Intrinsic-strain-induced ferroelectric order and ultrafine nanodomains in SrTiO3.

Nano ferroelectrics holds the potential application promise in information storage, electro-mechanical transformation, and novel catalysts but encounters a huge challenge of size limitation and manufacture complexity on the creation of long-range ferroelectric ordering. Herein, as an incipient ferroelectric, nanosized SrTiO3 was indued with polarized ordering at room temperature from the nonpolar cubic structure, driven by the intrinsic three-dimensional (3D) tensile strain. The ferroelectric behavior can be confirmed by piezoelectric force microscopy and the ferroelectric TO1 soft mode was verified with the temperature stability to 500 K. Its structural origin comes from the off-center shift of Ti atom to oxygen octahedron and forms the ultrafine head-to-tail connected 90° nanodomains about 2 to 3 nm, resulting in an overall spontaneous polarization toward the short edges of nanoparticles. According to the density functional theory calculations and phase-field simulations, the 3D strain-related dipole displacement transformed from [001] to [111] and segmentation effect on the ferroelectric domain were further proved. The topological ferroelectric order induced by intrinsic 3D tensile strain shows a unique approach to get over the nanosized limitation in nanodevices and construct the strong strain-polarization coupling, paving the way for the design of high-performance and free-assembled ferroelectric devices.

Characterization of the dual role of Plasmodium falciparum DNA methyltransferase in regulating transcription and translation.

DNA modifications are critical in fine-tuning the biological processes in model organisms. However, the presence of cytosine methylation (5mC) and the function of the putative DNA methyltransferase, PfDNMT2, in the human malaria pathogen, Plasmodium falciparum, remain controversial. Here, we revisited the 5mC in the parasite genome and the function of PfDNMT2. Low levels of genomic 5mC (0.1-0.2%) during asexual development were identified using a sensitive mass spectrometry procedure. Native PfDNMT2 displayed substantial DNA methylation activities, and disruption or overexpression of PfDNMT2 resulted in reduced or elevated genomic 5mC levels, respectively. PfDNMT2 disruption led to an increased proliferation phenotype, with the parasites having an extended schizont stage and producing a higher number of progenies. Consistent with PfDNMT2's interaction with an AP2 domain-containing transcription factor, transcriptomic analyses revealed that PfDNMT2 disruption led to a drastic alteration in the expression of many genes, some of which provided the molecular basis of enhanced proliferation after PfDNMT2 disruption. Furthermore, levels of tRNAAsp and its methylation rate at position C38, and the translation of a reporter containing an aspartate repeat were significantly reduced after PfDNMT2 disruption, while the levels of tRNAAsp and its C38 methylation were restored after complementation of PfDNMT2. Our study sheds new light on the dual function of PfDNMT2 during P. falciparum asexual development.

Decoding Active Sites for Highly Efficient Semihydrogenation of Acetylene in Palladium-Copper Nanoalloys.

Accurately decoding the three-dimensional atomic structure of surface active sites is essential yet challenging for a rational catalyst design. Here, we used comprehensive techniques combining the pair distribution function and reverse Monte Carlo simulation to reveal the surficial distribution of Pd active sites and adjacent coordination environment in palladium-copper nanoalloys. After the fine-tuning of the atomic arrangement, excellent catalytic performance with 98% ethylene selectivity at complete acetylene conversion was obtained in the Pd34Cu66 nanocatalysts, outperforming most of the reported advanced catalysts. The quantitative deciphering shows a large number of active sites with a Pd-Pd coordination number of 3 distributed on the surface of Pd34Cu66 nanoalloys, which play a decisive role in highly efficient semihydrogenation. This finding not only opens the way for guiding the precise design of bimetal nanocatalysts from atomic-level insight but also provides a method to resolve the spatial structure of active sites.

Covalent Organic Framework Membranes with Patterned High-Density Through-Pores for Ultrafast Molecular Sieving.

The creation of uniformly molecular-sized through-pores within polymeric membranes and the direct evidence of these pores are essential for fundamentally understanding the transport mechanism and improving separation efficiency. Herein, we report an electric-field-assisted interface synthesis approach to fabricating large-area covalent organic framework (COF) membranes that consist of preferentially oriented single-crystalline COF domains. These single-crystalline frameworks were translated into high-density, vertically aligned through-pores across the entire membrane, enabling the direct visualization of membrane pores with an ultrahigh resolution of 2 Å using the low-dose high-resolution transmission electron microscopy technique (HRTEM). The density of directly visualized through-pores was quantified to be 1.2 × 1017 m-2, approaching theoretical predictions. These COF membranes demonstrate ultrahigh solvent permeability, which is 10 times higher than that of state-of-the-art organic solvent nanofiltration membranes. When applied to high-value pharmaceutical separations, their COF membranes exhibit 2 orders of magnitude higher methanol permeance and 20-fold greater enrichment efficiency than their commercial counterparts.

Colossal Zero-Field-Cooled Exchange Bias via Tuning Compensated Ferrimagnetic in Kagome Metals.

Exchange bias (EB) is a crucial property with widespread applications but particularly occurs by complex interfacial magnetic interactions after field cooling. To date, intrinsic zero-field-cooled EB (ZEB) has only emerged in a few bulk frustrated systems and their magnitudes remain small yet. Here, enabled by high temperature synthesis, we uncover a colossal ZEB field of 4.95 kOe via tuning compensated ferrimagnetism in a family of kagome metals, which is almost twice the magnitude of known materials. Atomic-scale structure, spin dynamics, and magnetic theory revealed that these compensated ferrimagnets originate from significant antiferromagnetic exchange interactions embedded in the holmium-iron ferrimagnetic matrix due to supersaturated preferential manganese doping. A random antiferromagnetic order of manganese sublattice sandwiched between ferromagnetic iron kagome bilayers accounts for such unconventional pinning. The outcome of the present study outlines disorder-induced giant bulk ZEB and coercivity in layered frustrated systems.

High-Entropy Magnet Enabling Distinctive Thermal Expansions in Intermetallic Compounds.

The high-entropy strategy has gained increasing popularity in the design of functional materials due to its four core effects. In this study, we introduce the concept of a "high-entropy magnet (HEM)", which integrates diverse magnetic compounds within a single phase and is anticipated to demonstrate unique magnetism-related properties beyond that of its individual components. This concept is exemplified in AB2-type layered Kagome intermetallic compounds (Ti,Zr,Hf,Nb,Fe)Fe2. It is revealed that the competition among individual magnetic states and the presence of magnetic Fe in originally nonmagnetic high-entropy sites lead to intricate magnetic transitions with temperature. Consequently, unusual transformations in thermal expansion property (from positive to zero, negative, and back to near zero) are observed. Specifically, a near-zero thermal expansion is achieved over a wide temperature range (10-360 K, αv = -0.62 × 10-6 K-1) in the A-site equal-atomic ratio (Ti1/5Zr1/5Hf1/5Nb1/5Fe1/5)Fe2 compound, which is associated with successive deflection of average Fe moments. The HEM strategy holds promise for discovering new functionalities in solid materials.

Onametostat, a PfPRMT5 inhibitor, exhibits antimalarial activity to Plasmodium falciparum.

Protein arginine methyltransferases (PRMTs) play critical roles in Plasmodium falciparum, a protozoan causing the deadliest form of malaria, making them potential targets for novel antimalarial drugs. Here, we screened 11 novel PRMT inhibitors against P. falciparum asexual growth and found that onametostat, an inhibitor for type II PRMTs, exhibited strong antimalarial activity with a half-maximal inhibitory concentration (IC50) value of 1.69 ± 0.04 µM. In vitro methyltransferase activities of purified PfPRMT5 were inhibited by onametostat, and a shift of IC50 to onametostat was found in the PfPRTM5 disruptant parasite line, indicating that PfPRTM5 is the primary target of onametostat. Consistent with the function of PfPRMT5 in mediating symmetric dimethylation of histone H3R2 (H3R2me2s) and in regulating invasion-related genes, onametostat treatment led to the reduction of H3R2me2s level in P. falciparum and caused the defects on the parasite's invasion of red blood cells. This study provides a starting point for identifying specific PRMT inhibitors with the potential to serve as novel antimalarial drugs.

N, S-Codoped 3D Carbon Protected Nanoporous MnS With Record High Sodium Ion Storage Performance for Potential Industry Applications.

With a high theoretical capacity, the MnS anode, however, exhibits a rather complex sodium diffusion kinetics and poor mechanical stability that hinder its application in sodium-ion batteries (SIBs). In this work, a simple, economical, and scalable strategy is developed to inherently coat nanoporous MnS with a 3D N, S co-doped thin carbon layer by using commercially available MnCO3 as precursors. Specifically, the strategy involves a two-step annealing process, which converts the MnCO3 microparticles into nanoporous Mn2O3 and MnS step by step. The 3D N, S codoped carbon layer is in situ formed during the second annealing process by first coating the nanoporous Mn2O3 with a polyaniline layer. Due to the inherent 3D carbon protection and the strong electronic interaction between N, S dopants and MnS, the N, S codoped carbon protected MnS obtained at 900 °C (NS-C@MnS-900) anode displays a high specific capacity of 845 mAh g-1 at 0.1 A g-1, which is higher than all reported MnS-based SIB anodes. It also shows an outstanding cyclability and rate performance, maintaining a stable capacity of ≈493 mAh g-1 after 1300 cycles at 10 A g-1, which is also the best according to knowledge. These exceptional electrochemical performances and the scalable/simple/low-cost synthesis make the NS-C@MnS-900 attractive for industry application.

Stereointerface Structure Drives Ferroelectricity in BaZrO3 Films.

Interfacial strain engineering can induce structural transformation and introduce new physical properties into materials, which is an effective method to prepare new multifunctional materials. However, interfacial strain has a limited spatial impact size. For example, in 2D thin films, the critical thickness of biaxial strain is typically less than 20 nm, which is not conducive to the maintenance of a strained structure and properties in thick film materials. The construction of a 3D interface can solve this problem. The large lattice mismatch between the BaZrO3 thin film and the substrate can induce the out-of-phase boundary (OPB) structure, which can extend along the thickness direction with the stacking of atoms. The lattice distortion at the OPB structure can provide a clamping effect for each layer of atoms, thus expanding the spatial influence range of biaxial strain. As a result, the uniform in-plane strain distribution and strain-induced ferroelectricity (Pr = 13 µC/cm2) are maintained along the thickness direction in BaZrO3 films.

Identification of shared gene signatures and pathways for diagnosing osteoporosis with sarcopenia through integrated bioinformatics analysis and machine learning.

BACKGROUND: Prior studies have suggested a potential relationship between osteoporosis and sarcopenia, both of which can present symptoms of compromised mobility. Additionally, fractures among the elderly are often considered a common outcome of both conditions. There is a strong correlation between fractures in the elderly population, decreased muscle mass, weakened muscle strength, heightened risk of falls, and diminished bone density. This study aimed to pinpoint crucial diagnostic candidate genes for osteoporosis patients with concomitant sarcopenia. METHODS: Two osteoporosis datasets and one sarcopenia dataset were obtained from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) and module genes were identified using Limma and Weighted Gene Co-expression Network Analysis (WGCNA), followed by functional enrichment analysis, construction of protein-protein interaction (PPI) networks, and application of a machine learning algorithm (least absolute shrinkage and selection operator (LASSO) regression) to determine candidate hub genes for diagnosing osteoporosis combined with sarcopenia. Receiver operating characteristic (ROC) curves and column line plots were generated. RESULTS: The merged osteoporosis dataset comprised 2067 DEGs, with 424 module genes filtered in sarcopenia. The intersection of DEGs between osteoporosis and sarcopenia module genes consisted of 60 genes, primarily enriched in viral infection. Through construction of the PPI network, 30 node genes were filtered, and after machine learning, 7 candidate hub genes were selected for column line plot construction and diagnostic value assessment. Both the column line plots and all 7 candidate hub genes exhibited high diagnostic value (area under the curve ranging from 1.00 to 0.93). CONCLUSION: We identified 7 candidate hub genes (PDP1, ALS2CL, VLDLR, PLEKHA6, PPP1CB, MOSPD2, METTL9) and constructed column line plots for osteoporosis combined with sarcopenia. This study provides reference for potential peripheral blood diagnostic candidate genes for sarcopenia in osteoporosis patients.

Biomechanical study of spinal cord and nerve root in idiopathic scoliosis: based on finite element analysis.

BACKGROUND: Current research lacks comprehensive investigation into the biomechanical changes in the spinal cord and nerve roots during scoliosis correction. This study employs finite element analysis to extensively explore these biomechanical variations across different Cobb angles, providing valuable insights for clinical treatment. METHODS: A personalized finite element model, incorporating vertebrae, ligaments, spinal cord, and nerve roots, was constructed using engineering software. Forces and displacements were applied to achieve Cobb angle improvements, designating T1/2-T4/5 as the upper segment, T5/6-T8/9 as the middle segment, and T9/10-L1/2 as the lower segment. Simulations under traction, pushing, and traction + torsion conditions were conducted, and biomechanical changes in each spinal cord segment and nerve roots were analyzed. RESULTS: Throughout the scoliosis correction process, the middle spinal cord segment consistently exhibited a risk of injury under various conditions and displacements. The lower spinal cord segment showed no significant injury changes under traction + torsion conditions. In the early correction phase, the upper spinal cord segment demonstrated a risk of injury under all conditions, and the lower spinal cord segment presented a risk of injury under pushing conditions. Traction conditions posed a risk of nerve injury on both sides in the middle and lower segments. Under pushing conditions, there was a risk of nerve injury on both sides in all segments. Traction + torsion conditions implicated a risk of injury to the right nerves in the upper segment, both sides in the middle segment, and the left side in the lower segment. In the later correction stage, there was a risk of injury to the upper spinal cord segment under traction + torsion conditions, the left nerves in the middle segment under traction conditions, and the right nerves in the upper segment under pushing conditions. CONCLUSION: When the correction rate reaches 61-68%, particular attention should be given to the upper-mid spinal cord. Pushing conditions also warrant attention to the lower spinal cord and the nerve roots on both sides of the main thoracic curve. Traction conditions require attention to nerve roots bilaterally in the middle and lower segments, while traction combined with torsion conditions necessitate focus on the right-side nerve roots in the upper segment, both sides in the middle segment, and the left-side nerve roots in the lower segment.

Finite element biomechanical analysis of 3D printed intervertebral fusion cage in osteoporotic population.

OBJECTIVE: To study the biomechanical characteristics of each tissue structure when using different 3D printing Cage in osteoporotic patients undergoing interbody fusion. METHODS: A finite element model of the lumbar spine was reconstructed and validated with regarding a range of motion and intervertebral disc pressure from previous in vitro studies. Cage and pedicle screws were implanted and part of the lamina, spinous process, and facet joints were removed in the L4/5 segment of the validated mode to simulate interbody fusion. A 280 N follower load and 7.5 N·m moment were applied to different postoperative models and intact osteoporotic model to simulate lumbar motion. The biomechanical characteristics of different models were evaluated by calculating and analyzing the range of motion of the fixed and cephalic adjacent segment, the stress of the screw-rod system, the stress at the interface between cage and L5 endplate, and intervertebral disc pressure of the adjacent segment. RESULTS: After rigid fixation, the range of motion of the fixed segment of model A-C decreased significantly, which was much smaller than that of the osteoporotic model. And with the increase of the axial area of the interbody fusion cages, the fixed segment of model A-C tended to be more stable. The range of motion and intradiscal pressure of the spinal models with different interbody fusion cages were higher than those of the complete osteoporosis model, but there was no significant difference between the postoperative models. On the other hand, the L5 upper endplate stress and screw-rod system stress of model A-C show a decreasing trend in different directions of motion. The stress of the endplate is the highest during flexion, which can reach 40.5 MPa (model A). The difference in endplate stress between models A-C was the largest during lateral bending. The endplate stress of models A and B was 150.5% and 140.9% of that of model C, respectively. The stress of the screw-rod system was the highest during lateral bending (model A, 102.0 MPa), which was 108.4%, 102.4%, 110.4%, 114.2% of model B and 158.5%, 110.1%, 115.8%, 125.4% of model C in flexion, extension, lateral bending, and rotation, respectively. CONCLUSIONS: For people with osteoporosis, no matter what type of cage is used, good immediate stability can be achieved after surgery. Larger cage sizes provide better fixation without significantly increasing ROM and IDP in adjacent segments, which may contribute to the development of ASD. In addition, larger cage sizes can disperse endplate stress and reduce stress concentration, which is of positive significance in preventing cage subsidence after operation. The cage and screw rod system establish a stress conduction pathway on the spine, and a larger cage greatly enhances the stress-bearing capacity of the front column, which can better distribute the stress of the posterior spine structure and the stress borne by the posterior screw rod system, reduce the stress concentration phenomenon of the nail rod system, and avoid exceeding the yield strength of the material, resulting in the risk of future instrument failure.

In vivo axial load-share ratio measurement using a novel hexapod system for safe external fixator removal.

BACKGROUND: External fixation is widely used in the treatment of traumatic fractures; however, orthopedic surgeons encounter challenges in deciding the optimal time for fixator removal. The axial load-share ratio (LS) of the fixator is a quantitative index to evaluate the stiffness of callus healing. This paper introduces an innovative method for measuring the LS and assesses the method's feasibility and efficacy. Based on a novel hexapod LS-measurement system, the proposed method is to improve the convenience and precision of measuring LS in vivo, hence facilitating the safe removal of external fixators. METHODS: A novel hexapod system is introduced, including its composition, theoretical model, and method for LS measurement. We conducted a retrospective study on 82 patients with tibial fractures treated by the Taylor Spatial Frame in our hospital from September 2018 to June 2020, of which 35 took LS measurements with our novel method (Group I), and 47 were with the traditional method (Group II). The external fixator was removed when the measurement outcome (LS < 10%) was consistent with the surgeon's diagnosis based on the clinical and radiological assessment (bone union achieved). RESULTS: No significant difference was found in the fracture healing time (mean 25.3 weeks vs. 24.9 weeks, P > 0.05), frame-wearing duration (mean 25.5 weeks vs. 25.8 weeks, P > 0.05), or LS measurement frequency (mean 1.1 times vs. 1.2 times, P > 0.05). The measurement system installation time in Group I was significantly shorter compared to Group II (mean 14.8 min vs. 81.3 min, P < 0.001). The LS value of the first measurement in Group I was lower than that of Group II (mean 5.1% vs. 6.9%, P = 0.011). In Group I, the refracture rate was 0, but in Group II it was 4.3% (2/47, P > 0.05). CONCLUSION: The novel hexapod LS-measurement system and involved method demonstrated enhanced convenience and precision in measuring the LS of the external fixator in vivo. The LS measurement indicates the callus stiffness of fracture healing, and is applicable to evaluate the safety of removing the fixator. Consequently, it is highly recommended for widespread adoption in clinical practice.

The role of the paraspinal muscles in the development of adolescent idiopathic scoliosis based on surface electromyography and radiographic analysis.

BACKGROUND: Patients with idiopathic scoliosis commonly present with an imbalance of the paraspinal muscles. However, it is unclear whether this muscle imbalance is an underlying cause or a result of idiopathic scoliosis. This study aimed to investigate the role of paraspinal muscles in the development of idiopathic scoliosis based on surface electromyography (sEMG) and radiographic analyses. METHODS: This was a single-center prospective study of 27 patients with single-curve idiopathic scoliosis. Posteroanterior whole-spine radiographs and sEMG activity of the erector spinae muscles were obtained for all patients in the habitual standing position (HSP), relaxed prone position (RPP), and prone extension position (PEP). The Cobb angle, symmetrical index (SI) of the sEMG activity (convex/concave), and correlation between the two factors were analyzed. RESULTS: In the total cohort, the mean Cobb angle in the HSP was significantly greater than the mean Cobb angle in the RPP (RPP-Cobb) (p < 0.001), whereas the mean Cobb angle in the PEP (PEP-Cobb) did not differ from the RPP-Cobb. Thirteen patients had a PEP-Cobb that was significantly smaller than their RPP-Cobb (p = 0.007), while 14 patients had a PEP-Cobb that was significantly larger than their RPP-Cobb (p < 0.001). In the total cohort and two subgroups, the SI of sEMG activity at the apex vertebra (AVSI) in the PEP was significantly greater than 1, revealing significant asymmetry, and was also significantly larger than the AVSI in the RPP. In the RPP, the AVSI was close to 1 in the total cohort and two subgroups, revealing no significant asymmetry. CONCLUSION: The coronal Cobb angle and the SI of paraspinal muscle activity in AIS patients vary with posture changes. Asymmetrical sEMG activity of the paraspinal muscles may be not an inherent feature of AIS patients, but is evident in the challenging tasks. The potential significance of asymmetric paraspinal muscle activity need to be explored in further research.

Unraveling the Intertwining Factors Underlying the Assembly of High-Nuclearity Heterometallic Clusters.

Two closely related yet distinctly different cationic clusters, [Dy52Ni44(HEIDA)36(OH)138(OAc)24(H2O)30]10+ (1) and [Dy112Ni76(HEIDA)44(EIDA)24(IDA)4(OH)268(OAc)48(H2O)44]4+ (2) (HEIDA=N-(2-hydroxyethyl)iminodiacetate), each featuring a multi-shell core of Platonic and Archimedean polyhedra, were obtained. Depending on the specific conditions used for the co-hydrolysis of Dy3+ and Ni2+, the product can be crystallized out as one particular type of cluster or as a mixture of 1 and 2. How the reaction process was affected by the amount of hydrolysis-facilitating base and/or by the reaction temperature and duration was investigated. It has been found that a reaction at a high temperature and/or for an extended period favors the formation of the compact and thermodynamically more stable 1, while a brief reaction with a large amount of the base is good for the kinetic product 2. By tuning these intertwining conditions, the reaction can be regulated toward a particular product.

Interplanar Ferromagnetism Enhanced Ultrawide Zero Thermal Expansion in Kagome Cubic Intermetallic (Zr,Nb)Fe2.

A cubic metal exhibiting zero thermal expansion (ZTE) over a wide temperature window demonstrates significant applications in a broad range of advanced technologies but is extremely rare in nature. Here, enabled by high-temperature synthesis, we realize tunable thermal expansion via magnetic doping in the class of kagome cubic (Fd-3m) intermetallic (Zr,Nb)Fe2. A remarkably isotropic ZTE is achieved with a negligible coefficient of thermal expansion (+0.47 × 10-6 K-1) from 4 to 425 K, almost wider than most ZTE in metals available. A combined in situ magnetization, neutron powder diffraction, and hyperfine Mössbauer spectrum analysis reveals that interplanar ferromagnetic ordering contributes to a large magnetic compensation for normal lattice contraction upon cooling. Trace Fe-doping introduces extra magnetic exchange interactions that distinctly enhance the ferromagnetism and magnetic ordering temperature, thus engendering such an ultrawide ZTE. This work presents a promising ZTE in kagome metallic materials.

Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.

Plasmodium falciparum causes the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5's function in stress responses in P. falciparum. The protein level of PfGCN5 was substantially induced under three stress conditions [heat shock, low glucose starvation, and dihydroartemisinin, the active metabolite of artemisinin (ART)]. With a TetR-DOZI conditional knockdown (KD) system, we successfully down-regulated PfGCN5 to ~50% and found that KD parasites became more sensitive to all three stress conditions. Transcriptomic analysis via RNA-seq identified ~1,000 up- and down-regulated genes in the wild-type (WT) and KD parasites under these stress conditions. Importantly, DHA induced transcriptional alteration of many genes involved in many aspects of stress responses, which were heavily shared among the altered genes under heat shock and low glucose conditions, including ART-resistance-related genes such as K13 and coronin. Based on the expression pattern between WT and KD parasites under three stress conditions, ~300-400 genes were identified to be involved in PfGCN5-dependent, general, and stress-condition-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay, we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and ART-resistance-related stress responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention.

In Vitro Susceptibility of Plasmodium falciparum Isolates from the China-Myanmar Border Area to Piperaquine and Association with Candidate Markers.

Plasmodium falciparum from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the in vitro susceptibility of 120 P. falciparum isolates collected at the China-Myanmar border during 2007-2016. The parasite isolates displayed a relatively wide range of piperaquine susceptibility estimates. While 56.7% of the parasites showed bimodal drug response curves, all but five generated area-under-the-curve (AUC) estimates consistent with a susceptible phenotype. Using the piperaquine survival assay (PSA), 5.6% parasites showed reduced susceptibility. Of note, parasites from 2014-2016 showed the highest AUC value and the highest proportion with a bimodal curve, suggesting falling effectiveness in these later years. Unsupervised K-mean analysis of the combined data assigned parasites into three clusters and identified significant correlations between IC50, IC90, and AUC values. No parasites carried the E415G mutation in a putative exo-nuclease, new mutations in PfCRT, or amplification of the plasmepsin 2/3 genes, suggesting mechanisms of reduced piperaquine susceptibility that differ from those described in other countries of the region. The association of increased AUC, IC50, and IC90 values with major PfK13 mutations (F446I and G533S) suggests that piperaquine resistance may evolve in these PfK13 genetic backgrounds. Additionally, the Pfmdr1 F1226Y mutation was associated with significantly higher PSA values. Further elucidation of piperaquine resistance mechanisms and continuous surveillance are warranted.

A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum.

The histone acetyltransferase GCN5-associated SAGA complex is evolutionarily conserved from yeast to human and functions as a general transcription co-activator in global gene regulation. In this study, we identified a divergent GCN5 complex in Plasmodium falciparum, which contains two plant homeodomain (PHD) proteins (PfPHD1 and PfPHD2) and a plant apetela2 (AP2)-domain transcription factor (PfAP2-LT). To dissect the functions of the PfGCN5 complex, we generated parasite lines with either the bromodomain in PfGCN5 or the PHD domain in PfPHD1 deleted. The two deletion mutants closely phenocopied each other, exhibiting significantly reduced merozoite invasion of erythrocytes and elevated sexual conversion. These domain deletions caused dramatic decreases not only in histone H3K9 acetylation but also in H3K4 trimethylation, indicating synergistic crosstalk between the two euchromatin marks. Domain deletion in either PfGCN5 or PfPHD1 profoundly disturbed the global transcription pattern, causing altered expression of more than 60% of the genes. At the schizont stage, these domain deletions were linked to specific down-regulation of merozoite genes involved in erythrocyte invasion, many of which contain the AP2-LT binding motif and are also regulated by AP2-I and BDP1, suggesting targeted recruitment of the PfGCN5 complex to the invasion genes by these specific factors. Conversely, at the ring stage, PfGCN5 or PfPHD1 domain deletions disrupted the mutually exclusive expression pattern of the entire var gene family, which encodes the virulent factor PfEMP1. Correlation analysis between the chromatin state and alteration of gene expression demonstrated that up- and down-regulated genes in these mutants are highly correlated with the silent and active chromatin states in the wild-type parasite, respectively. Collectively, the PfGCN5 complex represents a novel HAT complex with a unique subunit composition including an AP2 transcription factor, which signifies a new paradigm for targeting the co-activator complex to regulate general and parasite-specific cellular processes in this low-branching parasitic protist.

Solvent- and Additive-Free Dehydrogenation of N-Heterocycles with Oxygen Catalyzed by Polyoxovanadate-Based Metal-Organic Frameworks.

N-heteroarenes are a family of organics with significant chemical and pharmaceutical applications. They are generally prepared by the catalytic oxidative dehydrogenation (ODH) of partially saturated N-heterocycles. In this work, we prepare and demonstrate the catalytic ODH applications of two polyoxovanadate-based metal-organic frameworks of the general formula {[MII(bibp)1.5][VV2O6]}·H2O (M = Ni 1, Co 2; bibp = 4,4'-bis(imidazol-1-ylmethyl)biphenyl). They are based on nonprecious metals, need no additives or organic solvents typically required for catalytic ODH, and utilize molecular O2 as the oxidant, thus possessing all the traits desirable for practical catalysis. Catalyst 1 shows tolerance for a range of substrates with different electronic and steric features, including 2,3-dihydro-1H-indole and tetrahydroquinolines substituted with various functional groups. Mechanistic studies supported primarily by evidence from electron paramagnetic resonance and X-ray photoelectron spectra suggest that the VV sites in 1 are catalytically responsible, first enabling the formation of the substrate-based radical species by a single electron transfer event while being converted into its mixed-valence form, followed by the production of the superoxide radical anion (O2•-) upon contact with O2. The reaction mixture containing O2•- and the initially formed substrate-based radical then undergoes a series of steps, including the hydrogen abstraction and formation of the hydroperoxyl radical, the production and tautomerization of the partially dehydrogenated intermediate, and finally a repeating cycle of the aforementioned steps, to achieve the high-yield conversion of substrates to the corresponding N-heteroarenes.