Biology subjects

Lerner, G.

Publications and source records attributed to Lerner, G..

12 recordsLinked to original sources

bioRxiv2026

Integration of cell-specific gene expression and chromatin accessibility facilitates localization of neurodegenerative risk in microglia

Genome-wide association studies (GWAS) have identified many loci that contribute to the risk of neurodegenerative diseases. However, a persistent challenge in interpretation of GWAS is to break loci down to specific genes, variants, and cell types, and thus nominate disease mechanisms. Here, we used iPSC-derived cells containing population-level variation to examine GWAS loci across NDDs including Alzheimer's disease, Parkinson's disease and Lewy body dementia. We differentiated a set of 135 iPSC donor lines into two cell types relevant to neurodegeneration, neurons and microglia, and completed single cell gene expression and chromatin accessibility profiling. Meta-analysis of these data with published human brain snRNAseq for QTL mapping identified multiple loci associated with NDDs that are restricted to either neurons or microglia. Colocalization of GWAS and these QTL supports microglia as having a strong contribution to disease risk. We tested peaks nominated at the BIN1 locus for enhancer activity using a perturb-seq-based method in microglia. Our results show one of the nominated peaks controls BIN1 expression in microglia but also modifies expression of other genes at the locus. These results support the hypothesis that common variants affecting gene expression specifically in microglia can contribute directly to NDD risk rather than functioning solely as a secondary response to neurodegeneration. These data also show that iPSC-derived cells are a useful model to experimentally dissect GWAS loci that colocalize with QTL.

genomics↗

bioRxiv2026

Brain dynamics supporting high cognitive performance reorganize after midlife

Quantifying functional brain aging trajectories at scale remains a fundamental challenge due to the scanner-bound limitations of traditional neuroimaging. Here, we deploy whole-head Time-Domain functional Near-Infrared Spectroscopy (TD-fNIRS) to map task-evoked cortical dynamics during a 30-minute cognitive battery across the adult lifespan (N = 302, age 18-87, 45% racial or ethnic minority). We developed a robust General Cognitive Factor (GCF) tracking age-related performance decline (r = -0.57, p < 0.0001). Analysis of brain activity patterns revealed systemic, age-dependent neural dedifferentiation, highlighting a distinct neurocognitive inflection point around age 55. Prior to this threshold, high performers exhibit more variable neural activation across tasks; post-age 55, high performance is sustained through reduced spatial differentiation, signaling a compensatory strategy. Furthermore, subjective anxiety and depression disrupt these compensatory mechanisms, and subjective cognitive complaints register as distinct neural signatures before behavioral GCF decline manifests. Together, these findings establish a scalable framework for mapping functional brain health across the human lifespan, uncovering the neural mechanics of cognitive resilience and vulnerability before behavioral decline manifests.

neuroscience↗

bioRxiv2025

Spatial analysis reveals the cellular microenvironments and mechanisms of inflammation and kidney injury in acute interstitial nephritis

Acute interstitial nephritis (AIN) causes 15-20% of all acute kidney injury cases but lacks effective therapies beyond corticosteroids. Using high-resolution imaging mass cytometry and single-cell spatial transcriptomics to analyze human kidney biopsies with AIN, non-immunologic acute tubular injury (ATI), and reference tissue, the CXCL9-CXCR3 axis was identified as the defining immunologic signature of AIN, with 44-fold higher predicted CXCL9-CXCR3 interactions than ATI, creating homotypic inflammatory T cell amplification networks concentrated in lymphoid aggregates. C3AR1+ immune cells were enriched in peritubular neighborhoods of complement 3-expressing injured tubule cells, predominantly VCAM1+ injured proximal tubules, linking tubular injury to immune activation in AIN. Nicotinamide phosphoribosyltransferase (NAMPT) was the strongest predictor of VCAM1+ tubular microenvironments, with expression by both injured tubules and surrounding immune cells coordinating metabolic-inflammatory niches. These findings reveal distinct molecular circuits underlying AIN pathogenesis and identify potential therapeutic targets for improving clinical management and preventing progression to chronic kidney disease.

immunology↗

bioRxiv2025

Anks3 mediates cilia dependent polycystin signaling and is essential for adult kidney homeostasis

The existence of a cilia-dependent cyst activation (CDCA) pathway underlying autosomal dominant polycystic kidney disease was identified by showing that cyst progression following loss of polycystins is significantly suppressed by removal of structurally intact cilia. We applied translating ribosome affinity purification RNASeq on pre-cystic mouse kidneys to determine a cell-autonomous in vivo translatome associated with CDCA and identified Glis2 as an early effector of polycystin signaling. Here, to discover additional components of CDCA, we used polycystin-dependent Glis2 expression as a functional readout and identified Anks3, from the CDCA pattern translatome, as a candidate cytosolic regulator of polycystin signaling. Anks3 regulates polycystin-dependent Glis2 expression both in vitro and in vivo. Anks3 also undergoes polycystin-dependent changes in phosphorylation state. Inactivation of Anks3 in Pkd1 mouse models suppresses cyst progression, but also results in rapidly progressive kidney injury independent of polycystins. Anks3 inactivation also normalizes a broader spectrum of polycystin-dependent CDCA translatome changes. These findings define Anks3 as a central regulator of cilia dependent polycystin signaling, functioning downstream of cilia and polycystins and upstream of Glis2, and show that Anks3 has broader functions in maintaining renal structural and functional homeostasis.

genetics↗

bioRxiv2024

Time-Domain Diffuse Optical Tomography for Precision Neuroscience

AbstractRecent years have witnessed a rise in research utilizing neuroimaging for precision neuromedicine, but clinical translation has been hindered by scalability and cost. Time Domain functional Near Infrared Spectroscopy (TD-fNIRS), the gold standard of optical neuroimaging techniques, offers a unique opportunity in this domain since it provides superior depth sensitivity and enables resolution of absolute properties unlike its continuous wave counterparts. However, current TD systems have limited commercial availability, slow sampling rates, and sparse head coverage. Our team has overcome the technical challenges involved in developing a whole-head time-domain diffuse optical tomography (TD-DOT) system. Here, we present the system characterization results using standardized protocols and compare them to the state-of-the-art. Furthermore, we showcase the system performance in retrieving cortical activation maps during standard hemodynamic, sensory, and motor tasks. A combination of the system performance, signal quality, and ease-of-use can enable future studies aimed at investigating TD-DOT clinical applications.

bioengineering↗

bioRxiv2023

Incorporation of the HIV-1 envelope glycoprotein into viral particles is regulated by the tubular recycling endosome in a cell type-specific manner

The HIV-1 envelope glycoprotein (Env) is incorporated into particles during assembly on the plasma membrane (PM). Env initially reaches the PM through the secretory pathway, after which it is rapidly endocytosed via an AP-2- and clathrin-dependent mechanism. Here we show that endocytosed cell surface Env enters the tubular recycling endosome compartment (TRE). Trafficking to the TRE was dependent upon motifs within the CT previously implicated in Env recycling and particle incorporation. Depletion of TRE components MICAL-L1 or EHD1 led to defects in Env incorporation, particle infectivity, and viral replication. Remarkably, defects were limited to cell types defined as nonpermissive for incorporation of CT-deleted Env, including monocyte-derived macrophages, and not observed in 293T, HeLa, or MT-4 cells. This work identifies the TRE as an essential component of Env trafficking and particle incorporation, and provides evidence that the cell type-dependent incorporation of Env is defined by interactions with components of the TRE.

microbiology↗

bioRxiv2023

Consolidation of sensorimotor adaptation depends both on the passage of time and sleep

Contrary to its well-established role in declarative learning the impact of sleep on motor memory consolidation remains a subject of debate. Motor learning involves skill acquisition and skill maintenance, two critical aspects in achieving movement precision. Current literature suggests that whereas motor skill acquisition benefits from sleep, consolidation of skill maintenance depends solely on the passage of time. This has led to the proposal that skill maintenance may be an exception to other types of memories. Here, we address this ongoing controversy in humans through three comprehensive experiments. We found that when training occurs throughout the day consolidation of skill maintenance proceeds independently of sleep. However, when it takes place closely before bedtime so that sleep aligns with the memory stabilization window, a 30% memory enhancement emerges along with a distinct modulation of neural markers of sleep consolidation. Our findings reconcile seemingly conflicting perspectives on the active role of sleep in procedural motor learning, and offer the potential to accelerate motor recovery in rehabilitation programs through the synchronization of training sessions with sleep.

neuroscience↗

bioRxiv2023

Tryptophan-based motifs in the LLP3 Region of the HIV-1 envelope glycoprotein cytoplasmic tail direct trafficking to the endosomal recycling compartment and mediate particle incorporation

The HIV-1 envelope glycoprotein complex (Env) is incorporated into developing particles at the plasma membrane (PM). The cytoplasmic tail (CT) of Env is known to play an essential role in particle incorporation, while the exact mechanisms underlying this function of the CT remain uncertain. Upon reaching the PM, trafficking signals in the CT interact with host cell endocytic machinery, directing Env into endosomal compartments within the cell. Prior studies have suggested that Env must traffic through the endosomal recycling compartment (ERC) in order for Env to return to the plasma membrane (PM) site of particle assembly. Expression of a truncated form of the ERC-resident trafficking adaptor Rab11-Family Interacting Proteins C (FIP1C) resulted in CT-dependent sequestration of Env in the condensed ERC, preventing recycling of Env to the PM. In this work, the motifs within the CT responsible for ERC localization of Env were systematically mapped. A small deletion encompassing the N-terminal portion of LLP3 eliminated ERC localization. Site-directed mutagenesis identified two tryptophan-based motifs (WE790-791 and WW796-797) within the N-terminus of LLP3 that were essential for ERC localization of Env. Mutant viruses bearing substitutions in these motifs were deficient in Env incorporation, with a corresponding loss of particle infectivity and a significant defect in replication in a spreading infection assay. These results identify two tryptophan-based motifs at the N-terminal portion of LLP3 that mediate ERC localization and Env incorporation, providing additional supporting evidence for the importance of cellular recycling pathways in HIV-1 particle assembly. IMPORTANCEThe HIV-1 envelope glycoprotein (Env) is an essential component of the virus, and has an exceedingly long cytoplasmic tail (CT). Previous studies have suggested that trafficking signals in the CT interact with host factors to regulate the incorporation of Env into particles. One particular area of interest is termed lentiviral lytic peptide 3 (LLP3), as small deletions in this region have been shown to disrupt Env incorporation. In this study, we identify a small region within LLP3 that regulates how Env associates with cellular recycling compartments. Mutants that reduced or eliminated Env from the recycling compartment also reduced Env incorporation into particles. These findings emphasize the importance of two tryptophan motifs in LLP3 to the incorporation of Env into particles, and provide additional support for the idea that the CT interacts with host recycling pathways to determine particle incorporation.

microbiology↗

bioRxiv2023

KIF16B mediates anterograde transport and modulates lysosomal degradation of the HIV-1 envelope glycoprotein

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) is incorporated into virions at the site of particle assembly on the plasma membrane (PM). The route taken by Env to reach the site of assembly and particle incorporation remains incompletely understood. Following initial delivery to the PM through the secretory pathway, Env is rapidly endocytosed, suggesting that recycling is required for particle incorporation. Endosomes marked by the small GTPase Rab14 have been previously shown to play a role in Env trafficking. Here we examined the role of KIF16B, the molecular motor protein that directs outward movement of Rab14-dependent cargo, in Env trafficking. Env colocalized extensively with KIF16B+ endosomes at the cellular periphery, while expression of a motor-deficient mutant of KIF16B redistributed Env to a perinuclear location. The half-life of Env labeled at the cell surface was markedly reduced in the absence of KIF16B, while a normal half-life was restored through inhibition of lysosomal degradation. In the absence of KIF16B, Env expression on the surface of cells was reduced, leading to a reduction in Env incorporation into particles and a corresponding reduction in particle infectivity. HIV-1 replication in KIF16B knockout cells was substantially reduced as compared to wildtype cells. These results indicate that KIF16B regulates an outward sorting step involved in Env trafficking, thereby limiting lysosomal degradation and enhancing particle incorporation. IMPORTANCEThe HIV-1 envelope glycoprotein is an essential component of HIV-1 particles. The cellular pathways that contribute to incorporation of envelope into particles are not fully understood. Here we identify KIF16B, a motor protein that directs movement from internal compartments toward the plasma membrane, as a host factor that prevents envelope degradation and enhances particle incorporation. This is the first host motor protein identified that contributes to HIV-1 envelope incorporation and replication.

microbiology↗

bioRxiv2020

Competition between parallel sensorimotor learning systems

Sensorimotor adaptation benefits from learning in two parallel systems: one that has access to explicit knowledge, and another that relies on implicit, unconscious correction. However, it is unclear how these systems interact: does enhancing one systems contributions, for example through instruction, impair the other, or do they learn independently? Here we illustrate that certain contexts can lead to competition between implicit and explicit learning. In some cases, each system is responsive to a task-related visual error. This shared error appears to create competition between these systems, such that when the explicit system increases its response, errors are siphoned away from the implicit system, thus reducing its learning. This model suggests that explicit strategy can mask changes in implicit error sensitivity related to savings and interference. Other contexts suggest that the implicit system can respond to multiple error sources. When these error sources conflict, a second type of competition occurs. Thus, the data show that during sensorimotor adaptation, behavior is shaped by competition between parallel learning systems.

neuroscience↗

bioRxiv2019

The origins of anterograde interference in visuomotor adaptation

Anterograde interference refers to the negative impact of prior learning on the propensity for future learning. Previous work has shown that subsequent adaptation to two perturbations of opposing sign, A and B, impairs performance in B. Here, we aimed to unveil the mechanism at the basis of anterograde interference by tracking its impact as a function of time through a 24h period. We found that the memory of A biased performance in B for all time intervals. Conversely, learning from error was hindered up to 1h following acquisition of A, with release from interference occurring at 6h. These findings suggest that poor performance induced by prior learning is driven by two distinct mechanisms: a long-lasting bias that acts as a prior and hinders the initial level of performance, and a short-lasting learning impairment that originates from a reduction in error-sensitivity. Our work provides insight into the timeline of memory stabilization in visuomotor adaptation.

neuroscience↗

bioRxiv2019

Improving spatial normalization of brain diffusion MRI to measure longitudinal changes of tissue microstructure in human cortex and white matter.

BackgroundFractional anisotropy (FA) and mean diffusivity (MD) are frequently used to evaluate longitudinal changes in white matter microstructure. Recently, there has been a growing interest in identifying experience-dependent plasticity in gray matter using MD. Improving registration has thus become a major goal to enhance the detection of subtle longitudinal changes in cortical microstructure. PurposeTo optimize normalization to improve registration in gray matter and reduce variability associated with multi-session registrations. Study TypeProspective longitudinal study SubjectsTwenty-one healthy subjects (18-31 years old) underwent 9 magnetic resonance imaging (MRI) scanning sessions each. Field Strength/Sequence3.0T, diffusion-weighted multiband-accelerated sequence, MP2RAGE sequence. AssessmentDiffusion-weighted images were registered to standard space using different pipelines that varied in the features used for normalization, namely the non-linear registration algorithm (FSL vs ANTs), the registration target (FA-based vs T1-based templates), and the use of intermediate individual (FA-based or T1-based) targets. We compared the across-session test-retest reproducibility error from these normalization approaches for FA and MD in white and gray matters. Statistical TestsReproducibility errors were compared using a repeated-measures analysis of variance with pipeline as within-subject factor. ResultsThe registration of FA data to the FMRIB58 FA atlas using ANTs yielded lower reproducibility errors in white matter (p<0.0001) with respect to FSL. Moreover, using the MNI152 T1 template as the target of registration resulted in lower reproducibility errors for MD (p<0.0001), whereas the FMRIB58 FA template performed better for FA (p<0.0001). Finally, the use of an intermediate individual template improved reproducibility when registration of the FA images to the MNI152-T1 was carried out within modality (FA-FA) (p<0.05), but not via a T1-based individual template. Data ConclusionA normalization approach using ANTs to register FA images to the MNI152 T1 template via an individual FA template minimized test-retest reproducibility errors both for gray and white matter.

neuroscience↗