.0006) and hippocampus (p = 0.01), and elevated NOE in the cortex (p = 0.001). At 12 WPI, vehicle-treated HIV-infected mice exhibited significantly decreased glutamate in the cortex (p = 0.004), hippocampus (p < 0.0001), and piriform cortex (p = 0.002); ART-treatment restored these levels in the cortex and hippocampus. Further, vehicle-treated mice exhibited decreased creatine in the cortex (p = 0.0002), hippocampus (p = 0.0003), piriform cortex (p = 0.0009), and thalamus (p = 0.006); ART-treatment restored these levels in the hippocampus, piriform cortex, and thalamus. Finally, vehicle-treated mice exhibited increased NOE in the cortex (p = 0.002) and thalamus (p = 0.003), but this was not restored by ART. CEST findings were supported by reductions in HIV-1 p24 + cells and neuroinflammatory markers in ART-treated brains. Discussion CEST MRI detects region-specific HIV-1-induced neurometabolic alterations and ART-mediated restorations. This work establishes CEST MRI as a translational potential, non-invasive technique for monitoring HAND pathology and therapeutic efficacy.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}