Biology subjects

Wang, J.-L.

Publications and source records attributed to Wang, J.-L..

7 recordsLinked to original sources

bioRxiv2025

Benchmarking datasets for machine learning in protein function prediction

Remarkable progress has been achieved by machine learning, particularly in accurate prediction of protein tertiary structures. Despite these advances, accurately annotating protein functions through machine learning approaches remains challenging, primarily due to the limited availability of large-scale benchmarking data. In this study, we addressed this gap by systematically screening proteins from the UniProt database for functional annotations, resulting in the creation of a benchmarking dataset that includes protein sequences and their corresponding annotations. The Protein Annotation Dataset (PAD) is a resource available to train a wide range of machine learning models for assignment of function annotations to previously unlabeled proteins. We curated a comprehensive dataset comprising four categories of functional annotations using enzyme commission (EC) numbers and gene ontology (GO) terms. The dataset was subsequently partitioned into training, validation, and test subsets. Furthermore, we incorporated an independent set from 12 diverse species, enabling the development and evaluation of innovative machine learning models.

bioinformatics↗

bioRxiv2025

Structural Basis of Asymmetric Class C GPCR activation and distinct Gq coupling induced by force stimulation

Mechanosensation is essential for diverse physiological processes. While many G protein-coupled receptors (GPCRs) are known to be mechanosensitive, the underlying mechanism remains largely unknown. Here, we reveal that mechanical force induces Gq activation of mGlu2, a balance modulator residing in kinocilia, but not other 7 mGlu members. Force activates mGlu2 through a conserved N-terminal force transduction motif (FTM) via a unique cis mechanism. We engineered a potent FTM-derived peptide agonist that recapitulates force-induced activation and resolved cryo-EM structures of apo-mGlu2, FTM-mGlu2, LFTM-{Psi}EK-mGlu2 and LFTM-{Psi}EK-mGlu2-Gq. The structures reveal that an atypical FTM binding to a previously uncharacterized pocket induces asymmetric 7TM domain rearrangement, enabling Gq coupling via an ICL1-TM3/6/7 interface, fundamentally distinct from the glutamate-induced Gi coupling mode of mGlu2. Compared with Gi-coupled mGlu2, the 5 helix of Gq rotated by 180{degrees}, penetrating deeper (8 [A]) into a hydrophobic pocket. Disruption of the M7947.32-F7806.57-F7766.53 hydrophobic triad core and a conformational propagation path predominantly comprising TM6-7 residues are identified as key elements mediating force induced mGlu2 activation. Further In vivo rescue experiments support that mGlu2s mechanosensitivity is dependent on FTM and is required for vestibular function. This work establishes a paradigm for class C GPCR mechanotransduction, revealing unprecedented structural mechanisms underlying force-induced Gq coupling and offering a chemical toolset to modulate mechanical signaling of GPCR.

cell biology↗

bioRxiv2025

A Mechanosensitive GPCR at vestibular kinocilium is required for normal balance

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq-PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq, or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68, causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER+/- Grm2fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

cell biology↗

bioRxiv2023

Enhancing glymphatic function with very low-intensity ultrasound via the transient receptor potential vanilloid-4-aquaporin-4 pathway

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has been associated with several neurological diseases such as Alzheimers disease, traumatic brain injury, and stroke. Therefore, it may be an important target for therapeutic interventions. In this study, we demonstrated that very low intensity ultrasound (VLIUS) (center frequency = 1 MHz; pulse repetition frequency = 1 kHz; duty factor = 1%, and spatial peak temporal average intensity [Ispta] = 3.68 mW/cm2; duration = 5 min) could significantly enhance the influx of cerebrospinal fluid tracers into the perivascular spaces of the brain and also facilitate interstitial substance clearance from the brain parenchyma. Notably, no evidence of brain damage was observed after VLIUS stimulation. We also demonstrated that VLIUS enhanced the glymphatic influx via the transient receptor potential vanilloid-4-aquaporin-4 pathway in the astrocytes. This mechanism may provide insights into VLIUS-regulated glymphatic function that modifies the natural course of central nervous system disorders related to waste clearance dysfunction. One Sentence SummaryVery low-intensity ultrasound enhances glymphatic influx via the TRPV4-AQP4 pathway in the astrocytes, without observable brain damage.

neuroscience↗

bioRxiv2022

Accelerated mass transfer from frozen thin films during thin-film freeze-drying

Freeze-drying, or lyophilization, is widely used to produce pharmaceutical solids from temperature-sensitive materials but the process is time and energy inefficient. Herein, using E. coli as a model live organism, whose viability in dry powders is highly sensitive to the water content in the powders, we demonstrated that the drying rate of thin-film freeze-drying (TFFD) is significantly higher than that of the conventional shelf freeze-drying, likely because the large total surface area from the loosely stacked frozen thin films and the low thickness of the thin-films enable faster and more efficient mass transfer during freeze-drying. The highly porous nature and high specific surface area of the thin-film freeze-dried powders may have contributed to the faster mass transfer as well. Moreover, we demonstrated that TFFD can be applied to produce dry powders of E. coli and L. acidophilus with minimum bacterial viability loss (i.e., within one log reduction), and the L. acidophilus dry powder is suitable for intranasal delivery. It is concluded that TFFD technology is promising in addressing the time-and cost-inefficient issue of conventional shelf freeze-drying.

pharmacology and toxicology↗

bioRxiv2020

18F-FDG-PET Hyperactivity in Alzheimers Disease Cerebellum and Primary Olfactory Cortex

Cerebellar involvement in Alzheimers disease (AD) has not been studied to the extent that cortical neuropathological changes have. Historical and recent histopathological literature demonstrate cerebellar AD pathology while functional investigation has demonstrated disrupted intrinsic cortical - cerebellar connectivity in AD. Additionally, olfactory deficits occur early in AD, prior to the onset of clinical symptoms. The neurological basis for the involvement of the cerebellum and olfactory system in the disease course remain unclear. 18F-fludeoxyglucose (FDG) positron emission tomography (PET) data from the Alzheimers Disease Neuroimaging Initiative (ADNI) were analyzed to characterize metabolism in the cerebellum and olfactory region of AD, mild-cognitive impaired (MCI), and age-matched cognitively normal (CN) controls. In contrast to known parietal and temporal lobe FDG hypo-metabolism within the default mode network in AD, a significant FDG hyper-metabolism was found in the cerebellum and olfactory cortical regions (including the piriform cortex, olfactory tubercle, anterior olfactory nucleus, and nucleus accumbens shell). The increase in cerebellum glucose utilization was shown also in late- verses early-MCI patients. The cerebellar and olfactory regions both contain inhibitory distal and inter-neuronal connections that are vulnerable to disruption in AD. The hyper-metabolism in the cerebellum and olfactory structures may reflect disruption of local and system-wide inhibitory networks due to AD neurodegeneration, suggesting a hypothetical mechanism for susceptibility of the olfactory system to early AD pathology.

neuroscience↗

bioRxiv2018

Bloodstream Infection with Extended-spectrum Beta-lactamase-producing Escherichia coli: the role of virulence genes

BackgroundVarious bacterial putative virulence factors are involved in the pathogenesis of bacterial infection. However, the effect of comorbidities or infection syndrome in the association of virulence factors and mortality remains inconclusive.\n\nMethodThis study addressed whether specific sequence type (ST) and virulence factors of extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) are associated with different outcomes in patients with bloodstream infection.121 adults from southern Taiwan with ESBL-producing E. coli bloodstream infections were enrolled during a 6-year period. Demographic data, including infection syndromes, underlying disease and outcomes, were collected. The virulence factors in isolates were analyzed by PCR and multilocus sequence typing.\n\nResultPositivity for the virulence genes iha, hlyD, sat, iut, fyu, malX, ompT, usp and traT was associated with ST131 positivity (P<0.05). Some ESBL-EC virulence genes associated with urinary tract infection (UTI) were revealed. Positivity for ST405 and the virulence genes iroN and iss was significantly associated with increased 30-day mortality (death within 30 days) on univariate analysis (P<0.05). Independent risk factors of 30-day mortality in bacteremic patients with UTI included underlying chronic liver disease and malignancy. ST131 was borderline associated with 30-day mortality. Independent risk factors associated with 30-day mortality among bacteremic patients without UTI included comorbidities and iroN positivity.\n\nConclusionIn bacteremic patients with UTI, and the ST131 clone was borderline associated with mortality. Positivity for the virulence gene iroN may be linked to mortality in bacteremic patients without UTI.

microbiology↗