Biology subjects

Blumenthal, A.

Publications and source records attributed to Blumenthal, A..

7 recordsLinked to original sources

bioRxiv2025

CD8+ T cells mediate vaccination-induced lymphatic containment of latent Mycobacterium tuberculosis infection following immunosuppression, while B cells are dispensable

It is estimated that two billion people are latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Latent Mtb infection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation. The immunological correlates of protection against TB, including against reactivation of LTBI, remain largely elusive. Here, we used a mouse model of latent lymphatic Mtb infection to dissect the immunological mechanisms underlying LTBI containment versus reactivation. We show that immunosuppression-mediated reactivation of lymphatic LTBI and the subsequent spread to non-lymphatic organs can be prevented by vaccination with multiple recombinant BCG (rBCG) strains despite the deficiency of CD4+ T cells. Using spatial transcriptomics, multi-parameter imaging, network analysis and bioinformatic integration of histopathological images, we reveal that immunosuppression is associated with a distinct repositioning of non-CD4 immune cells at the edge of TB lesions within the infection-draining cervical lymph nodes. While B cells increased in numbers, they are dispensable for the containment of LTBI. Lymphatic Mtb infection in different immune cell-deficient mouse strains, antibody-mediated cell depletion and adoptive transfer experiments into highly susceptible mice unequivocally show that vaccination-mediated prevention of LTBI reactivation is critically dependent on CD8+ T cells. These findings have profound implications for our understanding of immunity to TB and the management of LTBI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/634479v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@151fdd6org.highwire.dtl.DTLVardef@1efed47org.highwire.dtl.DTLVardef@c2e7e0org.highwire.dtl.DTLVardef@555c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Valence-dependent sensory-rhythmic neural entrainment modulates cortico-subcortical dynamics, attention, and memory

Sensory rhythmic stimulation enhances executive functions by entraining oscillations in higher- order cortical networks, but its effects on subcortical structures remain unclear. We propose that stimulus valence is a key feature to enable subcortical entrainment. Using intracranial EEG in epileptic patients, we first show that visual search is supported by cortico-subcortical theta (5Hz) activity. We then show that 5 Hz negative-valence visual stimulation entrains theta oscillations in a task-related network, including the ventral visual stream, hippocampus, and dorsolateral prefrontal cortex. Finally, in a behavioral experiment in healthy individuals, we show that both neutral and negative valence 5 Hz stimulation improved visual search speed, but only negative valence stimulation enhanced target image recognition as assessed through an additional memory task. These findings highlight the role of stimulus valence in modulating subcortical brain activity and behaviors through rhythmic sensory stimulation and pave the way for further applications in clinical intervention.

neuroscience↗

bioRxiv2021

DLPFC controls the rapid neural response to visual threat: An ERP and rTMS study

Individuals are faster at detecting threatening stimuli than neutral stimuli. While generally considered a rapid bottom-up response, this threat superiority effect is also modulated by top-down mechanisms known to rely on the dorsolateral prefrontal cortex (DLPFC). What remains unclear is whether the response is modulated only at later stages of processing, or whether rapid attention to threat itself is controlled in a top-down manner. To test this, we used repetitive transcranial magnetic stimulation (rTMS) to inhibit activity in the DLPFC, and measured EEG to index the immediate neural response to threat. Participants attended two sessions where they performed a visual search task with threatening or neutral targets. Prior to this, they received 15 minutes of 1 Hz inhibitory or sham rTMS targeting the right DLPFC. We measured the impact of rTMS on the P1, a rapid visually-evoked potential that is modulated by attention. We found that threatening targets increased the amplitude of the P1 in the sham condition, but inhibition of the DLPFC abolished this increase. These results suggest that the neural signature of rapid attentional detection of threat, even at its earliest stage, is influenced in a top-down fashion by the right DLPFC.

neuroscience↗

bioRxiv2021

Pre-diabetes increases tuberculosis disease severity, while high body fat without impaired glucose tolerance is protective

Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about pre-diabetes and the relative contribution of impaired glucose tolerance vs. obesity towards susceptibility to TB. Here, we developed a preclinical model of pre-diabetes and TB. Mice fed a high fat diet (HFD) for 12 weeks presented with impaired glucose tolerance and hyperinsulinemia compared to mice fed normal chow diet (NCD). Infection with M. tuberculosis (Mtb) H37Rv after the onset of dysglycemia was associated with significantly increased lung pathology, lower concentrations of TNF-a, IFN-g, IFN-{beta} and IL-10 and a trend towards higher bacterial burden at 3 weeks post infection. To determine whether the increased susceptibility of pre-diabetic mice to TB is reversible and is associated with dysglycemia or increased body fat mass, we performed a diet reversal experiment. Pre-diabetic mice were fed a NCD for 10 additional weeks (HFD/NCD) at which point glucose tolerance was restored, but body fat mass remained higher compared to control mice that consumed NCD throughout the entire experiment (NCD/NCD). Upon Mtb infection HFD/NCD mice had significantly lower bacterial burden compared to NCD/NCD mice and this was accompanied by restored IFN-{gamma} responses. Our findings demonstrate that pre-diabetes increases susceptibility to TB, but a high body mass index without dysglycemia is protective. This murine model offers the opportunity to further study the underlying immunological, metabolic and endocrine mechanisms of this association.

immunology↗

bioRxiv2021

Activity in perirhinal and entorhinal cortex predicts observer-specific perceived visual similarities between objects

Vision neuroscience has made great strides in understanding the hierarchical organization of object representations along the ventral visual stream (VVS). How VVS representations capture fine-grained visual similarities between objects that observers subjectively perceive has received limited examination so far. In the current study, we addressed this question by focusing on perceived visual similarities among subordinate exemplars of real world-categories. We hypothesized that these perceived similarities are reflected with highest fidelity in neural activity patterns downstream from inferotemporal regions, namely in perirhinal and anterolateral entorhinal cortex in the medial temporal-lobe. To address this issue with fMRI, we administered a modified 1-Back task that required discrimination between category exemplars as well as categorization. Further, we obtained observer-specific ratings of perceived visual similarities, which predicted behavioural performance during scanning. As anticipated, we found that activity patterns in perirhinal and anterolateral entorhinal cortex predicted the structure of perceived visual similarity relationships among category exemplars, including its observer-specific component, with higher precision than any other VVS region. Our findings provide new evidence that subjective aspects of object perception that rely on fine-grained visual differentiation are reflected with highest fidelity in the medial temporal lobe.

neuroscience↗

bioRxiv2019

Prolonged podocyte depletion in larval zebrafish resembles mammalian focal and segmental glomerulosclerosis

Although FSGS has been in the scientific focus for many years, it is still a massive burden for patients with no causal therapeutic option. In FSGS, podocytes are injured, parietal epithelial cells (PECs) are activated and engage in the formation of cellular lesions leading to progressive glomerular scarring. Herein we show that podocyte-depleted zebrafish larvae develop acute proteinuria, severe foot process effacement and activate PECs which create cellular lesions and deposit extracellular matrix on the glomerular tuft. We therefore propose that this model shows features of human FSGS and show its applicability for a high-throughput drug screening assay.

pathology↗

bioRxiv2018

Animacy and real world size shape object representations in the human medial temporal lobes

Identifying what an object is, and whether an object has been encountered before, is a crucial aspect of human behavior. Despite this importance, we do not have a complete understanding of the neural basis of these abilities. Investigations into the neural organization of human object representations have revealed category specific organization in the ventral visual stream in perceptual tasks. Interestingly, these categories fall within broader domains of organization, with distinctions between animate, inanimate large, and inanimate small objects. While there is some evidence for category specific effects in the medial temporal lobe (MTL), it is currently unclear whether domain level organization is also present across these structures. To this end, we used fMRI with a continuous recognition memory task. Stimuli were images of objects from several different categories, which were either animate or inanimate, or large or small within the inanimate domain. We employed representational similarity analysis (RSA) to test the hypothesis that object-evoked responses in MTL structures during recognition-memory judgments also show evidence for domain-level organization along both dimensions. Our data support this hypothesis. Specifically, object representations were shaped by either animacy, real-world size, or both, in perirhinal and parahippocampal cortex, as well as the hippocampus. While sensitivity to these dimensions differed when structures when probed individually, hinting at interesting links to functional differentiation, similarities in organization across MTL structures were more prominent overall. These results argue for continuity in the organization of object representations in the ventral visual stream and the MTL.

neuroscience↗