Biology subjects

Klukinov, M.

Publications and source records attributed to Klukinov, M..

3 recordsLinked to original sources

bioRxiv2026

Reprogramming transcription factor networks with a HOX inhibitor to address Huntington's disease biology beyond mutant huntingtin

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by CAG-repeat expansion in the huntingtin (HTT) gene. Although inherited CAG-repeat length and the underlying somatic instability are key determinants of age at onset, they explain only part of onset variability, suggesting additional disease mechanisms. We applied the Core Coefficient (CC), a transcription-factor (TF) network-decoding technology that quantifies TF functional dominance, to >100 post-mortem neuronal transcriptomes from HD and control brain datasets. Among human TF families, the HOX family is the only family that uniformly exhibits quiescence in controls versus large and significant functional dominance in vulnerable neurons of each HD donor brain we investigated. HOX TFs are already dominant at Vonsattel grade 0 and at inherited CAG-repeat length. The magnitude of HOX CC values correlates with age at onset and increases with disease grade and CAG-Age Product. HOX TFs form a self-sustained pathological unit targeting >4,000 genes implicated in neuronal patterning, identity, stress, signaling, structure, and senescence. In zQ175 mice, abrogation of mutant huntingtin (mHTT) protein production only transiently attenuates HOX dominance and does not durably eliminate it. COR-H800, a HOX inhibitor, restored TF-network hierarchy toward wild type, normalizing the functional dominance of transcription factors involved in neuronal differentiation, cell-fate determination, and developmental patterning, and improved disease-relevant phenotypes in R6/2 mice. These findings support the direct selective inhibition of HOX TFs to address the aberrant transcriptional state that can persist despite mHTT lowering or somatic instability-targeted therapeutic interventions.

neuroscience↗

bioRxiv2026

Core Coefficient quantifies transcription-factor functional dominance for therapeutic target selection

Transcription factors (TFs) operate in regulatory networks to control gene expression. The functional importance or leverage of a TF depends on the specific regulatory network in which it operates. Commonly used measurements of TF biology do not quantify the functional importance of TFs in these networks, which makes target selection for therapeutic intervention suboptimal. We developed the Core Coefficient (CC), a graph theory measure of TF functional dominance to overcome this limitation. Analysis of networks constructed from patient-biopsy and human post-mortem datasets revealed that these regulatory networks are organized in a functional hierarchy that is dominated by an identifiable and limited group of TFs, which we refer to as the Core. Analysis also revealed that the functional dominance of a TF, or the capacity to influence a cellular outcome, is a property of its position in the network hierarchy rather than its identity. While the Core consists of a group of functionally dominant TFs that control the network, the individual TFs forming that Core vary with cell type and cellular state. During the course of a given disease, from cancer to neurodegeneration, the functional dominance of TFs relevant to that disease shifts from low hierarchical importance to Core positions, whereas the functional dominance of other TFs is reduced or unchanged. CC can measure this shift in functional dominance and predict Core membership as a disease progresses. From a therapeutic standpoint, CC can also track the alterations in network hierarchy in diseased cells produced by treatments in the clinic. For example, network analyses of cancer cells before and after treatment from the same patients show dominant Core regulators shift from positions of high importance to positions of low importance after treatment. Experimental testing of these network mechanics in cancer cell lines showed CC can predict Core re-composition, signaling pathway reorganization and the cellular outcome of blocking a specific TF. In contrast, differential TF expression was informative in individual cases in these experiments but did not provide a general rule for measuring TF functional importance. This body of work introduces the CC, which quantifies TF functional dominance and enables the identification of targets for reprogramming TF networks to achieve a therapeutic objective.

systems biology↗

bioRxiv2026

Noninvasive Diagnostic Ultrasound-Guided Focused Ultrasound Enables Selective, Reversible Inhibition of Peripheral Nociceptive Fibers and Prevents Acute Pain

BackgroundAcute postoperative pain remains a major clinical therapeutic challenge. Current peripheral nerve blockade (PNB) techniques are effective for some patients but are limited by invasiveness, short duration, reliance on highly trained providers, and off-target motor and sensory effects. Focused ultrasound (FUS) is a novel neuromodulatory technology with the potential to achieve noninvasive, selective, reversible, and prolonged inhibition of peripheral nociceptive fibers to prevent and treat acute pain. We hypothesized that noninvasive transcutaneous targeting of the rat sciatic nerve using co-aligned diagnostic ultrasound (dUS) and FUS transducers could produce selective and reversible inhibition of nociceptive pain behaviors while preserving motor and non-nociceptive sensory functions. MethodsIn an in vivo rat hindpaw incisional (HPI) pain model, using a novel, transcutaneous dUS-guided FUS system, the sciatic nerve was located with dUS, and FUS energy was applied to it just prior to hindpaw incision. FUS parameters were iteratively adjusted to achieve reversible, selective inhibition of nociceptive behaviors without changing motor and non-pain sensory behaviors. Animals were randomized into six groups: No Intervention (Control), HPI Only (Disease Control), Sham FUS, FUS Only, FUS+HPI (Intervention), and LA+HPI (Positive Control). Primary outcomes were changes in nociceptive sensory functions, assessed by thermal and mechanical sensitivity. Secondary outcomes were changes in non-nociceptive sensory and motor functions, assessed by hindpaw flexion and extension reflexes. ResultsCompared with the HPI Only group, the FUS+HPI group demonstrated (1) significant attenuation of hindpaw thermal hypersensitivity from day 0 - week 5.0 and week 8.0 - 16.0 (p < 0.05-0.001); (2) significant attenuation of mechanical hypersensitivity from day 0 until week 4.0 (p < 0.05-0.001); (3) no significant attenuation of flexion; and (4) no significant attenuation of extension. ConclusionsTranscutaneous dUS-guided FUS enables selective, reversible inhibition of A{delta} and C nociceptive fiber mediated behaviors while sparing A motor and A{beta} sensory behaviors. FUS-induced PNB prevented both acute and persistent pain behaviors. These findings support FUS as a promising noninvasive peripheral nerve blockade strategy for acute pain management.

neuroscience↗