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Recent literature has reported neurodevelopmental changes in spinal muscular atrophy (SMA) type 1, especially autism spectrum disorder (ASD). Furthermore, previous reports before the advent of disease-modifying therapies suggested brain involvement in 5q-SMA. In this work, we present five SMA type 1 and pre-symptomatic patients with two copies of SMN2 who presented neurodevelopmental disorders and were submitted to brain MRI with DTI (diffusion tensor imaging). These patients presented with abnormalities in the white matter of the frontal lobes on brain MRI, which correlates with less representation association fibers (superior longitudinal fasciculus) on DTI. Brain involvement in SMA type 1 may occur even in patients treated with new disease-modifying therapies, and its correlation with neurodevelopmental disorders remains an open question. [ABSTRACT FROM AUTHOR]

Abnormal dystrophin proteins (Dps) in Duchenne muscular dystrophy (DMD) are known to alter retinal electrophysiology, but their repercussion on visual functions have not been investigated in detail. In the present study we investigated whether different Dps influence vision by measuring psychophysical dark-adapted visual thresholds driven by cone and rod photoreceptors in DMD patients with different genetic backgrounds. Control group comprised 28 healthy volunteers (mean age=17.9±6.5 years). DMD groups were 29 patients (mean age=14.9±4.4 years) divided in three genetic groups depending on presumable affected Dps: group 1 (only Dp427 affected), group 2 (Dp427+Dp260+Dp140 affected) and group 3 (all Dps affected). Visual detection thresholds to 625-nm (red, cone-driven) and 527-nm (green, rod-dominated) flashes of 2° were measured during dark adaptation after 1-minute exposure to a bleaching light (3000 cd/m2). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes. Control thresholds were -1.7 ± 0.4 (cone) and -4.2 ± 0.2 (rod) log cd/m². Affected Dp427 alone (group 1) was not sufficient to alter visual thresholds (p = 0.28 cone and p = 0.48 rod) while affected Dp427+Dp260+Dp140 (group 2) caused elevated rod thresholds (-3.4 ± 0.9 log cd/m², p < 0.01). Interestingly, patients with presumable alteration of all retinal Dps (Dp427+Dp260+Dp140+Dp71, group 3) showed visual thresholds similar to controls (cone: -2.4 ± 1.4 and rod: -3.9 ± 0.4 log cd/m², p = 0.99). Affected retinal dystrophins are associated with alterations of the visual detection thresholds in DMD patients besides their well-known associations with retinal electrophysiology. It is worthy to highlight that the visual thresholds of the patients with all Dps affected (presumably) were similar to control thresholds despite the alteration of Dp260+Dp140. We speculate that compensatory mechanisms may be operating in the retina of DMD patients presumably lacking all Dps. [ABSTRACT FROM AUTHOR]

Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Infectious diseases are among the strongest selective pressures driving human evolution 1,2 . This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis 3 . This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population 4 . To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The aim of this study was to compare the fractal dimension (FD) measured at 2 bone sites (second cervical vertebra and mandible) on cone-beam computed tomography (CBCT). The research question was whether FD could serve as an accessory tool to refer postmenopausal women for densitometric analysis. Therefore, the reliability and accuracy of FD were evaluated., Materials and Methods: In total, 103 postmenopausal women were evaluated, of whom 52 had normal bone mineral density and 51 had osteoporosis, according to dual X-ray absorptiometry of the lumbar spine and hip. On the CBCT scans, 2 regions of interest were selected for FD analysis: 1 at the second cervical vertebra and 1 located at the mandible. The correlations between both measurements, intra- and inter-observer agreement, and the accuracy of the measurements were calculated. A P value less than 0.05 was considered to indicate statistical significance for all tests., Results: The mean FD values were significantly lower at the mandibular region of interest in osteoporotic patients than in individuals with normal bone mineral density. The areas under the curve were 0.644 ( P =0.008) and 0.531 ( P =0.720) for the mandibular and vertebral sites, respectively., Conclusion: FD at the vertebral site could not be used as an adjuvant tool to refer women for osteoporosis investigation. Although FD differed between women with normal BMD and osteoporosis at the mandibular site, it demonstrated low accuracy and reliability., Competing Interests: Conflicts of Interest: None, (Copyright © 2022 by Korean Academy of Oral and Maxillofacial Radiology.)

Objectives: To verify radiomorphometric indices and fractal dimension (FD) in dental panoramic radiographs (DPRs) of children with different types of osteogenesis imperfecta (OI) and also to verify the effect of pamidronate (PAM) treatment in such panoramic analyses., Methods: In this retrospective study, 197 DPRs of 62 children with OI Types I, III and IV who were in treatment with a comparable dosage of intravenous PAM were selected. The mandibular cortical width (MCW), mandibular cortical index, visual estimation of the cortical width and FD of three standardized trabecular and cortical mandibular regions of interest were obtained from the radiographs. Factorial analysis of variance and Fisher test were used to compare FD and MCW measurements in children with different types of OI for different PAM cycles., Results: Children with all types of OI have thinner and more porous mandibular cortices at the beginning of treatment. There were significant differences between MCW and FD of the cortical bone, regarding different types of OI and number of PAM cycles (p = 0.037 and p = 0.044, respectively). FD measurements of the trabecular bone were not statistically different among OI types nor were PAM cycles (p > 0.05)., Conclusions: Children with OI presented cortical bone alterations after PAM treatment. Both MCW and the FD of the cortical bone were higher in children with OI after PAM treatment. It is argued that cortical bone should be considered for analyzing patients with OI, as well as to monitor the progress of PAM treatment.

Objective: To verify whether fractal dimensions (FD) on the mandibular trabecular and cortical bone and mandibular cortical width (MCW) differ between patients with normal bone mineral density (BMD) and osteoporosis., Study Design: In this retrospective study, 133 dental panoramic radiographs from men aged >60 years and postmenopausal women with a bone densitometry report of the lumbar spine and hip classified as either normal or osteoporotic were selected. Fractal dimensions of five standardized trabecular and cortical mandibular regions of interest and mandibular cortical width were measured on the panoramic radiographs by an experienced oral radiologist, blinded to the densitometric diagnosis. The following statistical analyses were performed: ANOVA and a forward logistic stepwise regression to verify associations between dental panoramic measurements and the densitometric diagnosis. P values less than .05 indicated statistical significance., Main Outcome Measures: Fractal dimension and mandibular cortical width., Results: Differences were found in the FD values on mandibular cortical bone and MCW between patients with normal BMD and with osteoporosis, but not in the FD values of trabecular bone. The odds of having lower mean values of MCW and FD on cortical bone were 2.16, 3125 and 1005 times in osteoporotic patients, respectively, compared with patients with normal BMD., Conclusion: The values of FD analysis on mandibular cortical bone and MCW were lower in women with osteoporosis. A well-adjusted logistic regression model showed that cortical bone measurements might be considered as auxiliary tools to referring patients for DXA exam., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)