Biology subjects

Jahn, A.

Publications and source records attributed to Jahn, A..

11 recordsLinked to original sources

bioRxiv2026

Fixel-wise Differences in White Matter Fiber-bundle Cross-section identified in Children who Stutter

Developmental stuttering has been repeatedly linked to decreased white matter integrity and structural connectivity differences in major white matter tracts. Prior diffusion-weighted MRI studies reporting such white matter structural differences involved voxel-averaged tensor measures (e.g., fractional anisotropy (FA)). A well-acknowledged limitation of this approach, however, has been that it cannot resolve distinct fiber populations within crossing-fiber regions. Fixel-based analysis addresses this limitation by quantifying individual fiber populations within a voxel and providing complementary measures of fiber density (FD), fiber-bundle cross-section (FC), and their combined measure (FDC).Here we applied Fixel-based analysis to diffusion MRI data from 171 children aged 3 - 13 years, including 84 children who stutter and 87 typically developing controls, to test whether white-matter differences associated with developmental stuttering were expressed as differences in FD, FC, and FDC and whether these measures show group-specific age-related patterns. We evaluated this at both the whole-brain level and within a priori white-matter tracts.FC, but not FD or FDC, showed significant Group and Group by Age effects, indicating that white-matter differences were primarily expressed in fiber-bundle macrostructure. Tract-of-interest analyses identified developmental differences in bilateral arcuate fasciculus FC that remained significant across tracts, with controls showing greater age-related increases in FC than children who stutter. Additional FC differences were observed across corticospinal and thalamocortical pathways, although these tract-wise effects were less robust to across-tract correction. These findings suggest that white-matter differences in developmental stuttering are prominently expressed in fiber-bundle macrostructure rather than fiber density and highlight divergent development of bilateral arcuate pathways. FBA provides fiber-specific information that complements conventional tensor-based diffusion measures and may improve characterization of white-matter development in childhood stuttering.

neuroscience↗

bioRxiv2023

ZBTB48 is a pioneer factor regulating B-cell-specific CIITA expression

CIITA is the master regulator of MHC II gene expression and hence the adaptive immune response. CIITA expression itself is tightly regulated by three cell type-specific promoters, pI, pIII, and by pIV, and can also be induced by IFN{gamma} in non-immune cells. While key regulatory elements have been identified within these promoters, knowledge of transcription factors regulating CIITA is incomplete. Here, we demonstrate that the telomere-binding protein and transcriptional activator ZBTB48 directly binds to both the critical activating elements within CIITA pIII and is essential for its gene expression. ZBTB48 establishes open chromatin at CIITA pIII upstream of activating H3K4me3 modifications both priming CIITA transcription for IFN{gamma}-induction and ensuring constitutive expression in primary murine B cells. Hence, ZBTB48 acts as a molecular on-off-switch for B-cell-specific CIITA expression.

immunology↗

bioRxiv2022

Quantitative assessment of angioplasty induced vascular inflammation with 19F cardiovascular magnetic resonance imaging

Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty. 19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. We aimed to non-invasively image monocyte/macrophage infiltration in response to angioplasty in pig carotid arteries using Fluorine-19 magnetic resonance imaging (19F MRI) to assess early inflammatory response to mechanical injury. Early macrophage rich vascular inflammation is a key feature in the pathophysiology of restenosis after angioplasty. 19F MRI with intravenously applied perfluorooctyl bromide-nanoemulsion (PFOB-NE) could offer ideal features for serial imaging of the inflammatory response after angioplasty. In eight minipigs, injury of the right carotid artery was induced by either balloon oversize angioplasty only (BA, n=4) or in combination with endothelial denudation (BA + ECDN, n=4). PFOB-NE was administered intravenously three days after injury followed by 1H and 19F MRI to assess vascular inflammatory burden at day six. Vascular response to mechanical injury was validated using immunohistology. Angioplasty was successfully induced in all eight pigs. Response to injury was characterized by positive remodeling with predominantly adventitial wall thickening and adventitial infiltration of monocytes/macrophages. 19F signal could be detected in vivo in four pigs following BA + ECDN with a robust signal-to-noise ratio (SNR) of 14.7 {+/-} 4.8. Ex vivo analysis revealed a linear correlation of 19F SNR to local monocyte/macrophage cell density. Minimum detection limit of infiltrated monocytes/macrophages was as about 400 cells/mm2. Therefore, 19F MRI enables quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity. This might open an avenue to non-invasively monitor inflammatory response to mechanical injury after angioplasty and thus to identify individuals with distinct patterns of vascular inflammation promoting restenosis. One Sentence Summary19F MRI enables radiation-free quantification of monocyte/macrophage infiltration after vascular injury with sufficient sensitivity.

immunology↗

bioRxiv2022

Auditory cortex encodes lipreading information through spatially distributed activity

Watching a speakers face improves speech perception accuracy. These benefits are owed, in part, to implicit lipreading abilities present in the general population. While it is established that lipreading can alter the perception of a heard word, it is unknown how information that is extracted from lipread words is transformed into a neural code that the auditory system can use. One influential, but untested, hypothesis is that visual speech modulates the population coded representations of phonetic and phonemic features in the auditory system. This model is largely supported by data showing that silent lipreading evokes activity in auditory cortex, but these activations could alternatively reflect general effects of arousal or attention, or the encoding of non-linguistic features such as visual timing information. This gap limits our understanding of how vision supports speech perception processes. To test the hypothesis that the auditory system encodes visual speech information, we acquired fMRI data from healthy adults and intracranial recordings from electrodes implanted in patients with epilepsy during auditory and visual speech perception tasks. Across both methods, linear classifiers successfully decoded the identity of silently lipread words using the spatial pattern of auditory cortex responses. Examining the time-course of classification using intracranial recordings, lipread words were classified at significantly earlier time-points relative to heard words, suggesting a predictive mechanism for facilitating speech. These results support a model in which the auditory system combines the joint neural distributions evoked by heard and lipread words to generate a more precise estimate of what was said. Significance StatementWhen we listen to someone speak in a noisy environment, watching their face can help us understand them better, largely due to automatic lipreading abilities. However, it unknown how lipreading information is transformed into a neural code that the auditory system can use. We used fMRI and intracranial recordings in patients to study how the brain processes silently lipread words and found that the auditory system encodes the identity of lipread words through spatially distributed activity. These results suggest that the auditory system combines information from both lipreading and hearing to generate more precise estimates of what is said, potentially by both activating the corresponding representation of the heard word and suppressing incorrect phonemic representations.

neuroscience↗

bioRxiv2022

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies. Author SummaryTuberculosis, a disease caused by the bacteria Mycobacterium tuberculosis (Mtb), claims around 1.6 million lives each year, making it one of the leading causes of death worldwide by an infectious agent. Based on principles of conventional immunological memory, prior exposure to either Mtb or M. bovis BCG leads to antigen-specific long-lasting changes to the adaptive immune response that can be effective at protecting against subsequent challenge. However, how these exposures may also impact the innate immune response is less understood. Alveolar macrophages are tissue-resident myeloid cells that play an important role during Mtb infection as innate immune sentinels in the lung and the first host cells to respond to infection. Here, we examined how prior mycobacterium exposure, either through BCG vaccination or a model of contained Mtb infection impacts the early innate response by alveolar macrophages. We find that prior exposure remodels the alveolar macrophage response to Mtb through both cell-intrinsic changes and signals that depend on the altered lung environment. These findings suggest that the early innate immune response could be targeted through vaccination or host-directed therapy and could complement existing strategies to enhance the host response to Mtb.

immunology↗

bioRxiv2021

The PRO model accounts for the anterior cingulate cortex role in risky decision-making and monitoring

The anterior cingulate cortex (ACC) has been implicated in a number of functions including performance monitoring and decision making involving effort. The prediction of responses and outcomes (PRO) model has provided a unified account of much human and monkey ACC data involving anatomy, neurophysiology, EEG, fMRI, and behavior. Here we explore the computational nature of ACC with the PRO model, extending it to account specifically for both human and macaque monkey decision-making under risk, including both behavioral and neural data. We show that the PRO model can account for a number of additional effects related to outcome prediction, decision-making under risk, gambling behavior, and we show that the ACC represents the variance of uncertain outcomes, suggesting a link between ACC function and mean-variance theories of decision making. The PRO model provides a unified account of a large set of data regarding the ACC.

neuroscience↗

bioRxiv2021

Morphology of migration: Associations between wing shape, bill morphology, and migration in kingbirds (Tyrannus)

Morphology is closely linked to locomotion and diet in animals. In animals that undertake long-distance migrations, limb-morphology is under selection to maximize mobility and minimize energy expenditure. Migratory behaviors also interact with diet, such that migratory animals tend to be dietary generalists, while sedentary taxa tend to be dietary specialists. Despite a hypothesized link between migration status and morphology, phylogenetic comparative studies have yielded conflicting findings. We tested for evolutionary associations between migratory status and limb and bill morphology across kingbirds, a pan-American genus of birds with migratory, partially migratory, and sedentary taxa. Migratory kingbirds had longer wings, in agreement with expectations if selection favors improved aerodynamics for long-distance migration. We also found an association between migratory status and bill shape, such that more migratory taxa had wider, deeper, and shorter bills compared to sedentary taxa. However, there was no difference in intraspecific morphological variation among migrants, partial migrants, and residents, suggesting that dietary specialization has evolved independently of migration strategy. The evolutionary links between migration, diet, and morphology in kingbirds uncovered here further strengthen ecomorphological associations that underlie long-distance seasonal movements in animals.

evolutionary biology↗

bioRxiv2019

Gestational diabetes using diverse diagnostic criteria, risk factors including dietary intakes, pregnancy outcomes and postpartum glycemic status: a nested case-control study in Ghana

BackgroundGestational diabetes mellitus (GDM) has risen considerably in recent years. Studies from Africa have investigated the risk factors but reported prevalence is often based on one diagnostic test/cut-off while short-term outcomes have scarcely been explored. This study estimated the prevalence of GDM using diverse diagnostic cut-offs. Associated maternal risk factors, birth outcomes and extent of attainment of euglycemia at 12 weeks postpartum were also assessed.\n\nMethods and FindingsThis study was an unmatched case-control nested in a prospective cohort involving 807 pregnant women recruited consecutively from five state-owned hospitals serving rural and peri-urban communities in Ghana. Dietary and obstetric risks were assessed retrospectively while physiologic measurements were repeated throughout pregnancy. Case definition was fasting venous plasma glucose (FPG) [≥]5.6 mmol/l and/or single-step 75-g 2-hour oral glucose tolerance test (OGTT) [≥]8.5 mmol/l measured between 20-34 gestational weeks for singleton, non-diabetic pregnant women (n=446). Participants whose random blood glucose was [≥]11.1 mmol/l and glycated hemoglobin [≥]6.5% were excluded. Pregnancy outcomes of 403 women were traced at delivery while 100 could be followed-up at 12 weeks postpartum. Adjusted odds ratio (aOR) for GDM was tested through unconditional logistic regression and Mantel-Haenszel statistic and the association of GDM on pregnancy outcomes was estimated by multiple logistic regression.\n\nPrevalence per 2-h OGTT [≥]8.5 mmol/l was 9.0% (n=39, 95% confidence interval [CI]; 6.3-11.6) and prevalence per FPG [≥]5.6 mmol/l was 10.8% (n=49, 95% CI; 8.1-13.9); 15.9% met the case definition. Independent risk factors included excess intake of high glycemic index foods (aOR:2.91 95% CI]:1.05-8.06), obesity (aOR:2.13 CI:1.12-4.03), previous cesarean delivery (aOR:4.01 CI:1.08-14.76) and antenatal care in a primary facility (aOR:4.951 CI:1.87-3.76). A unit rise in blood glucose significantly increased maternal blood loss and birthweight. Adjusting for covariates, adverse birth outcomes were perineal tear (Aor:2.91 CI:1.08-5.57) and birth asphyxia (aOR:3.24 CI:1.01-10.44). Cesarean section (aOR:1.9 CI:0.97-3.68), large for gestational age (aOR:2.7 CI:0.86-5.05) and newborn resuscitation (aOR:2.91 CI 0.94-9.01) were significant at 10%. At 12 weeks postpartum, 30% of the GDM cases were unable to achieve euglycemia. Different estimates could be obtained if other diagnostic criteria were used.\n\nConclusionsFindings show an increasing prevalence of GDM in peri-urban and rural settings highlighting the need to strengthen primary facilities to test and refer cases for management. Diet and adiposity are key risk factors necessitating lifestyle modification interventions focusing on nutrition education and weight control. GDM-exposed newborn need close monitoring as birth asphyxia which is a key outcome is likely to compromise neonatal survival. Postpartum follow-up of cases is crucial to avert transition of GDM into active diabetes.

epidemiology↗

bioRxiv2019

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

An efficacious vaccine against adult tuberculosis (TB) remains elusive. Progress is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB1. Over 90% of people who become infected with Mtb mount an immune response that contains the bacteria indefinitely, leading to a state known as "latent TB infection" (LTBI)2. A significant body of epidemiologic evidence indicates that LTBI protects against active TB after re-exposure, offering an intriguing avenue to identifying protective mechanisms3, 4. We show that in a mouse model, LTBI is highly protective against infection with Mtb for up to 100 days following aerosol challenge. LTBI mice are also protected against heterologous bacterial challenge (Listeria monocytogenes) and disseminated melanoma suggesting that protection is in part mediated by alterations in the activation state of the innate immune system. Protection is associated with elevated activation of alveolar macrophages (AM), the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma upon aerosol challenge. Systems approaches, including transcriptome analysis of both naive and infected AMs, as well as ex vivo functional assays, demonstrate that LTBI reconfigures the response of tissue resident AMs.. Furthermore, we demonstrate that both LTBI mice and latently infected humans show similar alterations in the relative proportions of circulating innate immune cells, suggesting that the same cellular changes observed in the LTBI mouse model are also occurring in humans. Therefore, we argue that under certain circumstances, LTBI could be beneficial to the host by providing protection against subsequent Mtb exposure.

immunology↗

bioRxiv2019

National HIV testing and diagnosis coverage in sub-Saharan Africa: a new modeling tool for estimating the \"first 90\" from program and survey data

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSObjectiveC_ST_ABSHIV testing services (HTS) are a crucial component of national HIV responses. Learning ones HIV diagnosis is the entry point to accessing life-saving antiretroviral treatment and care. Recognizing the critical role of HTS, the Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets stipulating that by 2020, 90% of people living with HIV know their status, 90% of those who know their status receive antiretroviral therapy, and 90% of those on treatment have a suppressed viral load. Countries will need to regularly monitor progress on these three indicators. Estimating the proportion of people living with HIV who know their status (i.e., the "first 90"), however, is difficult. MethodsWe developed a mathematical model (henceforth referred to as "F90") that formally synthesizes population-based survey and HTS program data to estimate HIV status awareness over time. The proposed model uses country-specific HIV epidemic parameters from the standard UNAIDS Spectrum model to produce outputs that are consistent with other national HIV estimates. The F90 model provides estimates of HIV testing history, diagnosis rates, and knowledge of HIV status by age and sex. We validate the F90 model using both in-sample comparisons and out-of-sample predictions using data from three countries: Cote dIvoire, Malawi, and Mozambique. ResultsIn-sample comparisons suggest that the F90 model can accurately reproduce longitudinal sex-specific trends in HIV testing. Out-of-sample predictions of the fraction of PLHIV ever tested over a 4-to-6-year time horizon are also in good agreement with empirical survey estimates. Importantly, out-of-sample predictions of HIV knowledge are consistent (i.e., within 4% points) with those of the fully calibrated model in the three countries, when HTS program data are included. The F90 models predictions of knowledge of status are higher than available self-reported HIV awareness estimates, however, suggesting -in line with previous studies- that these self-reports are affected by non-disclosure of HIV status awareness. ConclusionKnowledge of HIV status is a key indicator to monitor progress, identify bottlenecks, and target HIV responses. The F90 model can help countries track progress towards their "first 90" by leveraging surveys of HIV testing behaviors and annual HTS program data.

epidemiology↗

bioRxiv2017

Decomposing the neural pathways mediating value-based choice

Understanding the neural implementation of value-based choice has been an important focus of neuroscience for several decades. Although a consensus has emerged regarding the brain regions involved, disagreement persists regarding precise regional functions and how value information flows between value-based choice regions.\n\nIn the current study, we isolate neural activity related to decision-making using a gambling task where expected gains and losses are dissociated from the received outcomes of choices. We apply multilevel modelling and mediation analysis to formally test whether brain regions identified as part of the value-based choice network mediate between perceptions of expected value and choices to take or pass a gamble.\n\nA critical function in decision-making is accruing and representing value information to drive choice. Several regions have been assigned this role, including ventromedial prefrontal (vmPFC) and posterior parietal cortex (PPC), and the ventral striatum (VStr). The implied chain of events is one where regions that support the process of gathering relevant information mediate the relationship between choice and representations of value in other brain regions. Here, we formally test whether distinct brain regions express interregional mediation consistent with this chain of processes.\n\nWe observe that activity in vmPFC does not predict choice, but rather is highly associated with outcome evaluation. By contrast, both PPC and VStr (bilaterally) mediate between expected value and choice. Interregional mediation analyses reveal that VStr fully mediates between PPC and choice. Together these results suggest that VStr, and not vmPFC nor PPC, functions as an important driver of late stage choice.\n\nSignificance StatementMaking choices that maximize gain and minimize loss is critical for success. Our paradigm and analytic approach allowed isolation of choice-related neural signals from outcome-related signals. The vmPFC is involved at outcome rather than at choice. Isolating choice-related neural activity, we formally demonstrate that VStr and PPC mediate between expected value and choice. Our approach adds significant innovation by using generalized multilevel modelling to predict behavior with concurrent neural activity and formally testing the fully mediated pathway from stimulus through neural activity to behavior. Applying interregional multilevel mediation analysis, we demonstrate that ventral striatum comprises a final, critical step in processing value-based choice, mediating the relationship between value representation and choice.

neuroscience↗