Biology subjects

Chang, W.

Publications and source records attributed to Chang, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

A Human Biomimetic Intestinal Mucosa Model to Study Gastrointestinal Development and Disease

The intestinal mucosa plays a vital role in nutrient absorption, drug metabolism, and pathogen defence. Advances in single-cell technologies have highlighted the specialised roles of various cell types that execute these diverse functions. Aside from intestinal epithelial cells, fibroblasts play an essential role in regulating the extracellular matrix and controlling pro- inflammatory signalling, and antigen-presenting cells (macrophages and dendritic cells) maintain intestinal homeostasis and immune responses. The incorporation of such cellular complexity within the existing in vitro models of the human intestine is currently challenging. To address this, we developed a human intestinal model that accurately mimics the mucosal cellular environment comprising intestinal epithelial cells, intestinal fibroblasts, and antigen presenting cells. This model includes co-cultures of adult and foetal cells, facilitating studies on barrier function, inflammation, and viral infections. It replicates extracellular matrix deposition, Paneth cell differentiation, immune interactions, and can be used to model host- pathogen interactions. Our advanced co-culture model improves the physiological relevance of in vitro studies, enabling the exploration of epithelial-mesenchymal-immune crosstalk and its role in intestinal health and disease.

cell biology↗

bioRxiv2024

Causal role of frontocentral beta oscillation in comprehending linguistic communicative functions

Linguistic communication is often considered as an action serving the function of conveying the speakers goal to the addressee. Although neuroimaging studies have suggested a role of the motor system in comprehending communicative functions, the underlying mechanism is yet to be specified. Here, by 2 EEG experiments and a tACS experiment, we demonstrate that the frontocentral beta oscillation, which represents action states, plays a crucial part in linguistic communication understanding. Participants read scripts involving 2 interlocutors and rated the interlocutors attitudes. Each script included a critical sentence said by the speaker expressing a context-dependent function of either promise, request, or reply to the addressees query. These functions were behaviorally discriminated, with higher addressees will rating for the promise than for the reply and higher speakers will rating for the request than for the reply. EEG multivariate analyses showed that different communicative functions were represented by different patterns of frontocentral beta activity but not by patterns of alpha activity. Further tACS results showed that, relative to alpha tACS and sham stimulation, beta tACS improved the predictability of communicative functions of request or reply, as measured by the speakers will rating. These results convergently suggest a causal role of the frontocentral beta activities in comprehending linguistic communications. HighlightsO_LIThe frontocentral beta activity patterns discriminate communicative functions. C_LIO_LIThe frontocentral beta activity plays a causal role in comprehending the functions. C_LIO_LIThe comprehension could be subserved by the mental simulation of the communication. C_LIO_LIOur findings connect the idea of embedded semantics with the speech act theory. C_LI

neuroscience↗

bioRxiv2024

Cancer-Associated Hypercalcemia Signals Through the Hindbrain to cause Anorexia

Hypercalcemia, caused by tumor secretion of parathyroid hormone-related protein (PTHrP), is associated with anorexia and weight loss. We demonstrate that overexpression of PTHrP by tumor cells in a transgenic model of breast cancer causes anorexia and rapid weight loss. These changes are accompanied by activation of neurons in the area postrema (AP), the nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN), a hindbrain circuit regulating food intake. Blocking hypercalcemia prevents anorexia and activation of these brain centers in tumor bearing mice, whereas injecting calcium activates the same circuit in wild-type mice. Neurons in the AP express the calcium-sensing receptor (CaSR) and the same AP/NTS/PBN circuit is stimulated by treating WT mice with cinacalcet, an allosteric activator of the CaSR. Finally, treating diet-induced obese mice with cinacalcet reduces food intake and causes weight loss. These results suggest that CaSR-expressing neurons in the AP might be a pharmacologic target for obesity.

cancer biology↗

bioRxiv2024

Cdon is required for organ Left-Right patterning via regulating DFCs migration and the sequential ciliogenesis

Cdon and boc are members of the cell adhesion molecule subfamily III Ig/fibronectin. Although they were reported to be involved in muscle and neural development at late developmental stage, while their early roles in embryonic development are unknown. Here we discovered that zebrafish cdon but not boc was expressed in dorsal forerunner cells (DFCs) and epitheliums of Kupffers vesicle (KV), implying the possible role of cdon in organ LR patterning. Further data showed that the liver and heart LR patterning was disturbed in cdon morphants and cdon mutants. Mechanically, we found that cdon loss of function led to dispersed DFCs migration, smaller KV and defective ciliogenesis, which resulting in randomized Nodal/spaw signaling and the sequential organ LR patterning defect. Finally, predominant distribution of a cdon MO in DFCs led to defects in DFCs migration, KV morphogenesis/ciliogenesis, Nodal/spaw signaling and organ LR asymmetry, being similar to those in cdon morphants and cdon-/- embryos, indicating a cell-autonomous role of cdon in regulating KV formation and ciliogenesis during LR patterning. In conclusion, our data demonstrated that, during gastrulation stage and early somitogenesis stage, cdon is required for proper DFCs migration, KV formation and ciliogenesis, thus playing an important role in setting up organ LR asymmetry.

developmental biology↗

bioRxiv2024

Spatially conserved pathoprotein profiling in the human suprachiasmatic nucleus in progressive Alzheimer disease stages

Individuals with Alzheimers Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak stage 0) and 36 subjects at progressive Braak stages (I, II, and VI). To investigate potential AD-specific changes, we measured the neuronal counts of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) positive neurons, along with the Braak stages in the SCN. We investigated in adjacent hypothalamic nuclei which are also composed of AVP+ neurons but show more resilience to AD: paraventricular nucleus (PVN) and supraoptic nucleus (SON). To understand the dysregulated proteins associated to AD progression, we performed in-situ proteomics, investigating 57 proteins, including commonly dysregulated in AD, using GeoMx Digital Spatial Profiling (DSP) in the three nuclei (total of 703 area of interests). Neurofibrillary tangles (NFTs) and tau fibrils were found selectively in SCN. We failed to detect NFTs in SON, only a mild dysregulation of p-tau at Braak VI in PVN and SON. Amyloid plaque was absent in the SCN and SON. Additionally, the SCN showed increased glial proteins already at Braak stage I, whereas the level of these proteins sustained in the other nuclei. The SCN is exclusively vulnerable to AD-tau pathology and show immune dysregulation even at Braak I but is protected against amyloid plaque. This finding revealed selectively in amnestic AD, showing more resilience in AD variant. This tau-related molecular dysregulation in the SCN contributes to circadian rhythm disturbances in AD, a phenomenon observed before the onset of cognitive disorder.

neuroscience↗

bioRxiv2024

CMTM6 maintains B cell intrinsic CD40 expression to regulate anti-tumor immunity

HighlightsO_LIB cells participate in anti-tumor immunity by influencing the intratumoral infiltration and function of T cells; C_LIO_LICMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation to maintain CD40 cell membrane levels; C_LIO_LILoss of B cell-intrinsic CMTM6 significantly reduces CD40 signaling-mediated B cell activation, survival, differentiation, T/B cell interaction and anti-tumor immunity; C_LIO_LIB cell-intrinsic CMTM6 deficiency leads to a significant reduction in the anti-tumor activity CD40 agonists and ICB therapy. C_LI In BriefLong et al. demonstrate that B-cell intrinsic CMTM6 regulates CD40 signaling and function via maintaining the cell membrane level of B-cell CD40 through ubiquitin-proteasome pathway inhibition, thereby affecting B cell function, anti-tumor B-cell immunity and the efficacy of CD40 agonist and ICB therapy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/583639v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7639cdorg.highwire.dtl.DTLVardef@1ccddaaorg.highwire.dtl.DTLVardef@ecc9f3org.highwire.dtl.DTLVardef@1be8cb0_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractsC_FLOATNO C_FIG The essential role of B cells and B cell intrinsic molecules in tumor immunity is beginning to be recognized. Tumor cell CMTM6 is a novel tumor immunoregulator involved in maintaining membrane levels of several important molecules, such as PD-L1 and CD58. Host CMTM6 may also play a function in the tumor microenvironment. Here, we found that CMTM6 was highly expressed in splenic B cells and tumor-infiltrating B cells. CMTM6 deficiency resulted in impaired splenic development, germinal center B cell differentiation, memory B cell differentiation, T/B cell interaction and B cell anti-tumor immune responses. Through multi-omics data mining and B-cell agonist screening, we identified that CMTM6 interacted with CD40 and maintained CD40 membrane levels in B cells. CMTM6 cis-interacts with CD40 and inhibits ubiquitin/proteasome-mediated CD40 degradation. CMTM6 deficiency led to impaired CD40 signaling-mediated B cell activation, survival, proliferation, differentiation and T/B cell interaction. In vivo, CMTM6 deficiency leads to a significant decrease in the anti-tumor activity of ICB therapy and B cell-dependent CD40 agonists. Collectively, B-cell intrinsic CMTM6 maintains B cell CD40 levels and signaling to promote B cell function and anti-tumor immunity.

immunology↗

bioRxiv2023

Structure-based discovery of positive allosteric modulators for the calcium sensing receptor

Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, in ex vivo organ assays, and reduces serum PTH levels in mice by up to 80% without the hypocalcemia typical of CaSR drugs. Cryo-EM structures with the new PAMs show that they induce residue rearrangements in the binding pockets and promote CaSR dimer conformations that are closer to the G-protein coupled state compared to established drugs. These findings highlight the promise of large library docking for therapeutic leads, especially when combined with experimental structure determination and mechanism. One sentence summaryStructure-based virtual screening uncovers novel CaSR allosteric modulators with enhanced efficacy and less side effects.

biophysics↗

bioRxiv2023

Structural and functional analyses of viral H2 protein of the vaccinia virus entry fusion complex

Virus-mediated membrane fusion involves conformational changes of the viral fusion protein to fuse the opposing viral and host lipid bilayers. Unlike all other known viruses that contain a single fusion protein, poxviruses harbor a multimeric protein complex of 11 subunits, termed the entry fusion complex (EFC), to mediate fusion with host membranes. Yet, how the poxviral EFC mediates membrane fusion remains enigmatic. To establish the mechanism of EFC-triggered membrane fusion, we are deciphering the structure and function of individual EFC components. Here, we determined the crystal structure of the H2 ectodomain by X-ray diffraction, revealing a folded conformation comprising a central five-stranded {beta}-sheet and three cladding -helices. We reconstructed the full-length H2 by in silico prediction, revealing that the N-terminal region (aa 51-90) of H2 protein may fold as a long helix connecting the ectodomain and transmembrane region. Using alanine-mutagenesis screening in a transient complementation system, coimmunoprecipitation, isothermal titration calorimetry and MV-triggered membrane fusion assays, we concluded that the surface of the ectodomain of H2 protein, including two loop regions, 170LGYSG174 and 125RRGTGDAW132, constitutes a broad A28-binding region. Moreover, although not involved in A28 binding, the N-terminal helical region approximal to the transmembrane part, encompassing 64RIK66, 72W, and 83ESDRGR88, is also crucial for viral EFC formation and MV infectivity.

microbiology↗

bioRxiv2023

Optimizing learning via real-time neural decoding

BackgroundSpectral features of human electroencephalographic (EEG) recordings during learning predict subsequent recall variability. New methodCapitalizing on these fluctuating neural features, we develop a non-invasive closed-loop (NICL) system for real-time optimization of human learning. Participants play a virtual navigation and memory game; recording multi-session data across days allowed us to build participant-specific classification models of recall success. In subsequent closed-loop sessions, our platform manipulated the timing of memory encoding, selectively presenting items during periods of predicted good or poor memory function based on EEG features decoded in real time. ResultsWe observed greater memory modulation (difference between recall rates when presenting items during predicted good vs. poor learning periods) for participants with higher out-of-sample classification accuracy. Comparison with Existing MethodsThis study demonstrates greater-than-chance memory decoding from EEG recordings in a naturalistic virtual navigation task with greater real-world validity than basic word-list recall paradigms. Here we modulate memory by timing stimulus presentation based on noninvasive scalp EEG recordings, whereas prior closed-loop studies for memory improvement involved intracranial recordings and direct electrical stimulation. Other noninvasive studies have investigated the use of neurofeedback or remedial study for memory improvement. ConclusionsThese findings present a proof-of-concept for using non-invasive closed-loop technology to optimize human learning and memory through principled stimulus timing, but only in those participants for whom classifiers reliably predict out-of-sample memory function.

neuroscience↗

bioRxiv2023

Density Physics-Informed Neural Network reveals sources of cell heterogeneity in signal transduction

The transduction time between signal initiation and final response provides valuable information on the underlying signaling pathway, including its speed and precision. Furthermore, multimodality in transduction-time distribution informs that the response is regulated by multiple pathways with different transduction speeds. Here, we developed Density physics-informed neural network (Density-PINN) to infer the transduction-time distribution, challenging to measure, from measurable final stress response time traces. We applied Density-PINN to single-cell gene expression data from 16 promoters regulated by unknown pathways in response to antibiotic stresses. We found that promoters with slower signaling initiation and transduction exhibit larger cell-to-cell heterogeneity in response intensity. However, this heterogeneity was greatly reduced when the response was regulated by slow and fast pathways together. This suggests a strategy for identifying effective signaling pathways for consistent cellular responses to disease treatments. Density-PINN can also be applied to understand various time delay systems, including infectious diseases.

systems biology↗

bioRxiv2023

Structural and functional analysis of vaccinia viral fusion complex component protein A28 through NMR and molecular dynamic simulations

Host cell entry of vaccinia virus (a poxvirus) proceeds through multiple steps that involve many viral proteins to mediate cell infection. Upon binding to cells, vaccinia virus membrane fuses with host membranes via a viral entry fusion protein complex comprising 11 proteins: A16, A21, A28, F9, G3, G9, H2, J5, L1, L5 and O3. Despite vaccinia virus having two infectious forms, mature and enveloped, that have different membrane layers, both forms require an identical viral entry fusion complex for membrane fusion. Components of the poxvirus entry fusion complex that have been structurally assessed to date share no known homology with all other type I, II and III viral fusion proteins, and the large number of fusion protein components renders it a unique system to investigate poxvirus-mediated membrane fusion. Here, we determined the NMR structure of a truncated version of vaccinia A28 protein. We also expressed a soluble H2 protein and showed that A28 interacts with H2 protein at a 1:1 ratio in vitro. Furthermore, we performed extensive in vitro alanine mutagenesis to identify A28 protein residues that are critical for H2 binding, entry fusion complex formation, and virus-mediated membrane fusion. Finally, we used molecular dynamic simulations to model full-length A28-H2 subcomplex in membranes. In summary, we characterized vaccinia virus A28 protein and determines residues important in its interaction with H2 protein and membrane components. We also provide a structural model of the A28-H2 protein interaction to illustrate how it forms a 1:1 subcomplex on a modeled membrane.

microbiology↗

bioRxiv2023

Drought and recovery in barley: key gene networks and retrotransposon response.

O_LIDuring drought, plants close their stomata at a critical soil water content (SWC), together with diverse physiological, developmental, and biochemical responses. C_LIO_LIUsing precision-phenotyping lysimeters, we imposed pre-flowering drought on four barley varieties (Arvo, Golden Promise, Hankkija 673 and Morex) and followed their physiological responses. For Golden Promise, we carried out RNA-seq on leaf transcripts before and during drought, and during recovery, also examining retrotransposon BARE1 expression. Transcriptional data were subjected to network analysis. C_LIO_LIThe varieties differed by their critical SWC, Hankkija 673 responding at the highest and Golden Promise at the lowest. Pathways connected to drought and salinity response were strongly upregulated during drought; pathways connected to growth and development were strongly downregulated. During recovery, growth and development pathways were upregulated; altogether 117 networked genes involved in ubiquitin-mediated autophagy were downregulated. The differential response to SWC suggests adaptation to distinct rainfall patterns. C_LIO_LIWe identified several strongly differentially expressed genes not earlier associated with drought response in barley. BARE1 transcription is strongly transcriptionally upregulated by drought and downregulated during recovery unequally between the investigated cultivars. The downregulation of networked autophagy genes suggests a role for autophagy in drought response; its importance to resilience should be further investigated. C_LI

plant biology↗

bioRxiv2023

m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

RNA N6-methyladenosine (m6A) modification, balanced by methyltransferases and demethylases, has recently been shown to play critical roles in multiple cancers. However, the mechanism by which m6A modification regulates long noncoding RNA (lncRNA) stability and function during cancer progression remains unclear. Here, we show that m6A demethylase fat mass and obesity-associated protein (FTO) removes the m6A modification on long intergenic noncoding RNA for kinase activation (LINK-A) and stabilizes it to promote cell proliferation and cytotoxic chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Mechanistically, LINK-A enhances the interaction between minichromosome maintenance complex component 3 (MCM3) and cyclin-dependent kinase 1 (CDK1) to promote MCM3 phosphorylation by CDK1. MCM3 is a subunit of the hexameric protein complex and its phosphorylation facilitates loading of the MCM complex onto chromatin, which promotes cell cycle progression and subsequent cell proliferation. Meanwhile, LINK-A prevents the interaction of MCM3 and hypoxia-inducible factor 1 (HIF-1), abrogates MCM3-mediated transcriptional repression of HIF-1, and promotes glycolysis and chemoresistance of cancer cells. These results elucidate a mechanism whereby FTO-stabilized LINK-A plays oncogenic roles and present the FTO/LINK-A/MCM3/HIF-1 axis as a promising therapeutic target for ESCC.

cancer biology↗

bioRxiv2023

Preterm birth accelerates the maturation of spontaneous and resting activity in the visual cortex

Prematurity is among the leading risks for poor neurocognitive outcomes. The brains of preterm infants show alterations in structure and electrical activity, but the underlying circuit mechanisms are unclear. To address this, we performed a cross-species study of the electrophysiological activity in the visual cortices of prematurely born infants and mice. Using electroencephalography (EEG) in a sample of healthy preterm (N=29) and term (N=28) infants, we found that the maturation of the aperiodic EEG component was accelerated in the preterm cohort, with a significantly flatter 1/f slope when compared to the term infants. The flatter slope was a result of decreased spectral power in the theta and alpha bands and was correlated with the degree of prematurity. To determine the circuit and cellular changes that potentially mediate the changes in 1/f slope after preterm birth, we used in vivo electrophysiology in preterm mice and found that, similar to infants, preterm birth results in a flattened 1/f slope. We analyzed neuronal activity in the visual cortex of preterm mice (N=6 preterm and 9 term mice) and found suppressed spontaneous firing of neurons. Using immunohistochemistry, we further found an accelerated maturation of inhibitory circuits. In both preterm mice and infants, the functional maturation of the cortex was accelerated, underscoring birth as a critical checkpoint in cortical maturation. Our study points to a potential mechanism of preterm birth-related changes in resting neural activity, highlighting the utility of a cross-species approach in studying the neural circuit mechanisms of preterm birth-related neurodevelopmental conditions.

neuroscience↗

bioRxiv2023

Widespread distribution and evolution of poxviral entry-fusion complex proteins in giant viruses

Poxviruses are known to encode a set of proteins that form an entry-fusion complex (EFC) to mediate virus entry. However, the diversity, evolution, and origin of these EFC proteins remain poorly understood. Here we identify the EFC protein homologs in poxviruses and other giant viruses of phylum Nucleocytoviricota. The 11 EFC genes are present in almost all pox-viruses, with the two smallest, G3 and O3, absent in Entomopoxvirinae and basal lineages of Chordopoxvirinae. Five of the EFC genes are further grouped into two families, A16/G9/J5 and F9/L1, which are widely distributed across other major lineages of Nucleocytoviricota, including metagenome-assembled genomes, but are generally absent in viruses infecting algae or non-amoebozoan heterotrophic protists. The A16/G9/J5 and F9/L1 families co-occur, mostly as single copies, in 93% of the non-Poxviridae giant viruses that have at least one of them. Distribution and phylogenetic patterns suggest that both families originated in the ancestor of Nucleocytoviricota. In addition to the Poxviridae genes, homologs from each of the other Nucleo-cytoviricota families are largely clustered together, suggesting their ancient presence and vertical inheritance. Despite deep sequence divergences, we observed noticeable conservation of cysteine residues and predicted structures between EFC proteins of Poxviridae and other families. Overall, our study reveals widespread distribution of these EFC protein homologs beyond pox-viruses, implies the existence of a conserved membrane fusion mechanism, and sheds light on host range and ancient evolution of Nucleocytoviricota. ImportanceFusion between virus and host membranes is critical for viruses to release genetic materials and to initiate infection. Whereas most viruses use a single protein for membrane fusion, poxviruses employ a multi-protein entry-fusion complex (EFC). We report that two major families of the EFC proteins are widely distributed within the virus phylum Nucleocytoviricota, which include poxviruses and other dsDNA "giant viruses" that infect animals, amoebozoans, algae, and various microbial eukaryotes. Each of these two protein families is structurally conserved, traces its origin to the root of Nucleocytoviricota, was passed down to the major subclades of Nucleocytoviricota, and is retained in most giant viruses known to infect animals and amoebozoans. The EFC proteins therefore represent a potential mechanism for virus entry in diverse giant viruses. We hypothesize that they may have facilitated the infection of an animal/amoebozoan-like host by the last Nucleocytoviricota common ancestor.

evolutionary biology↗

bioRxiv2023

Comparing rapid rule-learning strategies in humans and monkeys

Inter-species comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of macaque monkey and human strategies on an analogue of the Wisconsin Card Sort Test, a widely studied and applied multi-attribute measure of cognitive function, wherein performance requires the inference of a changing rule given ambiguous feedback. We found that well-trained monkeys rapidly infer rules but are three times slower than humans. Model fits to their choices revealed hidden states akin to feature-based attention in both species, and decision processes that resembled a Win-stay lose-shift strategy with key differences. Monkeys and humans test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidates. An attention-set based learning stage categorization revealed that perseveration, random exploration and poor sensitivity to negative feedback explain the under-performance in monkeys.

animal behavior and cognition↗

bioRxiv2022

Searching memory in time and space

We investigated memory encoding and retrieval during a quasi-naturalistic spatial-episodic memory task in which subjects delivered items to landmarks in a desktop virtual environment and later recalled the delivered items. Transition probabilities and latencies revealed the spatial and temporal organization of memory. As subjects gained experience with the town, their improved spatial knowledge led to more efficient navigation and increased spatial organization during recall. Subjects who exhibited stronger spatial organization exhibited weaker temporal organization. Scalp-recorded electroencephalographic (EEG) signals revealed spectral correlates of successful encoding and retrieval. Increased theta power (T +) and decreased alpha/beta power (A-) accompanied successful encoding, with the addition of increased gamma (G+) accompanying successful retrieval. Logistic-regression classifiers trained on spectral features reliably predicted mnemonic success in held-out sessions. Univariate and multivariate EEG analyses revealed a similar spectral T +A-G+ of successful memory. These findings extend behavioral and neural signatures of successful encoding and retrieval to a naturalistic task in which learning occurs within a spatiotemporal context.

neuroscience↗

bioRxiv2022

The C-terminal domain of RNase H and the C-terminus amino acid residue regulate virus release and autoprocessing of a defective HIV-1 possessing M50I and V151I changes in integrase

Previously, we reported that an HIV-1 variant containing Met-to-Ile change at codon 50 and Val-to-Ile mutation at codon 151 of integrase (IN), HIV(IN:M50I/V151I), was an impaired virus. Despite the mutations being in IN, the virus release was significantly suppressed (p < 0.0001) and the initiation of autoprocessing was inhibited; the mechanism of the defect remains unknown. In the current study, we attempted to identify the critical domains or amino acid (aa) residue(s) that promote defects in HIV(IN:M50I/V151I), using a series of variants, including truncated or aa-substituted RNase H (RH) or IN. The results demonstrated that virus release and the initiation of autoprocessing were regulated by the C-terminal domains (CTDs) of RH and IN. Further studies illustrated that Asp at codon 109 of RH CTD and Asp at the C terminus of IN induces the defect. This result indicated that the CTD of RH and IN in GagPol and particular aa positions in RH and IN regulated the virus release and the initiation of autoprocessing, and these sites could be potential targets for the developing new therapies.

microbiology↗