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1.
bioRxiv ; 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39345439

ABSTRACT

Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is, therefore, an excellent target for developing small molecule inhibitors. While rupintrivir, a potent small-molecule inhibitor of several picornavirus proteases, effectively inhibits GI.1 protease, it is an order of magnitude less effective against GII protease. Other GI.1 protease inhibitors also tend to be less effective against GII proteases. To understand the structural basis for the potency difference, we determined the crystal structures of proteases of GI.1, pandemic GII.4 (Houston and Sydney), and GII.3 in complex with rupintrivir. These structures show that the open substrate pocket in GI protease binds rupintrivir without requiring significant conformational changes, whereas, in GII proteases, the closed pocket flexibly extends, reorienting arginine-112 in the BII-CII loop to accommodate rupintrivir. Structures of R112A protease mutants with rupintrivir, coupled with enzymatic and inhibition studies, suggest R112 is involved in displacing both substrate and ligands from the active site, implying a role in the release of cleaved products during polyprotein processing. Thus, the primary determinant for differential inhibitor potency between the GI and GII proteases is the increased flexibility in the BII-CII loop of the GII proteases caused by H-G mutation in this loop. Therefore, the inherent flexibility of the BII-CII loop in GII proteases is a critical factor to consider when developing broad-spectrum inhibitors for HuNoV proteases. IMPORTANCE: Human noroviruses are a significant cause of sporadic and epidemic gastroenteritis worldwide. There are no vaccines or antiviral drugs currently available to treat infections. Our work elucidates the structural differences between GI.1 and GII proteases in response to inhibitor binding and will inform the future development of broad-spectrum norovirus protease inhibitors.

3.
Proc Natl Acad Sci U S A ; 121(34): e2320143121, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39133850

ABSTRACT

Global warming during the Last Glacial Termination was interrupted by millennial-scale cool intervals such as the Younger Dryas and the Antarctic Cold Reversal (ACR). Although these events are well characterized at high latitudes, their impacts at low latitudes are less well known. We present high-resolution temperature and hydroclimate records from the tropical Andes spanning the past ~16,800 y using organic geochemical proxies applied to a sediment core from Laguna Llaviucu, Ecuador. Our hydroclimate record aligns with records from the western Amazon and eastern and central Andes and indicates a dominant long-term influence of changing austral summer insolation on the intensity of the South American Summer Monsoon. Our temperature record indicates a ~4 °C warming during the glacial termination, stable temperatures in the early to mid-Holocene, and slight, gradual warming since ~6,000 y ago. Importantly, we observe a ~1.5 °C cold reversal coincident with the ACR. These data document a temperature change pattern during the deglaciation in the tropical Andes that resembles temperatures at high southern latitudes, which are thought to be controlled by radiative forcing from atmospheric greenhouse gases and changes in ocean heat transport by the Atlantic meridional overturning circulation.

4.
Nat Commun ; 15(1): 5388, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38918376

ABSTRACT

Heparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.


Subject(s)
Acetyltransferases , Cryoelectron Microscopy , Lysosomes , Mucopolysaccharidosis III , Mucopolysaccharidosis III/genetics , Mucopolysaccharidosis III/metabolism , Mucopolysaccharidosis III/enzymology , Humans , Lysosomes/metabolism , Lysosomes/enzymology , Acetyltransferases/metabolism , Acetyltransferases/chemistry , Acetyltransferases/genetics , Catalytic Domain , Mutation , Heparitin Sulfate/metabolism , Acetyl Coenzyme A/metabolism , Acetyl Coenzyme A/chemistry , Models, Molecular , Glucosamine/metabolism , Glucosamine/chemistry , Acetylation , Intracellular Membranes/metabolism
5.
Nat Commun ; 15(1): 2460, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38503747

ABSTRACT

The mammalian orthoreovirus (reovirus) σNS protein is required for formation of replication compartments that support viral genome replication and capsid assembly. Despite its functional importance, a mechanistic understanding of σNS is lacking. We conducted structural and biochemical analyses of a σNS mutant that forms dimers instead of the higher-order oligomers formed by wildtype (WT) σNS. The crystal structure shows that dimers interact with each other using N-terminal arms to form a helical assembly resembling WT σNS filaments in complex with RNA observed using cryo-EM. The interior of the helical assembly is of appropriate diameter to bind RNA. The helical assembly is disrupted by bile acids, which bind to the same site as the N-terminal arm. This finding suggests that the N-terminal arm functions in conferring context-dependent oligomeric states of σNS, which is supported by the structure of σNS lacking an N-terminal arm. We further observed that σNS has RNA chaperone activity likely essential for presenting mRNA to the viral polymerase for genome replication. This activity is reduced by bile acids and abolished by N-terminal arm deletion, suggesting that the activity requires formation of σNS oligomers. Our studies provide structural and mechanistic insights into the function of σNS in reovirus replication.


Subject(s)
Orthoreovirus , Reoviridae , Animals , Orthoreovirus/genetics , Virus Replication , Reoviridae/genetics , RNA/metabolism , Bile Acids and Salts , RNA, Viral/genetics , Mammals/genetics
6.
Adv Mater ; 36(24): e2311559, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38520395

ABSTRACT

It is shown that structural disorder-in the form of anisotropic, picoscale atomic displacements-modulates the refractive index tensor and results in the giant optical anisotropy observed in BaTiS3, a quasi-1D hexagonal chalcogenide. Single-crystal X-ray diffraction studies reveal the presence of antipolar displacements of Ti atoms within adjacent TiS6 chains along the c-axis, and threefold degenerate Ti displacements in the a-b plane. 47/49Ti solid-state NMR provides additional evidence for those Ti displacements in the form of a three-horned NMR lineshape resulting from a low symmetry local environment around Ti atoms. Scanning transmission electron microscopy is used to directly observe the globally disordered Ti a-b plane displacements and find them to be ordered locally over a few unit cells. First-principles calculations show that the Ti a-b plane displacements selectively reduce the refractive index along the ab-plane, while having minimal impact on the refractive index along the chain direction, thus resulting in a giant enhancement in the optical anisotropy. By showing a strong connection between structural disorder with picoscale displacements and the optical response in BaTiS3, this study opens a pathway for designing optical materials with high refractive index and functionalities such as large optical anisotropy and nonlinearity.

7.
Chemphyschem ; 25(13): e202300953, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38396282

ABSTRACT

Chalcogenide perovskites are a class of materials with electronic and optoelectronic properties desirable for solar cells, infrared optics, and computing. The oxide counterparts of these chalcogenides have been studied extensively for their electrocatalytic and photoelectrochemical properties. As chalcogenide perovskites are more covalent, conductive, and stable, we hypothesize that they are more viable as electrocatalysts than oxide perovskites. The goal of this synthetic, experimental, and computational study is to examine the hydrogen evolution reaction (HER) activity of three Barium-based chalcogenides in perovskite and related structures: BaZrS3, BaTiS3, and BaVS3. Potential energy surfaces for hydrogen adsorption on surfaces of these materials are calculated using density functional theory and the computational hydrogen electrode model is used to contrast overpotentials with experiment. Although both experiments and computations agree that BaVS3 is the most active of the three materials, high overpotentials of these materials make them less viable than platinum for HER. Our work establishes a framework for future studies in the chemical and electrochemical properties of chalcogenide perovskites.

8.
Nat Commun ; 15(1): 1142, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38326301

ABSTRACT

The lasting threat of viral pandemics necessitates the development of tailorable first-response antivirals with specific but adaptive architectures for treatment of novel viral infections. Here, such an antiviral platform has been developed based on a mixture of hetero-peptides self-assembled into functionalized ß-sheets capable of specific multivalent binding to viral protein complexes. One domain of each hetero-peptide is designed to specifically bind to certain viral proteins, while another domain self-assembles into fibrils with epitope binding characteristics determined by the types of peptides and their molar fractions. The self-assembled fibrils maintain enhanced binding to viral protein complexes and retain high resilience to viral mutations. This method is experimentally and computationally tested using short peptides that specifically bind to Spike proteins of SARS-CoV-2. This platform is efficacious, inexpensive, and stable with excellent tolerability.


Subject(s)
COVID-19 , Humans , Peptides/chemistry , SARS-CoV-2/metabolism , Antiviral Agents/pharmacology , Viral Proteins , Spike Glycoprotein, Coronavirus/metabolism
10.
Physiol Meas ; 44(11)2023 Nov 28.
Article in English | MEDLINE | ID: mdl-37939391

ABSTRACT

Objective.Human activity recognition (HAR) has become increasingly important in healthcare, sports, and fitness domains due to its wide range of applications. However, existing deep learning based HAR methods often overlook the challenges posed by the diversity of human activities and data quality, which can make feature extraction difficult. To address these issues, we propose a new neural network model called MAG-Res2Net, which incorporates the Borderline-SMOTE data upsampling algorithm, a loss function combination algorithm based on metric learning, and the Lion optimization algorithm.Approach.We evaluated the proposed method on two commonly utilized public datasets, UCI-HAR and WISDM, and leveraged the CSL-SHARE multimodal human activity recognition dataset for comparison with state-of-the-art models.Main results.On the UCI-HAR dataset, our model achieved accuracy, F1-macro, and F1-weighted scores of 94.44%, 94.38%, and 94.26%, respectively. On the WISDM dataset, the corresponding scores were 98.32%, 97.26%, and 98.42%, respectively.Significance.The proposed MAG-Res2Net model demonstrates robust multimodal performance, with each module successfully enhancing model capabilities. Additionally, our model surpasses current human activity recognition neural networks on both evaluation metrics and training efficiency. Source code of this work is available at:https://github.com/LHY1007/MAG-Res2Net.


Subject(s)
Deep Learning , Humans , Neural Networks, Computer , Human Activities , Algorithms , Exercise
11.
bioRxiv ; 2023 Aug 24.
Article in English | MEDLINE | ID: mdl-37577609

ABSTRACT

The reovirus σNS RNA-binding protein is required for formation of intracellular compartments during viral infection that support viral genome replication and capsid assembly. Despite its functional importance, a mechanistic understanding of σNS is lacking. We conducted structural and biochemical analyses of an R6A mutant of σNS that forms dimers instead of the higher-order oligomers formed by wildtype (WT) σNS. The crystal structure of selenomethionine-substituted σNS-R6A reveals that the mutant protein forms a stable antiparallel dimer, with each subunit having a well-folded central core and a projecting N-terminal arm. The dimers interact with each other by inserting the N-terminal arms into a hydrophobic pocket of the neighboring dimers on either side to form a helical assembly that resembles filaments of WT σNS in complex with RNA observed using cryo-EM. The interior of the crystallographic helical assembly is positively charged and of appropriate diameter to bind RNA. The helical assembly is disrupted by bile acids, which bind to the same hydrophobic pocket as the N-terminal arm, as demonstrated in the crystal structure of σNS-R6A in complex with bile acid, suggesting that the N-terminal arm functions in conferring context-dependent oligomeric states of σNS. This idea is supported by the structure of σNS lacking the N-terminal arm. We discovered that σNS displays RNA helix destabilizing and annealing activities, likely essential for presenting mRNA to the viral RNA-dependent RNA polymerase for genome replication. The RNA chaperone activity is reduced by bile acids and abolished by N-terminal arm deletion, suggesting that the activity requires formation of σNS oligomers. Our studies provide structural and mechanistic insights into the function of σNS in reovirus replication.

13.
Adv Mater ; 35(49): e2303283, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37540897

ABSTRACT

As one of the most fundamental physical phenomena, charge density wave (CDW) order predominantly occurs in metallic systems such as quasi-1D metals, doped cuprates, and transition metal dichalcogenides, where it is well understood in terms of Fermi surface nesting and electron-phonon coupling mechanisms. On the other hand, CDW phenomena in semiconducting systems, particularly at the low carrier concentration limit, are less common and feature intricate characteristics, which often necessitate the exploration of novel mechanisms, such as electron-hole coupling or Mott physics, to explain. In this study, an approach combining electrical transport, synchrotron X-ray diffraction, and density-functional theory calculations is used to investigate CDW order and a series of hysteretic phase transitions in a dilute d-band semiconductor, BaTiS3 . These experimental and theoretical findings suggest that the observed CDW order and phase transitions in BaTiS3 may be attributed to both electron-phonon coupling and non-negligible electron-electron interactions in the system. This work highlights BaTiS3 as a unique platform to explore CDW physics and novel electronic phases in the dilute filling limit and opens new opportunities for developing novel electronic devices.

14.
Adv Mater ; 35(42): e2303588, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37529860

ABSTRACT

Materials with large birefringence (Δn, where n is the refractive index) are sought after for polarization control (e.g., in wave plates, polarizing beam splitters, etc.), nonlinear optics, micromanipulation, and as a platform for unconventional light-matter coupling, such as hyperbolic phonon polaritons. Layered 2D materials can feature some of the largest optical anisotropy; however, their use in most optical systems is limited because their optical axis is out of the plane of the layers and the layers are weakly attached. This work demonstrates that a bulk crystal with subtle periodic modulations in its structure-Sr9/8 TiS3 -is transparent and positive-uniaxial, with extraordinary index ne = 4.5 and ordinary index no = 2.4 in the mid- to far-infrared. The excess Sr, compared to stoichiometric SrTiS3 , results in the formation of TiS6 trigonal-prismatic units that break the chains of face-sharing TiS6 octahedra in SrTiS3 into periodic blocks of five TiS6 octahedral units. The additional electrons introduced by the excess Sr form highly oriented electron clouds, which selectively boost the extraordinary index ne and result in record birefringence (Δn > 2.1 with low loss). The connection between subtle structural modulations and large changes in refractive index suggests new categories of anisotropic materials and also tunable optical materials with large refractive-index modulation.

15.
Front Surg ; 10: 1111024, 2023.
Article in English | MEDLINE | ID: mdl-37065994

ABSTRACT

Objective: Pelvic incidence (PI) minus the lumbar lordosis (LL) angle (PI-LL) correlates with function and disability. It is associated with paravertebral muscle (PVM) degeneration and is a valuable tool for surgical planning of adult degenerative scoliosis (ADS). This study aims to explore the characteristics of PVM in ADS with PI-LL match or mismatch and to identify the risk factors for PI-LL mismatch. Methods: A total of 67 patients with ADS were divided into PI-LL match and mismatch groups. The visual analog scale (VAS), symptom duration, and Oswestry disability index (ODI) were used to assess patients' clinical symptoms and quality of life. The percentage of fat infiltration area (FIA%) of the multifidus muscle at the L1-S1 disc level was measured by using MRI with Image-J software. Sagittal vertical axis, LL, pelvic tilt (PT), PI, sacral slope, and the asymmetric and average degeneration degree of the multifidus were recorded. Logistic regression analysis was done to identify the risk factors for PI-LL mismatch. Results: In the PI-LL match and mismatch groups, the average FIA% of the multifidus on the convex side was less than that on the concave side (P < 0.05). There was no statistical difference of asymmetric degeneration degree of the multifidus between the two groups (P > 0.05). In the PI-LL mismatch group, the average degeneration degree of the multifidus, VAS, symptom duration, and ODI were significantly higher than that in the PI-LL match group, respectively (32.22 ± 6.98 vs. 26.28 ± 6.23 (%), 4.33 ± 1.60 vs. 3.52 ± 1.46, 10.81 ± 4.83 vs. 6.58 ± 4.23 (month), 21.06 ± 12.58 vs. 12.97 ± 6.49, P < 0.05). The average degeneration degree of the multifidus muscle was positively correlated with the VAS, symptom duration, and ODI, respectively (r = 0.515, 0.614, and 0.548, P < 0.05). Sagittal plane balance, LL, PT, and the average degeneration degree of the multifidus were the risk factors for PI-LL mismatch (OR: 15.447, 95% CI: 1.274-187.269; OR: 0.001, 95% CI: 0.000-0.099; OR: 107.540, 95% CI: 5.195-2,225.975; OR: 52.531, 95% CI: 1.797-1,535.551, P < 0.05). Conclusion: The PVM on the concave side was larger than that on the convex side in ADS irrespective of whether PI-LL matched or not. PI-LL mismatch could aggravate this abnormal change, which is an important cause of pain and disability in ADS. Sagittal plane imbalance, decreased LL, higher PT, and larger average degeneration degree of the multifidus were independent risk factors for PI-LL mismatch.

16.
Process Biochem ; 121: 656-660, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35965635

ABSTRACT

The B.1.617.2 (Delta) variant of concern is causing a new wave of infections in many countries. In order to better understand the changes of the SARS-CoV-2 mutation at the genetic level, we selected six mutations in the S region of the Delta variant compared with the native SARS-CoV-2 and get the conductance information of these six short RNA oligonucleotides groups by construct RNA: DNA hybrids. The electronic characteristics are investigated by the combination of density functional theory and non-equilibrium Green's function formulation with decoherence. We found that conductance is very sensitive to small changes in virus sequence. Among the 6 mutations in the Delta S region, D950N shows the largest change in relative conductance, reaching a surprising 4104.75%. These results provide new insights into the Delta variant from the perspective of its electrical properties. This may be a new method to distinguish virus variation and possess great research prospects.

17.
J Agric Food Chem ; 70(29): 9057-9065, 2022 Jul 27.
Article in English | MEDLINE | ID: mdl-35829707

ABSTRACT

Maltooligosaccharide-forming amylases (MFAs) hydrolyze starch into maltooligosaccharides with a defined degree of polymerization. However, the enzymatic mechanism underlying the product specificity remains partially understood. Here, we show that Saccharophagus degradans MFA (SdMFA) contains a noncatalytic starch-binding domain (SBD), which belongs to the carbohydrate-binding module family 20 and enables modulation of the product specificity. Removal of SBD from SdMFA resulted in a 3.5-fold lower production of the target maltopentaose. Conversely, appending SBD to another MFA from Bacillus megaterium improved the specificity for maltopentaose. SdMFA exhibited a higher level of exo-action and greater product specificity when reacting with amylopectin than with amylose. Our structural analysis and molecular dynamics simulation suggested that SBD could promote the recognition of nonreducing ends of substrates and delivery of the substrate chain to a groove end toward the active site in the catalytic domain. Furthermore, we demonstrate that a moderate temperature could mediate SBD to interact with the substrate with loose affinity, which facilitates the substrate to slide toward the active site. Together, our study reveals the structural and conditional bases for the specificity of MFAs, providing generalizable strategies to engineer MFAs and optimize the biosynthesis of maltooligosaccharides.


Subject(s)
Amylases , Starch , Amylases/chemistry , Binding Sites , Oligosaccharides , Starch/chemistry , Substrate Specificity , Temperature , alpha-Amylases/chemistry
18.
Faraday Discuss ; 239(0): 146-159, 2022 Oct 28.
Article in English | MEDLINE | ID: mdl-35837971

ABSTRACT

Chalcogenides in the perovskite and related crystal structures ("chalcogenide perovskites" for brevity) may be useful for future optoelectronic and energy-conversion technologies inasmuch as they have good excited-state, ambipolar transport properties. In recent years, several studies have suggested that semiconductors in the Ba-Zr-S system have slow non-radiative recombination rates. Here, we present a time-resolved photoluminescence (TRPL) study of excited-state carrier mobility and recombination rates in the perovskite-structured material BaZrS3, and the related Ruddlesden-Popper phase Ba3Zr2S7. We measure state-of-the-art single crystal samples, to identify properties free from the influence of secondary phases and random grain boundaries. We model and fit the data using a semiconductor physics simulation, to enable more direct determination of key material parameters than is possible with empirical data modeling. We find that both materials have Shockley-Read-Hall recombination lifetimes on the order of 50 ns and excited-state diffusion lengths on the order of 5 µm at room temperature, which bodes well for ambipolar device performance in optoelectronic technologies including thin-film solar cells.

19.
Sci Adv ; 8(12): eabm4346, 2022 Mar 25.
Article in English | MEDLINE | ID: mdl-35319972

ABSTRACT

Declining temperature has been thought to explain the abandonment of Norse settlements, southern Greenland, in the early 15th century, although limited paleoclimate evidence is available from the inner settlement region itself. Here, we reconstruct the temperature and hydroclimate history from lake sediments at a site adjacent to a former Norse farm. We find no substantial temperature changes during the settlement period but rather that the region experienced a persistent drying trend, which peaked in the 16th century. Drier climate would have notably reduced grass production, which was essential for livestock overwintering, and this drying trend is concurrent with a Norse diet shift. We conclude that increasingly dry conditions played a more important role in undermining the viability of the Eastern Settlement than minor temperature changes.

20.
Nat Commun ; 13(1): 625, 2022 02 02.
Article in English | MEDLINE | ID: mdl-35110534

ABSTRACT

A genetic knockout can be lethal to one human cell type while increasing growth rate in another. This context specificity confounds genetic analysis and prevents reproducible genome engineering. Genome-wide CRISPR compendia across most common human cell lines offer the largest opportunity to understand the biology of cell specificity. The prevailing viewpoint, synthetic lethality, occurs when a genetic alteration creates a unique CRISPR dependency. Here, we use machine learning for an unbiased investigation of cell type specificity. Quantifying model accuracy, we find that most cell type specific phenotypes are predicted by the function of related genes of wild-type sequence, not synthetic lethal relationships. These models then identify unexpected sets of 100-300 genes where reduced CRISPR measurements can produce genome-scale loss-of-function predictions across >18,000 genes. Thus, it is possible to reduce in vitro CRISPR libraries by orders of magnitude-with some information loss-when we remove redundant genes and not redundant sgRNAs.


Subject(s)
CRISPR-Cas Systems , Clustered Regularly Interspaced Short Palindromic Repeats , Genetic Engineering , Machine Learning , Animals , Cell Line , Gene Knockout Techniques , Genomics , Humans , Synthetic Lethal Mutations
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