Faculty Bibliography
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Department/Unit:Neuroscience Institute
Total Results:
13558
DNA mismatch and damage patterns revealed by single-molecule sequencing
Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other diseases1,2. Most mutations begin as nucleotide mismatches or damage in one of the two strands of the DNA before becoming double-strand mutations if unrepaired or misrepaired3,4. However, current DNA-sequencing technologies cannot accurately resolve these initial single-strand events. Here we develop a single-molecule, long-read sequencing method (Hairpin Duplex Enhanced Fidelity sequencing (HiDEF-seq)) that achieves single-molecule fidelity for base substitutions when present in either one or both DNA strands. HiDEF-seq also detects cytosine deamination-a common type of DNA damage-with single-molecule fidelity. We profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes, and derive from them single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumours deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples that are deficient in only polymerase proofreading. We also define a single-strand damage signature for APOBEC3A. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. As double-strand DNA mutations are only the end point of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable studies of how mutations arise in a variety of contexts, especially in cancer and ageing.
PMID: 38867045
ISSN: 1476-4687
CID: 5669192
PyDesigner v1.0: A Pythonic Implementation of the DESIGNER Pipeline for Diffusion Magnetic Resonance Imaging
PyDesigner is a Python-based software package based on the original Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline (Dv1) for dMRI preprocessing and tensor estimation. This software is openly provided for non-commercial research and may not be used for clinical care. PyDesigner combines tools from FSL and MRtrix3 to perform denoising, Gibbs ringing correction, eddy current motion correction, brain masking, image smoothing, and Rician bias correction to optimize the estimation of multiple diffusion measures. It can be used across platforms on Windows, Mac, and Linux to accurately derive commonly used metrics from DKI, DTI, WMTI, FBI, and FBWM datasets as well as tractography ODFs and .fib files. It is also file-format agnostic, accepting inputs in the form of .nii, .nii.gz, .mif, and dicom format. User-friendly and easy to install, this software also outputs quality control metrics illustrating signal-to-noise ratio graphs, outlier voxels, and head motion to evaluate data integrity. Additionally, this dMRI processing pipeline supports multiple echo-time dataset processing and features pipeline customization, allowing the user to specify which processes are employed and which outputs are produced to meet a variety of user needs.
PMID: 38829110
ISSN: 1940-087x
CID: 5664942
Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies
The tau protein undergoes pathological changes in Alzheimer's disease and other tauopathies that eventually lead to functional impairments. Over the years, several therapeutic approaches have been examined to slow or halt the progression of tau pathology but have yet to lead to an approved disease-modifying treatment. Of the drugs in clinical trials that directly target tau, immunotherapies are the largest category and mostly consist of antibodies in different stages of development. There is a reasonable optimism that at least some of these compounds will have a clinically meaningful efficacy. This view is based on the significant although modest efficacy of some antibodies targeting amyloid-β in Alzheimer's disease and the fact that tau pathology correlates much better with the degree of dementia than amyloid-β lesions. In Alzheimer's disease, clearing pathological tau may therefore improve function later in the disease process than when removing amyloid-β. This review provides a brief update on the active and passive clinical tau immunization trials with insight from preclinical studies. Various epitopes are being targeted and some of the antibodies are said to target extracellular tau but because almost all of pathological tau is found intracellularly, the most efficacious antibodies should be able to enter the cell.
PMID: 38427486
ISSN: 1875-8908
CID: 5664342
Single-Domain Antibody-Based Protein Degrader for Synucleinopathies
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
PMCID:10979981
PMID: 38558982
CID: 5664352
Neuronal hypofunction and network dysfunction in a mouse model at an early stage of tauopathy
UNLABELLED:activity deficits but failed to rescue altered network changes. Taken together, substantial neuronal and network dysfunction occurred in the early stage of tauopathy that was partially alleviated with acute tau antibody treatment, which highlights the importance of functional assessment when evaluating the therapeutic potential of tau antibodies. HIGHLIGHTS/UNASSIGNED:Layer 2/3 motor cortical neurons exhibited hypofunction in awake and behaving mice at the early stage of tauopathy.Altered neuronal network activity disrupted local circuitry engagement in tauopathy mice during treadmill running.Layer 2/3 motor cortical neurons in tauopathy mice exhibited enhanced neuronal excitability and altered excitatory synaptic transmissions.Acute tau antibody treatment reduced pathological tau and gliosis, and partially restored neuronal hypofunction profiles but not network dysfunction.
PMCID:11092661
PMID: 38746288
CID: 5664362
Single-domain antibody-based protein degrader for synucleinopathies
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
PMCID:11140919
PMID: 38816762
ISSN: 1750-1326
CID: 5663902
Unsupervised Exemplar-Based Image-to-Image Translation and Cascaded Vision Transformers for Tagged and Untagged Cardiac Cine MRI Registration
[S.l.] : Institute of Electrical and Electronics Engineers Inc., 2024
pp. 7629-7639
ISBN: 9798350318920
CID: 5661782
Prevention of Post-Mastectomy Pain Syndrome: A Review of Recent Literature on Perioperative Interventions
PURPOSE OF REVIEW/OBJECTIVE:Up to 60% of breast cancer patients continue to experience pain three months or more after surgery, with 15 to 25% reporting moderate to severe pain. Post-mastectomy pain syndrome (PMPS) places a high burden on patients. We reviewed recent studies on perioperative interventions to prevent PMPS incidence and severity. RECENT FINDINGS/RESULTS:Recent studies on pharmacologic and regional anesthetic interventions were reviewed. Only nine of the twenty-three studies included reported a significant improvement in PMPS incidence and/or severity, sometimes with mixed results for similar interventions. Evidence for prevention of PMPS is mixed. Further investigation of impact of variations in dosing is warranted. In addition, promising newer interventions for prevention of PMPS such as cryoneurolysis of intercostal nerves and stellate ganglion block need confirmatory studies.
PMID: 38814502
ISSN: 1534-6269
CID: 5663762
AI is a viable alternative to high throughput screening: a 318-target study
High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery.
SCOPUS:85191821387
ISSN: 2045-2322
CID: 5658952
Mapping the neural mechanism that distinguishes between holistic thinking and analytic thinking
Holistic and analytic thinking are two distinct modes of thinking used to interpret the world with relative preferences varying across cultures. While most research on these thinking styles has focused on behavioral and cognitive aspects, a few studies have utilized functional magnetic resonance imaging (fMRI) to explore the correlations between brain metrics and self-reported scale scores. Other fMRI studies used single holistic and analytic thinking tasks. As a single task may involve processing in spurious low-level regions, we used two different holistic and analytic thinking tasks, namely the frame-line task and the triad task, to seek convergent brain regions to distinguish holistic and analytic thinking using multivariate pattern analysis (MVPA). Results showed that brain regions fundamental to distinguish holistic and analytic thinking include the bilateral frontal lobes, bilateral parietal lobes, bilateral precentral and postcentral gyrus, bilateral supplementary motor areas, bilateral fusiform, bilateral insula, bilateral angular gyrus, left cuneus, and precuneus, left olfactory cortex, cingulate gyrus, right caudate and putamen. Our study maps brain regions that distinguish between holistic and analytic thinking and provides a new approach to explore the neural representation of cultural constructs. We provide initial evidence connecting culture-related brain regions with language function to explain the origins of cultural differences in cognitive styles.
PMID: 38723877
ISSN: 1095-9572
CID: 5658482
