Biology subjects

Zhou, Q. T.

Publications and source records attributed to Zhou, Q. T..

3 recordsLinked to original sources

bioRxiv2026

Liquid crystalline mesophase spacing as a quantitative predictor of release kinetics for co-loaded hydrophilic and hydrophobic payloads

Liquid crystalline mesophases exhibit structurally programmable internal architectures that enable co-loading of chemically orthogonal molecules within a single composite material. Realizing the potential of these materials for drug delivery requires a quantitative understanding of how tuning the composition affects internal mesophase architecture and consequently performance metrics such as payload release. Here, Flash NanoPrecipitation with hydrophobic ion pairing is used to prepare nanocarriers containing liquid crystalline mesophases co-encapsulating two compounds from widely different chemical classes: hydrophilic polymyxin B (logP -6) with one of four hydrophobic co-core materials (logP 7-11), achieving >75% encapsulation efficiency and up to 32% and 50% mass loadings for polymyxin and co-core. Synchrotron SAXS is used to quantify characteristic mesophase repeat spacing, which is found to be tunable as a function of composition. A strong correlation between d-spacing and polymyxin release rate is presented. Co-core chemistry and weight fraction jointly govern mesophase architecture, and repeat distance emerges as a structural metric linking these to the hydrophilic payload release kinetics. Mucus diffusivity and antibacterial efficacy are assessed as independent performance metrics, and results corroborate the release behavior. These findings establish a quantitative framework connecting material composition, mesophase architecture, and functional performance that can be applied toward rational co-formulation design. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/734853v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a0c38eorg.highwire.dtl.DTLVardef@86d33eorg.highwire.dtl.DTLVardef@196c83dorg.highwire.dtl.DTLVardef@3423c3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOToC Graphic TextC_FLOATNO Flash NanoPrecipitation yields liquid crystalline nanocarriers co-encapsulating with high efficiency payloads with widely distinct physicochemical properties. Synchrotron SAXS establishes characteristic repeat spacing as a quantitative structural metric directly governing hydrophilic release kinetics, providing a rational design framework linking mesophase architecture to functional performance across a range of payload structures. C_FIG

bioengineering↗

bioRxiv2026

The structure-interaction model of polymyxin lipopeptides with human oligopeptide transporter 2

Multidrug-resistant (MDR) Gram-negative bacteria pose a critical global health threat, while polymyxins remain a last-line therapy. However, their clinical use is limited by nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal cells and contributes to their nephrotoxicity, but the molecular basis of their interaction remains unclear. Here, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical, and cell biology approaches. Bioinformatic modelling predicted an outward-facing hPepT2 structure and a potential transport pathway, with polymyxins interacting at the lateral opening, particularly E214, D215, D317, D342, and E622. Transporter mutagenesis and molecular analyses confirmed that D215 is critical for polymyxin binding, while other residues influence transporter turnover and/or expression. We subsequently synthesised polymyxin analogues with modifications at Dab1, Dab3, Dab5, and Dab9 of polymyxins, which reduced interactions with hPepT2. Notably, alanine substitution at Dab3 reduced nephrotoxicity in mice while retaining antibacterial activity. Overall, this proof-of-concept study demonstrates that the hPepT2-polymyxin SIR model provides a viable strategy for developing novel, safer lipopeptide antibiotics.

biochemistry↗

bioRxiv2026

Regulation of spontaneous neurotransmission and homeostatic synaptic plasticity by synaptotagmin-1 disease variants at the SNARE primary interface.

De novo mutations in synaptotagmin-1 (syt1) cause a rare neurodevelopmental disorder, manifesting in global developmental delay, ophthalmic abnormalities, infantile hypotonia, facial dysmorphisms, absent speech, EEG abnormalities, and hyperkinetic movements, ranging from moderate to severe. Here, we evaluate eleven patient-relevant mutations spanning the Ca2+ binding domains of syt1--C2A and -C2B impact neurotransmission. We found that the mutation causing the most severe impact on neurotransmission, p.N341S, triggers aberrant spontaneous neurotransmission and occludes homeostatic synaptic plasticity signaling pathways. Our results suggest that potential phosphorylation of this newly introduced Ser residue underlies the functional change. A serine missense mutation creates a novel phosphorylation site as a broad spectrum protein kinase inhibitor rescues spontaneous neurotransmission. We identify key residues, localized to the primary interface between syt1 and SNAP-25, responsible for this shift in syt1 function in synaptic vesicle release. Substituting neutral amino acids at residue 341 alters the interaction of the Ser mutation, with double mutations in the surrounding amino acids in the primary interface rescuing synaptic function. These results provide a framework for how a syt1 point mutation introduces a substrate for phosphorylation and disrupts intermolecular interactions at the primary interface with SNAP-25 altering spontaneous neurotransmission and homeostatic plasticity. AUTHOR SUMMARYMutations in synaptotagmin-1 (SYT1), a protein essential for communication between neurons, cause a rare neurodevelopmental disorder marked by developmental delay, low muscle tone, abnormal movements, vision problems, and disrupted brain electrical activity. Disease severity varies, and how specific syt1 mutations alter brain signaling remains unclear. In this study, we examined 11 disease-associated syt1 mutations that affect regions of the protein responsible for sensing calcium, a key trigger for neurotransmitter release. Using a range of electrophysiological approaches, we measured how these mutations influence different modes of synaptic communication within neuronal networks. We found that one mutation, N341S, produced the most severe disruption. Neurons carrying this mutation released neurotransmitters abnormally at rest and were unable to engage normal homeostatic plasticity mechanisms that stabilize brain activity. These effects suggest a fundamental breakdown in how synapses regulate signaling strength. We investigated the molecular basis of this dysfunction and identified a likely explanation: the N341S mutation introduces a new serine residue that can be phosphorylated, a common regulatory modification in cells. Our data indicate that this newly created phosphorylation site alters syt1 function, as blocking phosphorylation pathways could modify the mutants effects. Importantly, we also show that N341 residue lies within a critical interaction interface between syt1 and another synaptic protein, SNAP-25. Adjusting nearby amino acids to neutralize this interaction restores wild-type levels of synaptic signaling. Together, these findings reveal how a single disease-associated mutation can rewire synaptic regulation by introducing a phosphorylation site, offering new insight into the underpinning of syt1-related neurodevelopmental disorders and potential therapeutic targets.

neuroscience↗