Biology subjects

Kireev, D.

Publications and source records attributed to Kireev, D..

4 recordsLinked to original sources

bioRxiv2025

BIOCOMPATIBILITY OF LARGE-AREA 2-DIMENSIONAL ELECTRONIC MATERIALS WITH NEURAL STEM CELLS

Two-dimensional (2D) electronic materials hold immense promise for next-generation bio/neuro-electronic interfaces, but their biocompatibility has remained uncertain due to conflicting reports from studies focused on exfoliated flakes and suspensions. In this work, we present a comprehensive in vitro evaluation of electronic-grade large-area, chemical vapor deposition (CVD)-grown 2D materials - including platinum diselenide (PtSe2), platinum ditelluride (PtTe2), molybdenum disulfide (MoS2), and graphene - as substrates for mouse neural stem cell culture. Across all CVD-grown materials, the stem cells exhibited outstanding viability, with no significant differences in metabolic activity or live/apoptotic cell ratios compared to laminin-coated glass controls (p > 0.05). Importantly, these large-area 2D materials robustly supported neuronal differentiation, as evidenced by widespread {beta}III-tubulin expression. Strikingly, we found that flaky MoS2 promoted significantly greater neuronal maturation (>75% NeuN neurons) than any other substrate tested (25-50% NeuN; p < 0.05), revealing the critical influence of material format on bioactivity. While PtSe2 showed a tendency to promote glial lineage differentiation, our findings firmly establish large-area CVD-grown 2D materials as biocompatible, tunable platforms for neural interfacing, paving the way for their integration into advanced bio/neuro-electronic devices.

bioengineering↗

bioRxiv2024

CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson's Disease associated protein.

The CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE #1 challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinsons disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Seventy-three of the 1955 procured molecules bound LRRK2 in an SPR assay with KD lower than 150 M and were advanced to a hit expansion phase where computational teams each selected up to 50 analogs each. Binding was observed in two orthogonal assays with affinities ranging from 18 to 140 M for seven chemically diverse series. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants sometimes adopted strikingly diverging screening strategies. Machine-learning accelerated methods achieved similar results to brute force (e.g. exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

biochemistry↗

bioRxiv2022

Graphene Biointerface for Cardiac Arrhythmia Diagnosis and Treatment

Heart rhythm disorders, known as arrhythmias, cause significant morbidity and are one of the leading causes of mortality. Cardiac arrhythmias are primarily treated by implantable devices, such as pacemakers and defibrillators, or by ablation therapy guided by electroanatomical mapping. Pharmacological treatments are mostly ineffective. Both implantable and ablation therapies require sophisticated biointerfaces for electrophysiological measurements of electrograms and delivery of therapeutic stimulation or ablation energy. In this work, we report for the first time on graphene biointerface for in vivo cardiac electrophysiology. Leveraging sub-micrometer thick tissue-conformable graphene arrays, we demonstrate sensing and stimulation of the open mammalian heart both in vitro and in vivo. Furthermore, we demonstrate graphene pacemaker treatment of a pharmacologically-induced arrhythmia, AV block. The arrays show effective electrochemical properties, namely interface impedance down to 40 Ohmxcm2 at 1kHz, charge storage capacity up to 63.7 mC/cm2, and charge injection capacity up to 704 C/cm2. Transparency of the graphene structures allows for simultaneous optical mapping of cardiac action potentials and optogenetic stimulation while performing electrical measurements and stimulation. Our report presents evidence of the significant potential of graphene biointerfaces for the future clinical device- and catheter-based cardiac arrhythmias therapies.

bioengineering↗

bioRxiv2021

Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization

NSD2 is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36me2), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two PWWP and five PHD domains believed to serve as chromatin reading modules, but their exact function in the regulation of NSD2 activity remains underexplored. Here we report a first-in-class chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 binds potently (Kd of 91 {+/-} 8 nM) to PWWP1, antagonizes its interaction with nucleosomal H3K36me2, and selectively engages endogenous NSD2 in cells. Crystal structures show that UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1 which is juxtaposed to the DNA-binding surface. In cells, UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 as a result of translocations prevalent in multiple myeloma. Mutation of other NSD2 chromatin reader domains also increases NSD2 nucleolar localization, and enhances the effect of UNC6934. Finally we identified two C-terminal nucleolar localization sequences in NSD2 that appear to drive nucleolar accumulation when one or more chromatin reader domains are disabled. These data support a model in which NSD2 chromatin engagement is achieved in a cooperative manner and subcellular localization is controlled by multiple competitive structural determinants. This chemical probe and the accompanying negative control, UNC7145, will be useful tools in defining NSD2 biology.

cell biology↗