Biology subjects

Ha, H.

Publications and source records attributed to Ha, H..

6 recordsLinked to original sources

bioRxiv2026

A sensor of oxidative stress confers virulence via response memory in Acinetobacter baumannii

All living organisms must adapt to environmental stresses to survive. The two-component system (TCS) is a prevalent signal transduction mechanism to alter gene expression in response to stress in bacteria. We report that the PmrB sensor of the PmrA/PmrB TCS senses sublethal oxidative stress and encodes a response memory that promotes virulence in Acinetobacter baumannii. PmrB detects oxidative stress through histidine residues with a nickel (Ni2+) cofactor. Nickel oxidation (Ni2+) induces an allosteric effect by altering PmrB conformation, enabling PmrA activation. Activated PmrA induces antioxidant defense genes, including iron-sulfur cluster repair, ferritin, catalase, and peroxidase. Notably, PmrB remains activated after sublethal oxidative stress is removed, as pathogens encounter in the bloodstream and airways during infection. This response memory enables bacteria to respond strongly to subsequent lethal oxidative stress and antimicrobial peptides. In a murine model, disrupting oxidative sensing reduces virulence. In addition, PmrB-mediated response memory is essential for high virulence in clinically isolated multidrug-resistant A. baumannii. Our findings demonstrate how subinhibitory stress detection enables pathogens to achieve full virulence potential and resist stresses during infection.

microbiology↗

bioRxiv2025

Potential beneficial effects of PD-1/PD-L1 blockade in Alzheimer's disease: A systematic review and meta-analysis of preclinical and clinical studies

Programmed cell death-1 (PD-1) and its ligand (PD-L1) play key roles in cancer immune evasion and in modulating neuroinflammation. This systematic review and meta-analysis investigated the effect of PD-1/PD-L1 blockade on pathology and cognitive function in Alzheimers disease (AD) in preclinical and clinical studies. Relevant studies were systematically identified using the MEDLINE, Embase, CENTRAL, and Web of Science databases from their inception until April 10, 2024. In total, 33 studies were included in this meta-analysis, conducted using R software. Preclinical studies revealed that blockade of PD-1 signaling reduces amyloid-beta plaque burden, tau phosphorylation, and astrocyte reactivity in AD mouse models, accompanied by improvements in cognitive function in behavioral tests. Furthermore, clinical studies demonstrated the beneficial effect of PD-1 signaling inhibitors on cognitive function in cancer patients. This study highlights the necessity for additional research to clarify the exact mechanisms by which PD-1/PD-L1 inhibition impacts AD pathology and cognitive function, opening avenues for potential therapeutic strategies targeting this pathway in AD.

neuroscience↗

bioRxiv2023

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction

Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 improves CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3. SummaryChronic stimulation of CARs containing the 41BB costimulatory domain leads to a novel state of T cell dysfunction that is distinct from T cell exhaustion.

immunology↗

bioRxiv2022

CD244 regulates both innate and adaptive immune axes in melanoma by inhibiting autophagy-mediated M1 macrophage maturation

Accumulating data have highlighted the role of monocytes/macrophages in immune escape by generating immunologically "cold" tumors that do not respond to immunotherapy. CD244 (SLAMF4, 2B4), a member of the signaling lymphocyte activation molecule family, is expressed on myeloid cells, but its precise role has not been elucidated. Using monocyte lineage-specific CD244-deficient (LysM-cre+/-CD244fl/fl;cKO) mice challenged with B16F10 melanoma, we report for the first time that CD244 negatively regulates tumor immunity by inhibiting the differentiation and functional maturation of CD11b+Ly6ChiF4/80lo monocytes into CD11b+Ly6CloF4/80hi macrophages within the tumor microenvironment. CD244-deficient macrophages more effectively activated antigen-specific T cell responses compared to WT macrophages, thus delaying tumor growth in the B16F10 melanoma model. Moreover, combinatorial intervention of anti-PD-L1 antibodies with CD244-KO BMDM markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with WT BMDM. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset (SCP398 from single-cell portal), revealed 221 differentially expressed genes of CD244- monocytes/macrophages were associated with phagocytosis, antigen presentation, and autophagy. Additionally, cell type deconvolution analysis within melanoma patients bulk RNA-seq datasets from TCGA database, revealed presence of CD244- monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Hence, we proposed that CD244 serve as a critical immune checkpoint receptor on macrophages, and CD244-deficient macrophages may represent a novel therapeutic modality to convert immunologically "cold" tumors to "hot" tumors, which can function synergistically with checkpoint blockade therapies.

immunology↗

bioRxiv2021

Control effectiveness of APL formulation against dengue- and Zika-transmitting Aedes mosquitoes in Gia Lai province, Vietnam

BackgroundDengue fever and Zika are two of the Aedes-borne diseases. Despite being widely used, synthetic mosquitocides become abortive for the mosquito control due to growing resistance and environmental pollution. In Gia Lai province (dengue-endemic area), a huge amount of cashew nut shell waste with roughly 100,000 tons/year has been disposed of into the environment, potentiating a high risk of pollution. Methodology/Principal findingsTo utilize it, anacardic acid was extracted and combined it with ethanol extract of the local lime peel, which contains limonene, to generate APL formulation. APL robustly exhibited inhibition of egg hatching, larvicidal effect, and repellent effect against female mosquitoes from oviposition sites in the laboratory and field. The results showed that, at a dose of 12.5 ppm, the APL formulation after 24 hours of treatment demonstrated oviposition deterrence against Ae. aegypti (43.6%) and Ae. albopictus (59.6%); inhibited egg hatching of Ae. aegypti (49.6%) and Ae. albopictus (59.6%); caused larval lethality in Ae. aegypti (LC50 = 9.5 ppm, LC90 = 21 ppm) and Ae. albopictus (LC50 = 7.6 ppm, LC90 = 18 ppm). Under natural field conditions, it showed a 100% reduction in larval density after 48 and 72 hours of the APL treatment at a tested concentration of 120 mg a.i./m2 and maintained a mortality rate of 100% in the next 14 days. Conclusions/SignificanceThe APL formulation is promisingly to become an environmentally friendly and highly effective biological product for future management programs of dengue and Zika-transmitting vectors. Here offer prospects in controlling critical illnesses transmitted by several mosquito species in dengue-endemic areas. Author summaryThe use of synthetic insecticide to control the dengue and Zika vector population has contributed to drug resistance and caused negative impacts on the environment. The plant-based insecticide should be beneficial for mosquito management in the current situation. Gia Lai province in Vietnam is a dengue-endemic area. A large amount of cashew nut shell waste gets discarded in the area every year, which imposes an increased risk of pollution. The authors took advantage of this by extracting anacardic acid to combine with ethanol extract of local lime peel (containing limonene) to produce APL formulation. This formulation demonstrated potential activities and efficiency in controlling mosquitoes transmitting disease. In the laboratory condition, at a low dose of 12.5 ppm, APL showed activities in inhibiting egg hatching, larviciding, and repelling female Aedes aegypti and Aedes albopictus. In the field condition, APL at a dose of 120 mg a.i./m2 thoroughly reduced the dengue larval density after two days of contact, and this effect lasted to the next 14 days. APL is a promising and environmentally friendly larvicidal product that is highly effective in controlling dengue and Zika vectors and can play as an alternative measure for vector-borne dengue in the locality.

biochemistry↗

bioRxiv2018

Pedigree-based estimation of human mobile element retrotransposition rates

Germline mutation rates in humans have been estimated for a variety of mutation types, including single nucleotide and large structural variants. Here we directly measure the germline retrotransposition rate for the three active retrotransposon elements: L1, Alu, and SVA. We utilized three tools for calling Mobile Element Insertions (MEIs) (MELT, RUFUS, and TranSurVeyor) on blood-derived whole genome sequence (WGS) data from 603 CEPH individuals, comprising 33 three-generation pedigrees. We identified 27 de novo MEIs in 440 births. The retrotransposition rate estimates for Alu elements, one in 40, is roughly half the rate estimated using phylogenetic analyses, a difference in magnitude similar to that observed for single nucleotide variants. The L1 retrotransposition rate is one in 62 births and is within range of previous estimates (1:20-1:200 births). The SVA retrotransposition rate, one in 55 births, is much higher than the previous estimate of one in 900 births. Our large, three-generation pedigrees allowed us to assess parent-of-origin effects and the timing of insertion events in either gametogenesis or early embryonic development. We find a statistically significant paternal bias in Alu retrotransposition. Our study represents the first in-depth analysis of the rate and dynamics of human retrotransposition from WGS data in three-generation human pedigrees.

genetics↗