Biology subjects

Basu, D.

Publications and source records attributed to Basu, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Linking cross-species hemodynamics with neuronal activity in prefrontal cortex during abstract sequence viewing

The ability to identify and predict abstract sequential patterns enables a wide range of complex cognition and behavior, but the mechanisms mediating it remain poorly understood. Lateral prefrontal cortex (LPFC) has been implicated in abstract sequence tracking in both humans and macaques, but it is unclear whether underlying processes are shared across species. Furthermore, most existing evidence relies on hemodynamic responses, which can have variable relationships with neuronal activity in a region. We leverage a combination of human fMRI, monkey fMRI, and monkey electrophysiology to bridge these gaps. We find that humans and non-human primates show functionally homologous hemodynamic activation in LPFC during abstract sequence viewing, and neuronal responses within fMRI-targeted regions in macaques contain information about sensory and abstract variables in parallel. However, neuronal activity does not directly mirror hemodynamic responses, and abstract sequence responses are found both near and far from fMRI peaks. In contrast, distinct dynamics of spiking activity are selectively present near fMRI peaks, suggesting that temporal coordination across neurons may influence hemodynamic activity in prefrontal cortex. Together, these experiments establish a link between human brain activity, macaque fMRI, and single neuron responses, providing a window into the neural processes that mediate abstract sequence detection.

neuroscience↗

bioRxiv2026

A bacteriophage split DNA polymerase incorporates a sliding clamp-derived processivity subunit

Viruses that infect bacteria, termed bacteriophages or phages, typically encode their own DNA replication machinery that rapidly generates many copies of the phage genomic DNA in an infected cell. Nucleus-forming phages of the chimallivirus family possess a distinctive repertoire of predicted DNA replication proteins, with two proteins annotated as DNA polymerases plus a DnaB-like replicative helicase, but lacking an identified primase or sliding clamp protein. Here, we demonstrate that in the Pseudomonas aeruginosa-infecting chimallivirus PhiKZ, the core DNA polymerase comprises a stable 1:1 complex of two DNA polymerase subunits, termed DNAPN and DNAPC. A 2.1 A resolution cryoelectron microscopy structure of this core complex reveals homology to other phage and bacterial B-family DNA polymerases. Next, we identify a direct but transient interaction between the core DNA polymerase complex and a third protein termed Rhc, which possesses an N-terminal RNase H domain and a C-terminal domain related to DNA sliding clamp proteins. Cryoelectron microscopy structures of a stabilized DNA polymerase-Rhc complex, and of this complex bound to a primer-template DNA, reveal a single Rhc subunit that cooperates with the DNA polymerase thumb domain to bind double-stranded DNA emerging from the DNA polymerase active site. While the Rhc RNase H domain is not resolved in our structures, this domain is situated such that it could degrade RNA associated with an incoming template DNA strand. In vitro primer-extension assays show that Rhc strongly boosts DNA polymerase activity, and that this boost relies on the Rhc-DNA polymerase interface we observe in our structures. Overall, our findings reveal a distinctive chimallivirus-specific DNA replication machine with an integrated DNA-binding subunit related to sliding clamp proteins, and a flexibly-linked RNase H domain.

biochemistry↗

bioRxiv2026

A bifunctional RNase H protein supports DNA replication and transcription in nucleus-forming Chimalliviridae phages

Jumbo bacteriophages of the Chimalliviridae family replicate their genomes within a proteinaceous phage nucleus that spatially segregates viral DNA replication and transcription from translation. While the phage nucleus protects viral DNA from host defenses, it also imposes unique constraints on genome replication and gene expression. Here we identify the phage-encoded protein Rhc (RNase H-clamp) as a central mediator of genome transactions within the phage nucleus. Using the Escherichia coli infecting bacteriophage Goslar, we show that Rhc functions as an essential component of a non-canonical three-subunit DNA polymerase complex composed of DNAPN, DNAPC and Rhc. Rhc physically interacts with the DNAPC subunit, and both the catalytic activity of Rhc's N-terminal RNase H domain and its C-terminal sliding clamp-derived DNA binding domain are required for genome replication, nuclear maturation, and productive infection. Further, Goslar Rhc also supports transcription within the phage nucleus through a function that is separable from its DNA replication function. Rhc depletion results in reduced transcription of a subset of late genes, in a pattern that suggests a role for Rhc in resolving R-loops. Imaging and cryo-electron tomography reveal that loss of Rhc arrests phage development at a nascent nuclear stage, uncoupling nuclear assembly from maturation. Together, these findings identify Rhc as a multifunctional nuclear factor that mediates both DNA replication and transcription in nucleus-forming jumbo phages, revealing how viruses repurpose a conserved enzymatic activity to coordinate gene expression within a compartmentalized replication environment.

cell biology↗

bioRxiv2026

The Estuary Effect: Variations in Temperature and Salinity Alter msh Promoter Activity in Vibrio cholerae

Vibrio cholerae, the facultative pathogen underlying cholera, naturally inhabits warm aquatic estuaries. Environmental persistence is enhanced by the ability of V. cholerae to colonize host reservoirs and form multicellular biofilms, causing seasonally endemic outbreaks in many tropical regions. Most toxigenic strains utilize the type IVa mannose-sensitive hemagglutinin (MSHA) pilus for host reservoir colonization and biofilm formation. Temperature and salinity can alter V. cholerae biofilm formation, yet their impact on MSHA production specifically remains largely unknown. Here, we utilized transcriptional reporters of predicted msh promoters (msh-P1/msh-P2/msh-P3) and functional assays, to determine temperature and salinity impacts on msh expression and pilus biogenesis. Under standard laboratory conditions (30{degrees}C, 1% NaCl) only msh-P1/P2 are active and inversely-coordinated with one another. Both msh-P1/P2 activity were elevated by high temperature (37{degrees}C) and low salinity (0.25%/0.5% NaCl), and reduced by low temperature (20{degrees}C/25{degrees}C) and high salinity (2%/3% NaCl). Temperature-mediated alterations in promoter activity were not immediately reflected in changes to cell-surface MSHA levels, whereas high salinity led to decreased MSHA production. Combining high temperature (37{degrees}C) and high salinity (2%/3% NaCl), attenuated the salinity-mediated reduction of msh-P1/P2 activity. Biofilm biomass levels were only substantially heightened at 25{degrees}C and 20{degrees}C, likely a result of no temperature-dependent changes in cell-surface MSHA, and additional temperature-controlled biofilm regulation previously described. We also found msh-P1/P2 promoter activity and MSHA production varies widely across toxigenic O1 and O139 serogroups despite complete sequence homology. These results shed new light on how key signals regulate MSHA pilus production to support V. cholerae persistence in aquatic environments.

microbiology↗

bioRxiv2026

Structure of the Chimalliviridae bacteriophage Goslar reveals host recognition and infection machinery

Large-genome bacteriophages (phages) of the Chimalliviridae family possess a distinctive life cycle, building compartments inside infected bacterial cells that broadly protect their genomes from host defenses. Here, we use cryoelectron microscopy to determine a high-resolution structure of the E. coli-infecting Chimalliviridae phage Goslar, generating a composite model with 2,888 protein chains from 28 different structural proteins, totaling over 1.4 million amino acid residues. Our structure reveals the architecture of the Goslar capsid, portal, tail, and baseplate, highlighting structural similarities and differences with other tailed phages. Combining our structural data with quantitative mass spectrometry of Goslar virions, we identify several high-copy virion-associated proteins that likely play key roles when injected into host cells upon infection. We also identify a Chimalliviridae-specific family of proteins that form long, flexible filaments anchored at the phage baseplate and which incorporate carbohydrate-binding domains, suggesting a key role in host recognition.

microbiology↗

bioRxiv2026

Regulation of itch-induced scratching by nucleus accumbens dopamine receptor-expressing neurons

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch-scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaShD1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaShD1R neurons activity promotes scratching bouts, whereas NAc LaShD2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaShD1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaShD2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.

neuroscience↗

bioRxiv2026

Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor azenosertib (ZN-c3) mediates tumor control through both cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells and conventional dendritic cells. Mechanistically, HPV tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.

cancer biology↗

bioRxiv2025

E2 displacement of CIP2A from TOPBP1 activates the DNA damage response during papillomavirus life cycles

The papillomavirus life cycle is intricately linked to epithelial differentiation, and the virus manipulates the differentiation process to facilitate viral production. One such manipulation is activation of the DNA damage response (DDR) which promotes viral replication via homologous recombination. This report demonstrates that the papillomavirus transcription/replication/segregation factor E2 activates the DNA damage response (DDR). During differentiation, E2 displacement of CIP2A from TOPBP1 causes CIP2A to bind and inhibit PP2A resulting in DDR activation via ATM phosphorylation. The DDR promotes inhibitory interaction of DBC1 with the class III deacetylase SIRT1, which further boosts the DDR via increased acetylation and stability of viral and host proteins. E2 forms a complex with TOPBP1 and ATM, while preventing ATR activation by blocking TOPBP1-ATR interaction. This "ATM up ATR down" phenotype promotes viral replication via ATM promotion of homologous recombination, and cell proliferation via inhibition of ATR. We demonstrate this mechanism of DDR activation in multiple systems: keratinocytes expressing only E2, in foreskin keratinocytes immortalized by HPV16, in HPV16 positive keratinocytes derived from a cervical lesion, in pre-neoplastic lesions induced by mouse papillomavirus MmuPV1, in head and neck cancer cell lines that retain E2 expression, and in HPV16 positive oropharyngeal patient derived xenografts that retain E2 expression. ATM inhibition preferentially killed cells expressing E2, presenting a novel strategy for treating HPV early preneoplasia and a large subset of HPV+ oropharyngeal cancers retaining E2 expression and episomal genomes.

cancer biology↗

bioRxiv2025

Divergent ontogeny of Tissue Resident Memory and Tissue Resident Exhausted CD8+ T cells underlies distinct functional potential

Persistent antigen stimulation promotes differentiation of exhausted CD8+ T (TEX) cells. TEX cells are distinct from circulating memory T (TCIRCM) cells but share many features with tissue-resident memory (TRM) cells established following infection resolution. CD8+ T cells co-expressing residency- and exhaustion-associated molecules in chronic diseases often correlate with clinical outcomes. However, the relationship between these cells and conventional TRM or TEX cells remains unclear. Here, we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are ontologically and functionally distinct from TRM cells generated after antigen clearance. TR-TEX phenotypically resembled TRM cells but were regulated by distinct transcriptional networks and were uniquely dependent on Tox for residency programming. Although TEX progenitor cells acquired residency features upon entering chronically infected tissues, they failed to generate conventional TRM cells after antigen withdrawal. Conversely, TRM cells were able to differentiate into TEX cells during chronic antigen stimulation. Deriving cell-state specific transcriptional signatures revealed a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally distinct cell types that share a tissue-residency program but have distinct roles in disease control.

immunology↗

bioRxiv2025

Subtype-Specific Roles of Nigrostriatal Dopaminergic Neurons in Motor and Associative Learning

Nigrostriatal dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) comprise distinct subtypes defined by unique gene expression profiles and anatomical characteristics. However, their specific contributions to motor and non-motor functions remain elusive. Using Calbindin 1 (Calb1) and Aldehyde dehydrogenase 1a1 (Aldh1a1) as molecular markers, we investigated the functions of these nigrostriatal DAN subtypes in mice. Through intersectional genetics and chemogenetic manipulation, we selectively inhibited Calb1+ or Aldh1a1+ DANs by stereotactically delivering an adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) into the SNc of ThFlp; Calb1IRESCre or ThFlp; Aldh1a1CreERT2 double knock-in (KI) mice. This approach enabled subtype-specific neuronal inhibition via designer receptors exclusively activated by designer drugs (DREADD). Following DREADD ligand administration, both Calb1+ and Aldh1a1+ DAN-inhibited mice exhibited significant reduction in voluntary movement and impaired motor skill learning, demonstrating their essential roles in motor function. However, only Calb1+ DAN inhibition affected early associative-learning behavior, suggesting a unique role in reinforcement learning. These findings establish Calb1+ and Aldh1a1+ nigrostriatal DANs as key regulators of movement and motor learning, with Calb1+ neurons additionally modulating reward-based associative learning. This study advances our understanding of the functional heterogeneity of nigrostriatal DAN subtypes and identifies potential therapeutic targets for addressing motor and non-motor deficits in Parkinsons disease.

neuroscience↗

bioRxiv2025

MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by Preserving Mitochondrial Integrity

Intrinsic antiviral defenses can restrict infection independent of paracrine interferon (IFN) signaling. While mitochondrial homeostasis is essential for immunity, its direct role in viral restriction remains incompletely understood. Here, we identify mitochondrial antiviral signaling protein (MAVS) as a central effector of a potent IFN-independent antiviral immunity orchestrated though mitochondrial safeguarding. We demonstrate that MAVS is critical for mitochondrial integrity as its loss leads to mitochondrial fragmentation, depolarization, and elevated mitophagy, alongside impaired bioenergetics and protein import. Mechanistically, MAVS maintains mitochondrial integrity by stabilizing the translocase of the outer membrane (TOM) complex and sustaining the abundance of its core components. Remarkably, this mitochondria-driven immunity restricts SARS-CoV-2 replication even under IFN-deficient conditions, and operates alongside the IFN pathways during JEV infection. Our findings redefine MAVS as a mitochondrial guardian that preserves organellar stability to enact host defense. These results highlight mitochondrial integrity as a fundamental determinant of broad antiviral immunity, integrating intrinsic and IFN-dependent mechanisms to counteract viral pathogenesis.

immunology↗

bioRxiv2024

Both tobacco TA29 and sesame GN13 promoters provide anther-specific GUS expression in transgenic sesame (Sesamum indicum L.)

Yield improvement is one of the most concerning areas of the "Queen of Oilseed" sesame (Sesamum indicum L.) for its successful commercialisation. Heterosis breeding is an alternate approach for improving sesame compared to the time- and labour-consuming conventional breeding. However, tedious hand emasculation and pollination processes restrict the implementation of commercial heterosis on sesame. The unavailability of male sterile, restorer, and maintainer lines further complicates the problem. Biotechnological gene manipulation can silence anther-specific vital gene(s) leading to male sterility. Anther-specific gene study is therefore crucial to reach such a goal. In this study, we have cloned two established anther-specific promoters: sesame SiBGproplus (hereafter GN13, NCBI accession no. KT246471) and tobacco TA29 (NCBI accession no. X52283) in the plant expression vector pCAMBIA2301 producing respective GN13::GUS and TA29::GUS chimeric vectors. We recovered putatively transgenic T0 sesame lines using conventional Agrobacterium-mediated transformation with 1.76% and 1.71% frequencies, respectively. The T0 lines were segregated at the 3:1 Mendelian segregation ratio for kanamycin resistance and generated T1 transgenic lines by self-fertilisation. Most of the T1 transgenics had a single copy of transgene integration. The histological assay revealed the tapetum-specific GUS expression in the T1 transgenic lines; GUS expression was undetected in other tested plant parts. The results depict successful anther/tapetum-specific expression of two promoters in transgenic sesame lines. In further research, these promoters could be used for anther-specific cytotoxic gene expression, RNAi, or CRISPR-mediated mutational approaches to destroy androecium selectively and exhibit male sterility in sesame, resulting in heterosis-mediated improvement.

plant biology↗

bioRxiv2024

Association of oropharyngeal cancer recurrence with tumor-intrinsic and immune-mediated sequelae of reduced genomic instability

BackgroundLimited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors. Methods50 HPV+ OPSCCs that later recurred (cases) and 50 non-recurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability. ResultsCases downregulated pathways linked to anti-tumor immunity (FDR-adjusted p<.05) and contained fewer tumor-infiltrating lymphocytes (p<.001), including cytotoxic T-cells (p=.005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r=.603, p<.001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (p=.006) and {gamma}-H2AX (p=.005) and downregulated pro-inflammatory components of the cytoplasmic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to three external cohorts. ConclusionsWe provide novel evidence that limiting genomic instability makes tumor-intrinsic and immune-mediated contributions to HPV+ OPSCC recurrence risk, opening opportunities to detect and target this treatment-resistant biology.

cancer biology↗

bioRxiv2024

Optimisation of explant-specific isolation, culture, and micro-callus induction of sesame (Sesamum indicum L.) protoplasts

The low yield of sesame (Sesamum indicum L.) compared to other oilseed crops hinders its successful commercialisation process. Sesame yield improvement using molecular-biotechnological tools involving gene manipulation is a better alternative than traditional breeding because it requires less time, effort, and labour. Protoplasts are plant cells devoid of the cell wall. Protoplast systems are deployed as versatile cell-based tools for tissue culture, genomics, transcriptomics, proteomics, metabolomics, and epigenetics studies leading to crop improvement. Inadequate reports of sesame protoplasts restrict its potential use in this crop. In the present study, we are reporting the successful isolation and purification of sesame protoplasts from four different sesame explants: hypocotyl, internode, leaf, and hypocotyl-derived callus using the one-step enzymatic digestion method. We have carefully optimised enzyme combinations, digestion durations, temperatures, and shaking speeds for every tested explant to obtain the highest protoplast yield and viability. Maximum yield (9.9 x 106 protoplasts/gm fresh weight) and viability (92.1%) were achieved from callus explants. We purified isolated protoplasts by floating them over a 20% (w/v) sucrose solution. Among tested media, callus-derived protoplasts divided rapidly in Murashige and Skoog broth medium supplemented with 17.77 M 6-benzylaminopurine (BAP) and 0.54 M -naphthalene acetic acid (NAA). In the same medium, protoplasts divided into the 2-cell stage after 2-3 days of culture and progressed to the micro-callus stage at 0.24 {+/-} 0.05% frequency within 16-20 days of culture. Sesame protoplasts could be an excellent system for investigating potential avenues for biotechnological improvements of sesame including transient gene expression and CRISPR-based studies.

plant biology↗

bioRxiv2024

Monkey lateral prefrontal cortex subregions differentiate between perceptual exposure to visual stimuli

Each day, humans must parse visual stimuli with varying amounts of perceptual experience, ranging from incredibly familiar to entirely new. Even when choosing a novel to buy at a bookstore, one sees covers they have repeatedly experienced intermixed with recently released titles. Visual exposure to stimuli has distinct neural correlates in the lateral prefrontal cortex (LPFC) of nonhuman primates. However, it is currently unknown if this function may be localized to specific subregions within LPFC. Specifically, we aimed to determine whether the posterior fundus of area 46 (p46f), an area that responds to deviations from learned sequences, also responds to less frequently presented stimuli outside of the sequential context. We compare responses in p46f to the adjacent subregion, posterior ventral area 46 (p46v), which we propose may be more likely to show exposure-dependent responses due to its proximity to novelty responsive regions. To test whether p46f or p46v represent perceptual exposure, we performed awake functional magnetic resonance imaging (fMRI) on three male monkeys as they observed visual stimuli that varied in their number of daily presentations. Here we show that p46v, but not p46f, shows preferential activation to stimuli with low perceptual exposure, further localizing exposure-dependent effects in monkey LPFC. These results align with previous research that has found novelty responses in ventral LPFC and are consistent with the proposal that p46f performs a sequence-specific function. Further, they expand on our knowledge of the specific role of LPFC subregions and localize perceptual exposure processing within this broader brain region.

neuroscience↗

bioRxiv2024

Monkey dorsolateral prefrontal cortex shows anatomically and functionally specific responses to sequential but not temporal or image changes

Sequential information permeates daily activities, such as when watching for the correct series of buildings to determine when to get off the bus or train. These sequences include periodicity (the spacing of the buildings), the identity of the stimuli (the kind of house), and higher-order more abstract rules that may not depend on the exact stimulus (e.g. house, house, house, business). Previously, we found that the posterior fundus of area 46 in the monkey lateral prefrontal cortex (LPFC) responds to rule changes in such abstract visual sequences. However, it is unknown if this region responds to other components of the sequence, i.e., image periodicity and identity, in isolation. Further, it is unknown if this region dissociates from other, more ventral LPFC subregions that have been associated with sequences and their components. To address these questions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task contained abstract visual sequences, and the other contained no visual sequences but maintained the same image periodicity and identities. We found the fundus of area 46 responded only to abstract sequence rule violations. In contrast, the ventral bank of area 46 responded to changes in image periodicity and identity, but not changes in the abstract sequence. These results suggest a functional specialization within anatomical substructures of LPFC to signal different kinds of stimulus regularities. This specialization may provide key scaffolding to identify abstract patterns and construct complex models of the world for daily living. Significance StatementDaily tasks, such as a bus commute, require tracking or monitoring your place (same, same, same, different building) until your stop. Sequence components such as rule, periodicity (timing), and item identity are involved in this process. While prior work located responses to sequence rule changes to area 46 of monkey lateral prefrontal cortex (LPFC) using awake monkey fMRI, less was known about other components. We found that LPFC subregions differentiated between sequence components. Area 46 posterior fundus responded to abstract visual sequence rule changes, but not to changes in image periodicity or identity. The converse was true for the more ventral, adjacent shoulder region. These results suggest that interactions between adjacent LPFC subregions provide key scaffolding for complex daily behaviors.

neuroscience↗

bioRxiv2022

Monkey dorsolateral prefrontal cortex represents abstract visual sequences during a no-report task

Monitoring sequential information is an essential component of our daily lives. Many of these sequences are abstract, in that they do not depend on the individual stimuli, but do depend on an ordered set of rules (e.g., chop then stir when cooking). Despite the ubiquity and utility of abstract sequential monitoring, little is known about its neural mechanisms. Human rostrolateral prefrontal cortex (RLPFC) exhibits specific increases in neural activity (i.e., "ramping") during abstract sequences. Monkey dorsolateral prefrontal cortex (DLPFC) has been shown to represent sequential information in motor (not abstract) sequence tasks, and contains a sub-region, area 46, with homologous functional connectivity to human RLPFC. To test the prediction that area 46 may represent abstract sequence information, and do so with parallel dynamics to those found in humans, we conducted functional magnetic resonance imaging (fMRI) in monkeys. When monkeys performed no-report abstract sequence viewing, we found that left and right area 46 responded to abstract sequential changes. Interestingly, responses to rule and number changes overlapped in right area 46 and left area 46 exhibited responses to abstract sequence rules with changes in ramping activation, similar to that observed in humans. Together, these results indicate that monkey DLPFC monitors abstract visual sequential information, potentially with a preference for different dynamics in the two hemispheres. More generally, these results show that abstract sequences are represented in functionally homologous regions across monkeys and humans. Significance StatementDaily, we complete sequences that are "abstract" because they depend on an ordered set of rules (e.g., chop then stir when cooking) rather than the identity of individual items. Little is known about how the brain tracks, or monitors, this abstract sequential information. Based on previous human work showing abstract sequence related dynamics in an analogous area, we tested if monkey dorsolateral prefrontal cortex (DLPFC), specifically area 46, represents abstract sequential information using awake monkey fMRI. We found that area 46 responded to abstract sequence changes, with a preference for more general responses on the right and dynamics similar to humans on the left. These results suggest that abstract sequences are represented in functionally homologous regions across monkeys and humans.

neuroscience↗

bioRxiv2022

Systematic analysis of IL-1 cytokine signaling suppression by high-risk HPV oncoproteins

Human papillomavirus (HPV) E6 and E7 oncoproteins are expressed at all stages of HPV-mediated carcinogenesis and are essential drivers of cancers caused by high-risk HPV. Some of the activities of HPV E6 and E7, such as their interactions with host cellular tumor suppressors, have been characterized extensively. There is less information about how high-risk HPV E6 and E7 alter cellular responses to cytokines that are present in HPV-infected tissues and are an important component of the tumor microenvironment. We used several models of HPV oncoprotein activity to assess how E6 and E7 alter the cellular response to the pro-inflammatory cytokine IL-1{beta}. Models of early-stage HPV infection and of established HPV-positive head and neck cancers exhibited similar dysregulation of IL-1 pathway genes and suppressed transcriptional responses to IL-1{beta} treatment. Such overlap in cell responses supports that changes induced by HPV E6 and E7 early in infection could persist and contribute to a dysregulated immune environment throughout carcinogenesis. HPV E6 and E7 also drove the upregulation of several suppressors of IL-1 cytokine signaling, including SIGIRR, both in primary keratinocytes and in cancer cells. SIGIRR knockout was insufficient to increase IL-1{beta}-dependent gene expression in the presence of HPV16 E6 and E7, suggesting that multiple suppressors of IL-1 signaling contribute to dampened IL-1 responses in HPV16-positive cells. IMPORTANCEHuman papillomavirus (HPV) infection is responsible for nearly 5% of the worldwide cancer burden. HPV-positive tumors develop over years to decades in tissues that are subject to frequent stimulation by pro-inflammatory cytokines. However, the effects of HPV oncoproteins on the cellular response to cytokine stimulation are not well defined. We analyzed IL-1 cytokine signaling in several models of HPV biology and disease. We found that HPV16 E6 and E7 oncoproteins mediate a broad and potent suppression of cellular responses to IL-1{beta} in models of both early and late stages of carcinogenesis. Our data provide a resource for future investigation of IL-1 signaling in HPV-positive cells and cancers.

microbiology↗