Biology subjects

Ren, L.

Publications and source records attributed to Ren, L..

At least 19 recordsLinked to original sources

bioRxiv2026

A multivalent docking platform and Rcn1-mediated inhibition control the extent of calcineurin recruitment to the cell division site for the dephosphorylation of multiple cytokinetic proteins

Cytokinesis requires coordinated signaling to ensure the accurate physical separation of daughter cells. Calcineurin (CN), a conserved Ca2+/calmodulin-dependent phosphatase, is required for cytokinesis in organisms ranging from yeast to humans, yet how CN is regulated at the division site and the substrates through which it promotes cell division remain poorly understood. Here we use the fission yeast Schizosaccharomyces pombe, which display striking cell division defects in the absence of CN, to define how CN is anchored at the cell division site. We show that CN recruitment to the cytokinetic ring (CR) requires its PxIxIT- and LxVP-binding surfaces and is mediated by multivalent interactions with the CR components paxillin-like Pxl1 and the F-BAR protein Cdc15. Disrupting these interactions nearly eliminates CN from the CR and causes gross cytokinetic defects similar to complete loss of CN function. Cell cycle stage-specific quantitative phosphoproteomics combined with proximity labeling-based proteomics were used to identify candidate CN substrates involved in cytokinesis. Validation of a cohort of these proteins localizing to the CR, including the F-BAR protein Rga7, the actin regulator Aim21 and three protein kinases, revealed that CN targets a broad network of structural and signaling components involved in cell division. We also identify the conserved CN inhibitor Rcn1 as a CN substrate and show that Rcn1 restricts CN accumulation at the CR to provide an additional layer of spatial regulation. Thus, spatial control of CN enables proper protein dephosphorylation for successful cytokinesis.

cell biology↗

bioRxiv2026

Early Emergence of Cultural Differences in Audiovisual Speech Perception

Integrating auditory and visual cues is a hallmark of human speech perception, yet adults from East Asian backgrounds show less reliance on visual speech than their Western counterparts. The origins of this cultural difference, however, remain unknown. To investigate whether this divergence is established early in infancy, we examined audiovisual integration in 6- to 12- month-old White Canadian (n=111) and Chinese (n=115) infants using a novel paradigm measuring their perception of the McGurk effect. Across four experiments, we found a clear developmental divergence: Canadian infants showed a stable McGurk effect from 6 months onward, whereas Chinese infants showed a more protracted developmental trajectory, a cultural pattern that was further highlighted when their integration was challenged by other-race faces. These findings provide the first direct evidence that cultural differences in multisensory speech perception are established within the first year of life, suggesting that the brains strategy for binding sight and sound is shaped by early experience, with broad implications for theories of language acquisition and developmental science.

developmental biology↗

bioRxiv2026

Pangenome discovery and characterization of human protein-coding duplicated genes

Protein-coding genes mapping to high-identity segmental duplications (SDs) have been difficult to annotate and characterize and are the source of most previously unknown protein-coding genes being discovered as part of the human pangenome. Here, we combine long-read assembled human genomes (298) and long-read transcriptome data (5.6 billion full-length cDNA from 83 tissues) to phylogenetically interrogate 493 gene families discovering 2713 potentially copy number polymorphic genes not present in the human reference genome. For reference SD gene families where paralog specificity can be assigned, we find that 60.0% are expressed and maintain open reading frames, with 45.7% showing high expression in brain, embryo, or testis. We revise 386 gene models, including 150 that absent or different from current T2T-CHM13 gene annotation and 236 (35.1%) pseudogenes as protein-coding where we find evidence of transcription, an open reading frame, and chromatin-accessible promoters. We find that 24.2% of SD genes show evidence of constraint for both copy number and amino acid mutation. The majority of these constraint genes are ancestral, whereas only 16.2% of derived duplicated genes that emerged recently in the human lineage show evidence of constraint. The pangenome provides unparalleled specificity to understand genetic variation in SD genes allowing us to distinguish functional genes from pseudogenes and highlighting potential gene innovations that arose most recently in human evolution.

genomics↗

bioRxiv2026

Reference Regulatory Element-Guided Gene Expression Analysis for Mechanistic Inference of Gene Regulatory Networks

Regulatory genomics faces a depth-breadth gap: deep multi-omics provides regulatory detail but is difficult to scale, whereas broad expression datasets often lack the regulatory structure needed for mechanistic Gene Regulatory Network (GRN) analysis. We developed Regulatory Elements Guided Analysis (REGA), an interpretable framework that uses reference Regulatory Element (RE) catalogs to infer transcription factor (TF)-RE-gene programs from gene expression data. Across ChIP-seq, knockdown, Hi-C, cis- and trans-eQTL benchmarks, REGA prioritized functional REs, improved RE-gene and TF-gene inference over existing baselines, including methods using more data, and recovered coherent regulatory modules. In PsychENCODE snRNA-seq, REGA identified disease-associated modules and TF activities, linked regulatory dysregulation to genetic risk, and detected cross-cell-type neuronal-glial programs. In spatial transcriptomics, REGA linked cell-intrinsic regulatory programs with intercellular ligand-receptor communication; in Perturb-seq, it mapped perturbation responses to trait-associated regulatory architectures. REGA enables scalable, interpretable GRN analysis across expression datasets.

bioinformatics↗

bioRxiv2026

Systematic benchmarking of zero-shot utility and robustness in single-cell transcriptomic foundation models

Single-cell foundation models (scFMs) have emerged as powerful representation learning approaches for single-cell transcriptomics. However, the utility and robustness of their pretrained representations across diverse analytical tasks and data conditions remain insufficiently characterized, particularly in zero-shot settings without task-specific fine-tuning. Here, we systematically analyze zero-shot performance of single-cell transcriptomic representations across 20 methods, 6 downstream tasks and 1,607 datasets comprising nearly 21.8 million cells. We evaluate model behavior along three complementary dimensions: utility on original datasets, robustness to controlled changes in dataset structure, and exploratory associations between dataset characteristics and performance variation. Our results show that scFM performance is strongly task dependent, with no single method consistently outperforming others across cell- and gene-level analyses. Notably, high utility on original datasets did not necessarily translate into robustness under structural perturbations, and several top-ranking methods were sensitive to changes in cell number, gene number, class composition, class imbalance, and batch complexity. Conventional statistical and task-specific methods remained competitive in several settings, while greater computational cost did not consistently correspond to better performance. Driver analyses further identified task-specific associations between performance and dataset characteristics, including cell-type complexity, train-test class overlap, batch number, and regulatory target-set size. Together, these findings show that the zero-shot utility and robustness of pretrained scFM representations depend jointly on analytical task and dataset structure. Our study provides a practical basis for context-aware representation selection and underscores the importance of evaluating structural robustness alongside utility when developing and applying scFMs.

bioinformatics↗

bioRxiv2026

Population-scale Y chromosome assemblies reveal recurrent remodeling within constrained architectures

The human Y chromosome is among the most structurally dynamic chromosomes in the human genome, yet much of its diversity remains unresolved because of extensive palindromes, ampliconic gene families, satellite-rich heterochromatin and large segmental duplications. What remained unclear was how these diverse forms of variation fit together across the full chromosome, how often similar structures recur in different lineages, and which aspects of organization remain constrained despite rapid sequence turnover. Here, we generated and analyzed 142 nearly complete human Y chromosome assemblies from 17 major haplogroups spanning approximately 180,000 years of evolution, creating a population-scale resource for studying Y chromosome biology and diversity. These assemblies show that structural change on the Y chromosome is recurrent but constrained, even in its most repetitive regions. In the fertility-associated azoospermia factor c (AZFc) region, recurrent inversions, deletions, and complex rearrangements generate a limited repertoire of structural haplotypes. Multicopy ampliconic gene families follow distinct evolutionary paths: DAZ paralogues differ in structural constraint, RBMY evolves within a modular array, and TSPY copy number varies mainly through local expansion and contraction. The centromere and Yq12 heterochromatin vary greatly in size but retain a stable higher-order organization, including a single hypomethylated centromeric core and conserved Yq12 repeat composition and orientation. Methylation across palindromic and ampliconic regions is likewise structured by repeat class, copy order and local architecture. Together, these results provide a population-scale resource for the human Y chromosome and show that its rapid structural evolution is repeatedly funneled into a limited set of architectural outcomes.

genomics↗

bioRxiv2026

Novel Engineered AAV Variants Demonstrate Superior Blood-Brain Barrier Penetration and Safety in Non-Human Primates

Systemic delivery of adeno-associated virus (AAV) for gene therapy of central nervous system (CNS) disorders is limited by inefficient blood-brain barrier (BBB) penetration and dose-limiting toxicity in peripheral organs, notably the liver and dorsal root ganglia (DRG)1-5. Here, we report the development of novel AAV variants via a proprietary capsid engineering platform (REACH). In non-human primates (NHPs), intravenous administration of lead variants resulted in transgene expression levels in the brain that were 600-2000 fold higher than AAV9 at the RNA level, concomitant with a 10-50 fold reduction in liver tropism and minimal off-target exposure in the heart and DRG. These engineered capsids achieve unprecedented, pan-CNS transduction with a markedly improved safety profile, representing a transformative platform for treating a broad spectrum of neurological diseases.

neuroscience↗

bioRxiv2026

Population genomics reveal genetic variants associated with lunar-regulated spawning time in grass puffer

High and low tides occur twice a day (every [~]12.4 hours), with the largest tidal ranges during spring tides around new and full moons (every [~]14.765 days). Although lunar cycles shape diverse animal phenotypes, particularly the reproduction of coastal animals, the genetic basis of lunar-related rhythms remains unclear. Since phenotypic variation is a valuable resource for elucidating such mechanisms, we examined geographic variation in the lunar-regulated mass spawning of the grass puffer (Takifugu alboplumbeus) along the Japanese coast. Western populations spawned during the first half of the spring tides, whereas eastern populations spawned during the second half. Furthermore, the spawning was restricted to a narrow daily time window that occurred earlier in the western populations than in the eastern ones. Assuming that spawning is regulated by circadian gating, this geographic shift in the daily spawning window could account for the population difference in semilunar spawning timing. Consistent with this hypothesis, the free-running circadian period ({tau}), which can affect the phase of the gating window, was shorter in the western populations. Mathematical modeling recapitulated the observed geographic difference in the spawning time window based on variation in {tau}. To identify candidate genes responsible for these differences, we conducted population genomics analysis and identified proline-rich transmembrane protein 1-like (prrt1l) as a candidate. Expression of prrt1l was observed in the circadian pacemaker suprachiasmatic nucleus, and triple CRISPR F0 knockout of prrt1l shortened the free-running period in larvae. These findings suggest a potential mechanism underlying the geographic variation in lunar-synchronized spawning behavior. HighlightsO_LIThe geographic variation exists in the lunar-regulated spawning of the grass puffer, with differences in spawning dates and times between western and eastern Japan. C_LIO_LIThe free-running period of western populations is shorter than that of eastern populations, which is consistent with their earlier spawning timing. C_LIO_LIPopulation genomics analysis identified prrt1l as a candidate gene harboring population-specific missense mutations, the knockout of which shortens the free-running period. C_LI

evolutionary biology↗

bioRxiv2026

LRP6-Guided Engineering of AAV9 Variants with Enhanced Blood-Brain Barrier Penetration and Reduced Liver Tropism in Non-Human Primates

The blood-brain barrier (BBB) severely restricts the delivery of systemically administered adeno-associated virus (AAV) vectors for central nervous system (CNS) gene therapy. To overcome this limitation, we engineered a library of AAV9 capsid variants through rational design focused on the low-density lipoprotein receptor-related protein 6 (LRP6), a conserved mediator of transcytosis. A multi-tiered screening strategy, encompassing human BBB endothelial cells followed by neuronal and glial target cells in vitro, identified three lead variants (QL9-21, QL9-22, and QL9-25) with markedly enhanced transduction potential. In mice, these variants achieved a 5-28 fold increase in brain-wide gene delivery compared to AAV9, without elevating hepatic tropism. Crucially, evaluation in non-human primates (NHPs) revealed that the lead variant, QL9-21, mediated a striking 3-40 fold enhancement in viral genome delivery across all examined brain regions versus AAV9, while concurrently reducing liver accumulation by 2.6 fold. Our study establishes an LRP6-guided engineering platform that yields novel AAV9 vectors capable of efficient, species-conserved BBB penetration coupled with a favorable safety profile, representing a significant advance toward clinically translatable CNS gene therapies.

neuroscience↗

bioRxiv2026

Donor-specific assemblies enhance somatic structural variant detection in complex genomic regions

Structural variants (SVs) contribute substantially to genomic variation and disease, but detecting somatic SVs (sSVs) remains difficult due to reference bias, mosaicism, and enrichment in repetitive regions. Linear reference genomes, like GRCh38 and CHM13, do not fully capture individual genomic structure, which can obscure true somatic variation. Donor-specific assemblies (DSAs) generated from the same genome where sSVs are being assayed provide a personalized alternative, yet their performance for sSV detection has not been systematically assessed. As part of the Somatic Mosaicism across Human Tissues (SMaHT) Network, we benchmark a DSA for sSV discovery in the COLO829 melanoma cell line with a matched normal sample from the same individual. We compare sSV detection across GRCh38, CHM13, and the COLO829BL_DSA using three different sSV callers (Delly, Severus, and Sniffles2) and sequence data from multiple long-read platforms. The COLO829BL_DSA identifies 1.8-fold more manually validated sSVs than linear references, in regions both shared with GRCh38 and CHM13 and unique to the COLO829BL_DSA. Variants detected only with the COLO829BL_DSA are often found in satellite and other repeat-rich regions that are difficult to resolve using standard references. In addition, several COLO829BL_DSA-specific sSVs are located in genes, some of which are associated with cancer. Overall, these results underscore the utility of DSAs in improving sSV detection.

genomics↗

bioRxiv2026

Metabolic Perturbation Exacerbates Sinoatrial Node Dysfunction in Heart Failure

Heart failure (HF) affects approximately 6.2 million people in the United States, with a 5-year mortality exceeding 50%. Bradyarrhythmia, a known complication in HF due to sinoatrial node (SAN) dysfunction (SAND), increases the morbidity and mortality of HF patients. Insights into the mechanistic underpinnings of SAND in HF could therefore uncover vital therapeutic targets to improve clinical outcomes. The SAN cells are endowed with a dense mitochondrial network crucial for sustaining their pacemaking function on a beat-to-beat basis. We have previously demonstrated significant disruptions in the mitochondrial-sarcoplasmic reticulum connectomics, resulting in abnormal mitochondrial Ca2+ handling and impaired mitochondrial function in HF. Here, we hypothesize that the metabolic perturbation is one of the critical mechanisms underlying SAND. To this end, we took advantage of a multi-omics approach combined with ultra-resolution imaging and functional analyses to decipher the metabolic shift that transpires in the HF SAN. Our findings revealed significant metabolic remodeling within the SAN mitochondria in HF, with a diminished reliance on fatty acid {beta}-oxidation, enhanced utilization of ketone bodies, and heightened dependence on carbohydrate catabolism. Notably, metabolomics analyses identified the pronounced increase of glucosylceramides and ceramides as one of the mechanisms leading to mitochondrial dysfunction. We directly test this hypothesis and demonstrate that ceramides induce a dose-dependent metabolic shift from oxidative phosphorylation to glycolysis. Importantly, these alterations lead to a significant impairment in SAN automaticity in a dose-dependent manner. Collectively, the findings support the notion that ceramides are not only markers of metabolic derangement, but also active mediators of mitochondrial and metabolic dysfunction in the SAN. Overall, the study provides evidence that ceramides may be a potential therapeutic target for mitigating SAND in HF.

physiology↗

bioRxiv2026

NPEPPS segmental duplication drives position effect expression of TBC1D3 in the human brain

In humans, the TBC1D3 gene family is thought to play a critical role in the expansion of the frontal cortex by promoting neuronal proliferation during brain development. This gene family shows some of the greatest structural heterozygosity ([~]97%) with haplotype copy numbers ranging from 3-39 among different human haplotypes. This raises the question as to how a gene so crucial in the evolutionary expansion of the human frontal cortex can be so variable in the human population. Here, we characterize the regulatory architecture that explains this paradox. We show that 45-96% of TBC1D3 expression is attributable to a single paralog located at the most telomeric position at the edge of a cluster of TBC1D3 genes. We find that its >3-fold higher expression relative to other copies is driven by a 110 kbp segmental duplication that occurred [~]8.9 million years ago, relocating a partial duplication of the puromycin-sensitive aminopeptidase gene (NPEPPS), including its promoter, adjacent to this TBC1D3 locus. Using neurospheres and comparative transcriptomics of iPSC-derived cultures, we show that expression of NPEPPSP1-TBC1D3 increases as neurons differentiate as a result of alternative splicing and differential polyadenylation usage. While the fusion exists in other ape lineages, we show subsequent deletion of the NPEPPSP1 promoter in Gorilla and a separate, lineage-specific duplication in the Pan lineage ablated the production of this fusion product, rendering this position effect of TBC1D3 specific to humans.

genomics↗

bioRxiv2026

KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage

Chemoresistance remains a major obstacle to effective cancer treatment, often driven by enhanced DNA repair mechanisms that enable tumor cells to withstand genotoxic therapies. One such pathway involves the atypical DNA damage repair complex ALKBH3-ASCC, activated by the E3 ligase RNF113A in response to alkylation damage. We previously showed that SMYD3-dependent methylation of RNF113A stimulates this pathway, enhancing DNA repair and promoting resistance. Here, we identify KDM7B/PHF8 as the bona fide RNF113A demethylase, establishing one of the first functional examples of a dynamic, reversible non-histone methylation event regulating genome integrity. KDM7B antagonizes SMYD3 activity by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. To dissect this regulation in depth, we focused on small cell lung cancer (SCLC), a particularly aggressive malignancy characterized by limited therapeutic options and rapid acquisition of resistance. In SCLC, high KDM7B levels correlate with improved patient prognosis, whereas xenografts with reduced expression exhibit diminished responses to alkylating treatment. Moreover, CRISPR-based on/off modulation of KDM7B in genetically engineered SCLC mouse models demonstrates its central role in determining tumor response to chemotherapy. Our findings position the RNF113A-ASCC axis as a central modulator of chemoresistance, regulated through a post-translational methylation switch representing an innovative therapeutic vulnerability that could be exploited to enhance the efficacy of alkylating agents. Targeting this pathway may provide new opportunities to overcome chemoresistance, with KDM7B levels serving as a predictive biomarker to guide treatment in SCLC.

cell biology↗

bioRxiv2025

Ecology of hydrocarbon degradation in widespread viruses

Hydrocarbons are vital for energy production and lead to serious environmental issues due to pollution. Microorganisms largely drive the production and degradation of hydrocarbons, yet little is known about viral contributions to hydrocarbon degradation. Here we identified 786 viral contigs from IMG/VR(v4), encoding five aerobic (alkB, ladA, almA, ndoB and dszC) and three anaerobic (bssA, ebdA and abcA) hydrocarbon-degrading genes (HDGs). vOTUs encoding HDGs span 26 distinct viral families, including 249 are mainly associated with host-associated environment and 463 are derived from aquatic habitat, respectively, implying that these viruses are broadly engaged in hydrocarbon-degradation processes across the entire biosphere. alkB (35%) and almA (28%) was tended to be encoded by Schizomimiviridae, bssA was tended to be encoded by T5-like bacteriophages (29%) and SPO1-like bacteriophages (22%), suggesting that the carriage of HDGs by viruses exhibits taxonomic specificity. With respect to host associations, Pseudomonadota and Bacillota constitute the two main potential host lineages, associated with 268 and 71 vOTUs, respectively. The profiling of ecological footprint reveals that viruses contribute a total of up to 30% gene abundance and 32% transcribing activity to hydrocarbon degradation in the global ocean. This study systematically revealed the distribution, diversity, virus-host correlation and activity of virus-encoded HDGs, underscoring the significant role of viruses in hydrocarbon metabolism on a global scale.

ecology↗

bioRxiv2025

Water body size shapes body size evolution via subgenomic selection in allopolyploid fish

Allopolyploidization is a major force in species evolution, and studying allopolyploids in diverse environments provides insights into their genetic mechanisms. Here, we investigated how water body size variation influences body size in allopolyploid fish. We used a nascent allopolyploid lineage derived from goldfish (Carassius auratus) and common carp (Cyprinus carpio) and established two populations in small and large water bodies for two generations. Genomic, transcriptomic, and epigenomic analyses revealed that the larger population had higher genetic diversity in subgenome R, while the smaller population had higher diversity in subgenome C. Potential selection regions were associated with growth regulatory genes, suggesting a role for gene regulation in body size adaptation. Dynamic gene expression patterns in various tissues indicated potential mechanisms underlying muscle development and adaptation to smaller water bodies. Furthermore, selection regions were linked to changes in chromatin accessibility, with subgenome R being more susceptible to these changes during genetic divergence. Our findings demonstrate that water body size variation drives body size in allopolyploid fish through subgenomic selection, impacting genetic variation, gene regulation, and epigenetic mechanisms.

genomics↗

bioRxiv2025

Hierarchical and Spatial Mapping of Whole-Brain c-Fos Activity Reveals Distinct Opioid and Withdrawal Neuronal Ensembles

How opioid exposure and withdrawal states shape brain activity at the systems and circuit level remains poorly understood. Here, we use whole-brain, cellular-resolution c-Fos mapping to define brain-wide activity patterns and neuronal ensembles associated with morphine administration and withdrawal. To account for the brains anatomically nested structure, we developed and applied a hierarchical statistical framework that detects region-specific changes in activity and outperforms conventional methods that treat brain regions as individual, unrelated units. These distributed signals formed ensembles with consistent and anatomically structured patterns of activity, both within subregions and across multiple connected brain areas. By combining TRAP2-based activity tagging with acute whole-brain c-Fos staining, we identified morphine- and withdrawal-activated ensembles and found that they are largely non-overlapping at the single-cell level, even within the same brain region. Integration with existing spatial transcriptomics datasets identified molecular markers for these state-specific ensembles in key brain areas such as the nucleus of accumbens, amygdala and ventral tegmental areas. Lastly, by integrating Allen mouse whole-brain transcriptional datasets, we identified the molecular identity of the morphine- administration and withdrawal ensembles. These findings define dissociable neuronal ensembles that encode opposing drug states and introduce a scalable framework for linking whole-brain activity to molecular and circuit-level mechanisms. HighlightsO_LIWhole-brain neural activity mapping identifies the regional and spatial difference of morphine-administration and withdrawal neuronal ensembles. C_LIO_LIBRANCH, a hierarchical statistical testing framework, offers increased sensitivity and anatomical interpretability for whole-brain datasets. C_LIO_LITRAP2-based activity tagging reveals brain-wide separation of acute morphine and withdrawal ensembles at the cellular level. C_LIO_LIA systematic analysis of the whole brain neural activity data combined with spatial transcriptomic data revealed molecular features of opioid-related neural ensembles. C_LI

neuroscience↗

bioRxiv2025

Tumor Organoids Modeling Reveals Timed Responses and Interplay of Radiotherapy and Chemotherapy in Pancreatic Cancer

PurposeModel the therapeutic effects of chemotherapy, radiotherapy, and chemoradiotherapy to study the heterogeneous responses of patient-derived tumor organoids (PDTOs). MethodsWe proposed novel mathematical forecasting frameworks based on logistic growth ordinary differential equations (ODEs) and the characteristics of tumor responses to model the therapeutic effects of chemo- and radiation-induced killing. To validate the models, we cultured PDTOs from different patients and treated them with radiation (4 Gy and 8 Gy), chemotherapy (FOLFIRINOX at a previously determined organoid-specific IC50 dose), and combined regimens, respectively. The diameters of 20-40 organoids per patient were tracked and measured using brightfield images up to 7 or 9 days following each treatment to capture organoid growth dynamics data, which was used for model fitting. The accuracy of the modeling was evaluated by the average normalized mean squared errors (NMSE) of data fitting. ResultsThe proposed mathematical modeling frameworks accurately captured the observed growth dynamics of three PDTO samples after chemotherapy, radiotherapy, and chemoradiotherapy, as reflected by the average NMSE of data fitting, which are all close to zero (less than 0.0045). The fitted parameters, including killing strength, effect window, and peak killing timing, revealed significant heterogeneities in treatment responses across different PDTOs. Chemotherapy shows pronounced effectiveness in the early stage, while radiotherapy exhibits the effect later in the first week, and a significantly stronger secondary response occurs one week after radiation. Chemoradiotherapy combines the strengths of both modalities, producing pronounced effects in both response phases, with modeling results suggesting that the radiation-induced killing effect may play a dominant role in the synergistic interaction. ConclusionsOur modeling frameworks demonstrated high accuracy in modeling the heterogeneous therapeutic responses of PDTOs and provided insights into the dynamic killing effects and interplay between chemotherapy and radiotherapy. The modeling of therapeutic responses of PDTOs provides a valuable tool for optimizing treatment regimens and informing clinical trial design, thereby improving the efficacy of personalized medicine.

cancer biology↗

bioRxiv2025

Response dynamics of discrete subiculum->retrosplenial cortex projections underlying trace fear conditioning

Associating events separated in time depends on the CA1, subiculum (SUB), and retrosplenial cortex (RSP). The degree to which their connectivity and underlying circuit mechanisms contribute to the association of such temporally discontiguous events is not known. Here we showed, using trace fear conditioning (TFC), wherein mice learn to associate tone and shock separated by a temporal trace, that molecularly distinct excitatory VGluT1+ and VGluT2+ SUB[->]RSP projections subserve the associative and temporal components of TFC. During trace memory formation, VGluT2+ SUB[->]RSP projections showed increased and decreased bulk calcium activity at tone and trace onset, respectively, an activity pattern that was reestablished during memory recall. Such pattern was not observed in CA subfields, suggesting that associative and temporal components of TFC are integrated at the SUB or SUB[->]RSP synapses before being presented to the RSP. Our findings establish a circuit mechanism for representing complex temporal information in episodic memory.

neuroscience↗