Biology subjects

Cha, K.

Publications and source records attributed to Cha, K..

8 recordsLinked to original sources

bioRxiv2025

Visual field specializations in mouse dLGN

Neural circuits throughout the visual system process features differently depending on where they appear in the visual field. While such location-specific processing exists in retina and in superior colliculus, the dorsal lateral geniculate nucleus (dLGN) is thought to lack this specialization. Here, we show systematic visual field biases in dLGNs representation of spatial frequency, orientation, direction, and temporal frequency. Using axon-localized calcium indicators and widefield imaging, we discovered that dLGN boutons show systematic gradients in feature selectivity across the visual cortex (V1), while its retinal inputs lack such gradients for these features. Selective disruption of V1 feedback to dLGN perturbed gradient structure and magnitude. These results suggest that dLGN circuits transform uniformly distributed retinal feature inputs into spatially-biased representations along with cortical feedback. dLGN feature biases would allow a functional stream to detect ethologically salient visual inputs.

neuroscience↗

bioRxiv2024

Serotonergic neurons in the dorsal raphe regulate visual attention

Visual attention enhances the neural representation of salient stimuli within the visual cortex. It is generally thought that this enhancement is driven by glutamatergic feedback from frontal cortical areas. Here we report the unexpected observation that dorsal raphe (DR) derived serotonin (5HT) controls visual attention. We developed a behavioral model that captured the way mice allocated attention to cued and uncued visual locations and features. Simultaneous photometry showed reduced DR activity when mice deployed attention to the cued locations and features, whereas high DR activity was observed when mice were less attentive. Optogenetic excitation of DR-5HT neurons impaired attention to the cue and degraded behavioral performance, while optogenetic suppression improved attention and performance. A genetically encoded sensor of 5HT release showed reduced 5HT levels in visual cortex when mice attend and detect stimuli. These results demonstrate that DR-5HT neurons are members of the brains attentional circuit and suggest that 5HT is a novel biological carrier of visual attention.

neuroscience↗

bioRxiv2024

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗

bioRxiv2023

Potent immunogenicity and protective efficacy of a multi-pathogen vaccination targeting Zaire ebolavirus, Sudan ebolavirus, Marburg and Lassa viruses

Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan ebolavirus resulted in 164 cases with 55 deaths. In February 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea resulting in 15 confirmed and 23 suspected cases to date, with a second outbreak occurring concurrently in Tanzania. There are no clearly defined correlates of protection against these VHF, impeding targeted subunit vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Zaire ebolavirus, Sudan ebolavirus, Marburg) and an arenavirus (Lassa). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19 /AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Zaire ebolavirus, Sudan ebolavirus and Marburg virus challenges in a small animal model. Author summaryOutbreaks caused by Ebola and Lassa viruses have made headlines worldwide in recent years. Most recently, in 2023 a Marburg virus outbreak has claimed tens of lives with a high case fatality rate. As yet, no licensed vaccine exists to protect against this and other viral haemorrhagic fevers. An ideal vaccine would induce long-lasting immunity to, and protection from, viruses causing viral haemorrhagic fevers. We developed vaccines which can target multiple strains of Ebolavirus, the closely related Marburg virus and Lassa virus. The geographical ranges of these viruses overlap in West and Central Africa. We used viral vector platform technologies to generate these vaccines; ChAdOx1 has now been administered worldwide as part of COVID-19 vaccine rollouts, and MVA has been used in numerous clinical trials thus far. We found that both long lasting, antigen specific T cell and antibody responses were induced after vaccination. Lastly, we demonstrated these vaccines could protect small animals against challenge with Zaire ebolavirus, Sudan ebolavirus and Marburg virus.

immunology↗

bioRxiv2023

NULISA: a novel proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing

The blood proteome holds great promise for precision medicine but poses substantial challenges due to the low abundance of most plasma proteins and the vast dynamic range across the proteome. We report a novel proteomic technology - NUcleic acid Linked Immuno-Sandwich Assay (NULISA) - that incorporates a dual capture and release mechanism to suppress the assay background and improves the sensitivity of the proximity ligation assay by over 10,000-fold to the attomolar level. It utilizes pairs of antibodies conjugated to DNA oligonucleotides that enable immunocomplex purification and generate reporter DNA containing target- and sample-specific barcodes for a next-generation sequencing-based, highly multiplexed readout. A 200-plex NULISA targeting 124 cytokines and chemokines and 80 other immune response-related proteins demonstrated superior sensitivity for detecting low-abundance proteins and high concordance with other immunoassays. The ultrahigh sensitivity allowed the detection of previously difficult-to-detect, but biologically important, low-abundance biomarkers in patients with autoimmune diseases and COVID-19. Fully automated NULISA addresses longstanding challenges in proteomic analysis of liquid biopsies and makes broad and in-depth proteomic analysis accessible to the general research community and future diagnostic applications.

genomics↗

bioRxiv2022

Probing visual sensitivity and attention in mice using reverse correlation

Visual attention is a fundamental cognitive operation that allows the brain to evoke behaviors based on the most important stimulus features. Although mouse models offer immense potential to gain a circuit-level understanding of this phenomenon, links between visual attention and behavioral decisions in mice are not well understood. Here, we describe a new behavioral task for mice that addresses this limitation. We trained mice to detect weak vertical bars in a background of checkerboard noise while audiovisual cues manipulated their spatial attention. We then modified a reverse correlation method from human studies to link behavioral decisions to stimulus locations and features. We show that mice attended to stimulus locations just rostral of their optical axis, which was highly sensitive for vertically oriented stimulus energy whose spatial frequency matched those of the weak vertical bars. We found that the tuning of sensitivity to orientation and spatial frequency grew stronger during training, was multiplicatively scaled with attention, and approached that of an ideal observer. These results provide a new task to measure spatial- and feature-based attention in mice which can be leveraged with new recording methods to uncover attentional circuits.

neuroscience↗

bioRxiv2019

Albumin inhibits the activation of hepatic stellate cells by suppressing TGF-β/Smad3 signaling via IL-1β

Activated hepatic stellate cells (HSCs) play a key role in liver fibrosis and inactivating HSCs has been considered a promising therapeutic approach. We previously showed that albumin and its derivative, retinol binding protein (RBP)-albumin domain III fusion protein (named R-III), inhibit HSC activation. Here, we investigate the mode of action of albumin and R-III. NF-{kappa}B in activated HSCs was evenly distributed in the cytoplasm, but albumin expression and R-III treatment (albumin/R-III) induced NF-{kappa}B nuclear translocation via retinoic acid (RA) sequestration, resulting in increased expression of interleukin-1{beta} (IL-1{beta}). In an IL-1{beta} dependent manner, albumin/R-III inhibited Smad3 nuclear translocation via TAK1-, JNK-mediated Smad3 linker phosphorylation and decreased expression of Smad3 target genes, such as -smooth muscle actin and collagen type I. Mutation of the Smad3 linker phosphorylation sites abolished R-III effects on Smad3. In conclusion, our data suggest that the anti-fibrotic effects of albumin/R-III are due to RA sequestration which downregulates RAR-mediated signaling and also TGF-{beta}/Smad3 signaling. This mechanistic elucidation of albumin function in HSCs provides clues to understanding the frequent albumin mutations found in hepatocellular carcinoma.

molecular biology↗

bioRxiv2016

Training qualitatively shifts the neural mechanisms that support attentional selection

Attention supports the selection of relevant sensory information from competing irrelevant sensory information. This selective processing is thought to be supported via the attentional gain amplification of sensory responses evoked by attended compared to unattended stimuli. However, recent studies in highly trained subjects suggest that attentional gain plays a relatively modest role and that other types of neural modulations - such as a reduction in neural noise - better explain attention-related changes in behavior. We hypothesized that the amount of training may alter neural mechanisms that support attentional selection in visual cortex. To test this hypothesis, we investigated the influence of training on attentional modulations of stimulus-evoked visual responses by recording electroencephalography (EEG) from humans performing a selective visuospatial attention task over the course of one month. Early in training, visuospatial attention induced a robust attentional gain amplification of sensory-evoked responses in contralateral visual cortex that emerged within ~100ms after stimulus onset, and a quantitative model based on signal detection theory (SDT) successfully linked this attentional gain amplification to attention-related improvements in behavior. However, after training, this attentional gain amplification of visual responses was almost completely eliminated and modeling suggested that noise reduction was required to link the amplitude of visual responses with attentional modulations of behavior. These findings suggest that the neural mechanisms supporting selective attention can change as a function of training and expertise, and help to bridge different results from studies carried out in different model systems that require substantially different amount of training.

neuroscience↗