Biology subjects

Hall, S. D.

Publications and source records attributed to Hall, S. D..

4 recordsLinked to original sources

bioRxiv2026

Structure of a dopamine-binding RNA aptamer reveals metal-mediated ligand recognition

The selection of small-molecule binding RNA aptamers enables the creation of ligand-responsive RNA tools, yet most aptamers fail to operate reliably across diverse environments. Scaffolded selection addresses this limitation by preserving the tertiary architecture of a riboswitch scaffold while driving the evolution of a new ligand-binding pocket. Using the xpt purine riboswitch aptamer, we previously generated dopamine-binding aptamers. Here, we report the crystal structures of two representative variants in their apo and dopamine-bound states to define how they recognize ligand while maintaining scaffold integrity. The structures demonstrate that scaffolded selection enforces global fold conservation and retains the defining tertiary interactions of the parental riboswitch. Local remodeling, triggered by deletions acquired during selection, rewires the three-way junction to build extensive interaction networks that host the dopamine-binding pocket. A deeply buried potassium ion anchors ligand recognition by coordinating the dopamine hydroxyl group while the RNA engages the catechol ring through stacking and hydrogen bonding interactions. Structure probing shows minimal conformational changes upon ligand binding, indicating that the aptamers adopt a largely preorganized fold. These findings strengthen the central premise of scaffolded selection: riboswitch-derived "superfolder" architectures can bias in vitro selections towards aptamers that conserve global structure while supporting locally diverse binding pockets. This balance between structural stability and local plasticity expands the capacity of a single RNA fold to recognize chemically distinct ligands and positions scaffolded selection as a powerful platform for engineering robust RNA-based sensing and regulatory devices. TOC Abstract (graphical) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/729643v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1c92ee4org.highwire.dtl.DTLVardef@1258d16org.highwire.dtl.DTLVardef@51d755org.highwire.dtl.DTLVardef@1102c63_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

In vivo CRISPR screening links NFKB1 to endocrine resistance in ER⁺ breast cancer

Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. NFKB1 emerged as a top candidate whose loss promoted estrogen-independent tumor growth and recurrence. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 loss activated canonical NF-{kappa}B signaling, leading to inflammatory gene induction and hyperactivation of ER signaling. Importantly, pharmacologic inhibition of NF-{kappa}B signaling restored ET sensitivity in NFKB1-deficient cells. Clinically, NFKB1 downregulation was enriched in ER breast tumors and associated with poor patient outcomes. Collectively, these findings establish NFKB1 as a key suppressor of ET resistance, uncover a mechanistic link between inflammation and ER reactivation, and highlight NF-{kappa}B signaling as a therapeutic vulnerability in NFKB1-deficient ER breast cancer.

cancer biology↗

bioRxiv2023

Transcranial focused ultrasound-mediated neurochemical and functional connectivity changes in deep cortical regions in humans

Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive technique for focally modulating human brain function. The mechanisms and neurochemical substrates underlying TUS neuromodulation in humans and how these relate to excitation and inhibition are still poorly understood. In 24 healthy controls, we separately stimulated two deep cortical regions and investigated the effects of theta-burst TUS, a protocol shown to increase corticospinal excitability, on the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and functional connectivity. We show for the first time in humans that theta-burst TUS selectively reduces GABA levels in the posterior cingulate, but not the dorsal anterior cingulate cortex. Functional connectivity increased following TUS in both regions. Our findings suggest that TUS changes overall excitability by reducing GABAergic inhibition, that changes in TUS-mediated neuroplasticity last at least 50 minutes after stimulation, and that these effects may be state-dependent - a mechanism increasingly recognized to influence the brains response to neuromodulation.

neuroscience↗

bioRxiv2020

The role of anxiety in the perception of pain: exploring the cumulative & temporal mechanisms of hypercapnic analgesia

BackgroundAnxiety, evoked by continuous inspiration of a 5 - 8% CO2 mixture, has been found to have an analgesic eLect on self-reported pain. The precise mechanism whereby this effect obtains remains unknown. MethodsThe present study tested whether temporal summation, the psychological counterpart of wind-up, is involved in hypercapnic analgesia. 21 healthy participants received painful transcutaneous electrical stimuli of varied intensity, during continuous inhalation of 7.5% CO2 mixture and medical air, presented in a single-blinded counterbalanced order. Continuous pain ratings were acquired to measure the temporal development of the pain response. Several points and events of interest that characterise the pain response profile were extracted from the continuous data. ResultsMixed-eLects modelling demonstrated a reduction of all pain measures during inspiration of the anxiogenic mixture, but not air. This was accompanied by an increase in the psychological and physiological measures of anxiety. Analyses of the characteristic measures of temporal summation suggested that the hypercapnic mixture has an analgesic property evident from the start of the pain response. The same was true for the remainder of the response, the adaptation period, where pain ratings were also inhibited. The reduced pain ratings persisted during the remainder of the response. Anxiety was found to be a mediating factor for summative pain ratings but not the temporally sensitive TS measures, suggesting an overall, cumulative effect. ConclusionsThe findings provide an explanation for the previously observed low self-reported pain during the inhalation of an anxiogenic hypercapnic mixture.

physiology↗