bioRxiv : the preprint server for biology最新文献

To navigate their environments effectively, animals frequently integrate distance or time information to seek food and avoid threats. This integration process is thought to engage hippocampal neurons that fire at specific distances or times. Using virtual-reality environments, we uncovered two previously unknown functional subpopulations of CA1 pyramidal neurons that encode distance or time through a novel two-phase coding mechanism. The first subpopulation exhibits a collective increase in activity that peaks at similar times, marking the onset of integration; subsequently, individual neurons gradually diverge in their firing rates due to heterogeneous decay rates, enabling time encoding. In contrast, the second subpopulation initially decreases its activity before gradually ramping up. Closed-loop optogenetic experiments revealed that inactivating somatostatin-positive (SST) interneurons disrupts the first subpopulation, behaviorally impairing integration accuracy, while inactivating parvalbumin-positive (PV) interneurons disrupts the second subpopulation, impairing behavior during integration initiation. These findings support the conclusion that SST interneurons establish an integration window, while PV interneurons generate a reset to reinitiate integration. This study elucidates parallel neural circuits that facilitate distinct aspects of distance or time integration, offering new insights into the computations underlying navigation and memory encoding.

Explore-exploit research faces challenges in generalizability due to a limited theoretical basis for exploration and exploitation. Neuroimaging can help identify whether explore-exploit decisions involve an opponent processing system to address this issue. Thus, we conducted a coordinate-based meta-analysis (N=23 studies) finding activation in the dorsal lateral prefrontal cortex, anterior insula, and anterior cingulate cortex during exploration versus exploitation, which provides some evidence for opponent processing. However, the conjunction of explore-exploit decisions was associated with activation in the dorsal anterior cingulate cortex and dorsal medial prefrontal cortex, suggesting that these brain regions do not engage in opponent processing. Furthermore, exploratory analyses revealed heterogeneity in brain responses between task types during exploration and exploitation respectively. Coupled with results suggesting that activation during exploration and exploitation decisions is generally more similar than it is different suggests that there remain significant challenges in characterizing explore-exploit decision making. Nonetheless, dorsal lateral prefrontal cortex, anterior insula, and dorsal anterior cingulate cortex activation differentiate explore and exploit decisions and identifying these responses can aid in targeted interventions aimed at manipulating these decisions.

HiChIP enables cost-effective and high-resolution profiling of chromatin loops. To leverage the increasing number of HiChIP datasets, we developed Loop Catalog (https://loopcatalog.lji.org), a web-based database featuring loop calls from 1000+ distinct human and mouse HiChIP samples from 152 studies plus 44 high-resolution Hi-C samples. We demonstrate its utility for interpreting GWAS and eQTL variants through SNP-to-gene linking, identifying enriched sequence motifs and motif pairs, and generating regulatory networks and 2D representations of chromatin structure. Our catalog spans over 4.19M unique loops, and with embedded analysis modules, constitutes an important resource for the field.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear.

Methods: In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction.

Results: Carcinogenesis begins during MAFLD, with tumor cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to turnover of liver cells but do not primarily target the tumor. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response-not merely immune activation-dictates whether tumors grow or regress, emphasizing the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming.

Conclusion: These findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment.

Phosphoinositide (PIP _n ) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP _n complexes (p53-PIP _n signalosome) that activate Akt by a PI3,4,5P ₃ -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP _n s that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP _n synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIP _n complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze the formation of p53-PI4P. p53-PI4P is then sequentially phosphorylated to synthesize p53-PIP _n complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this way, PITPα/β and PI4KIIα bind p53 and collaborate to initiate p53-PIP _n signaling by mechanisms that require PI transfer by PITPα/β and the catalytic activity of PI4KIIα. Moreover, the identification of these critical upstream regulators of p53-PIP _n signaling point to PITPα/β and PI4KIIα as novel therapeutic targets in this pathway for diseases like cancer.

Significance statement: PI transfer proteins and a PI 4-kinase initiate nuclear p53-phosphoinositide signaling in membrane-free regions to promote stress resistance.

Chromatin organization in the mammalian cell nucleus plays a vital role in the regulation of gene expression. The lamina-associated domain at the inner nuclear membrane has been shown to harbor heterochromatin, while the nuclear interior has been shown to contain most of the euchromatin. Here, we show that a sub-set of actively transcribing genes, marked by RNA Pol II pSer2, are associated with Lamin B1 at the inner nuclear envelope in mouse embryonic stem cells (mESCs) and the number of genes proportionally increases upon in vitro differentiation of mESC to olfactory precursor cells. These nuclear periphery-associated actively transcribing genes primarily represent housekeeping genes, and their gene bodies are significantly enriched with guanine and cytosine compared to genes actively transcribed at the nuclear interior. We found the promoters of these gene's to also be significantly enriched with guanine and to be predominantly regulated by zinc finger protein transcription factors. We provide evidence supporting the emerging notion that the Lamin B1 region is not solely transcriptionally silent.

ApoE4 is the primary risk factor for Alzheimer Disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that apoE4 localizes to lysosomes, the influence of apoE4 on lysosomal function remains unexplored. We find that expression of apoE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function. To identify driving factors for these defects, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in differential regulation of numerous lysosomal proteins, correlating with apoE allele status and disease severity in AD brains. In particular, apoE4 expression results in the depletion of lysosomal Lgals3bp and the accumulation of lysosomal Tmed5. We additionally validated that these lysosomal protein changes can be targeted to modulate lysosomal function. Taken together, this work thereby reveals that apoE4 causes widespread lysosomal defects through remodeling the lysosomal proteome, with the lysosomal Tmed5 accumulation and Lgals3bp depletion manifesting as lysosomal alkalinization in apoE4 neurons.

Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial insight into the relationship between the brain's topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient architecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their development throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing thereafter. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.

When highly stretched, double-stranded DNA exhibits a plateau region in its force-extension curve. Using a bead-spring coarse-grained dynamic model based on a non-convex potential, we predict that a long double-stranded DNA fragment made of several consecutive segments with substantially different plateau force values for each segment will exhibit multiple distinct plateau regions in the force-extension curve under physiologically relevant solvent conditions. For example, a long composite double-stranded (ds) DNA fragment consisting of two equal-length segments characterized by two different plateau force values, such as the poly(dA-dT)-poly(dG-dC) fragment, is predicted to exhibit two distinct plateau regions in its force-extension curve; a long composite dsDNA fragment consisting of three segments having three different plateau force values is predicted to have three distinct plateau regions. The formation of mixed states of slightly and highly stretched DNA, co-existing with macroscopically distinct phases of uniformly stretched DNA is also predicted. When one of the segments overstretches, the extensions of the segments can differ drastically. For example, for the poly(dA-dT)-poly(dG-dC) composite fragment, in the middle of the first plateau, 96.7 % of the total extension of the fragment (relative to $L_x/L_0\approx 1.0$ ) comes from the poly(dA-dT) segment, while only 3.3 % of it comes from the poly(dG-dC) segment. The order of the segments has little effect on the force-extension curve or the distribution of conformational states. We speculate that the distinct structural states of stretched double-stranded DNA may have functional importance. For example, these states may modulate, in a sequence-dependent manner, the rate of double-stranded DNA processing by key cellular machines.