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Anvarian, Z.

Publications and source records attributed to Anvarian, Z..

5 recordsLinked to original sources

Beyond Mean Pooling: Statistical Meta-Aggregation for Subject-Level EEG Classification in Parkinson's Disease

Electroencephalography (EEG) provides a non-invasive, temporally precise tool for studying neural alterations associated with Parkinson's disease (PD). When labels are defined at the subject level but inputs are epoch level, a key design choice is how epoch-wise predictions are aggregated to a single subject-level decision. Most prior work uses mean pooling, which assumes all epochs contribute equally and independently. This study proposes a statistical meta-aggregation strategy that represents each subject by 14 descriptors of the epoch-wise prediction distribution, including measures of central tendency, dispersion, shape, and high-confidence concentration. Using a self-supervised contrastive encoder trained on task-evoked EEG from the Simon conflict task, and a sample of 90 subjects including 57 PD and 33 control, this work evaluates the proposed framework under subject-wise five-fold cross-validation. Replacing mean pooling with statistical meta-aggregation lifts subject-level ROC-AUC from 0.655 to 0.872 for logistic regression and from 0.724 to 0.840 for support vector machines, without modifying the encoder or the classifier family. Averaging predictions across three independent self-supervised pretraining seeds yields competitive performance and improved balanced accuracy. These results suggest that, in this dataset, the way epoch-level predictions are summarized at the subject level has a substantial effect on final PD classification performance.

neuroscience↗

Loss of KIF13B causes time-dependent changes in ciliary polycystin-2 levels and extracellular vesicle release

Dynamic control of ciliary membrane protein content is crucial for the organelles homeostasis and signaling function and involves removal of ciliary components by BBSome-mediated export, endocytic retrieval and/or extracellular vesicle (EV) shedding. We report that KIF13B regulates ciliary protein composition and EV shedding in cultured kidney epithelial cells, with effects that vary over time. In early stages of ciliation Kif13b-/- cells aberrantly accumulate PC2, FLOT1, and HGS within cilia. These cells also produce fewer small EVs through the GW4869-sensitive, nSMase2 pathway, and release large EVs enriched with CCDC198 and the centriole distal appendage protein CCDC92, which also localizes to the ciliary tip. Upon cilia maturation, Kif13b-/- cells accelerate large EV release of numerous ciliary proteins, including PC2, BBSome components, and IFT proteins, which correlates with gradual depletion of CCDC92 and PC2 from the ciliary tip and shaft, respectively. Furthermore, over time, Kif13b-/- cells show an upregulation in the release of small EVs, which differ in composition from wild-type small EVs. Specifically, the mutant small EVs lack several proteins that are enriched in small EVs from BBSome-deficient cells, such as the palmitoyl transferase ZDHHC5, which localizes to cilia, accumulates within cilia of BBSome-deficient cells, and regulates ciliary length and PC2 levels. Collectively, our work suggests that KIF13B acts at the level of centriole distal appendages to limit ciliary protein entrance and promote endocytic retrieval downstream of the BBSome. Furthermore, this study shows for the first time that CCDC198 and ZDHHC5 localize to primary cilia, suggesting they are potential novel ciliopathy candidates.

cell biology↗

DLG1 functions upstream of SDCCAG3 and IFT20 to control targeting of polycystin-2 to the primary cilium

Polarized vesicular trafficking directs specific receptors and ion channels to cilia, but the underlying mechanisms are poorly understood. Here we describe a role for DLG1, a core component of the Scribble polarity complex, in regulating ciliary protein trafficking in kidney epithelial cells. Conditional knockout of Dlg1 in mouse kidney caused ciliary elongation and cystogenesis, and cell-based proximity labelling proteomics and fluorescence microscopy showed alterations in the ciliary proteome upon loss of DLG1. Specifically, the retromer-associated protein SDCCAG3, IFT20 and polycystin-2 (PC2) were reduced in cilia of DLG1 deficient cells compared to control cells. This phenotype was recapitulated in vivo and rescuable by re-expression of wildtype DLG1, but not a Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-associated DLG1 variant, p.T489R. Finally, biochemical approaches and Alpha Fold modelling suggested that SDCCAG3 and IFT20 form a complex that associates, at least indirectly, with DLG1. Our work identifies a key role for DLG1 in regulating ciliary protein composition and suggests that ciliary dysfunction of the p.T489R DLG1 variant may contribute to CAKUT.

cell biology↗

Angiomotin isoform 2 promotes binding of PALS1 to KIF13B at the base of primary cilia and suppresses ciliary elongation

The kinesin-3 motor KIF13B functions in endocytosis, vesicle transport, and regulation of ciliary length and signaling. Direct binding of the membrane-associated guanylate kinase (MAGUK) DLG1 to KIF13Bs MAGUK-binding stalk (MBS) domain relieves motor autoinhibition and promotes microtubule plus end-directed cargo transport. Here we characterize Angiomotin isoform 2 (Ap80) as a novel KIF13B interactor that promotes binding of another MAGUK, the polarity protein and Crumbs complex component PALS1, to KIF13B. Live cell imaging analysis indicated that Ap80 is concentrated at the base of primary cilia and recruits PALS1 to this site, but is not itself a cargo of KIF13B. Consistent with a ciliary function for Ap80, its depletion led to elongated primary cilia while its overexpression caused ciliary shortening. Our results suggest that Ap80 may specifically activate KIF13B cargo binding at the base of primary cilia to regulate ciliary length.

cell biology↗

Transient accumulation and bidirectional movement of KIF13B in primary cilia

Primary cilia are microtubule-based sensory organelles whose assembly and function rely on the conserved bidirectional intraflagellar transport (IFT) system, which is powered by anterograde kinesin-2 and retrograde cytoplasmic dynein 2 motors. Nematodes additionally employ a cell type-specific kinesin-3 motor, KLP-6, which moves within cilia independently of IFT and regulates ciliary content and function. Here we provide evidence that a KLP-6 homolog, KIF13B, undergoes bursts of bidirectional movement within primary cilia of cultured immortalized human retinal pigment epithelial (hTERT-RPE1) cells. Anterograde and retrograde intraciliary velocities of KIF13B were similar to those of IFT (IFT172-eGFP), but intraciliary movement of KIF13B required its own motor domain and appeared to be cell-type specific. Our work provides the first demonstration of motor-driven, intraciliary movement by a vertebrate kinesin other than kinesin-2 motors.

biophysics↗