Search

Hollow semiconductor nanostructures with direct Z-scheme heterojunction have significant advantages for photocatalytic reactions, and optimizing the interfacial charge transmission of Z-scheme heterojunction is the hinge to achieve excellent solar conversion efficiency. In this work, tubular Ni1-xCoxS2-CdS heterostructures with reinforced Z-scheme charge transmission were constructed through an In-metal-organic framework (MOF) templated strategy. The Z-scheme charge transfer mechanism was sufficiently confirmed by combining density functional theory (DFT) calculation, X-ray photoelectron spectroscopy (XPS), surface photovoltage spectroscopy (SPV), and radical testing results. Crucially, the use of sodium citrate complexant contributes to the formation of intimate heterointerface, and the Fermi level gap between CdS and NiS2 is enlarged through Co doping into NiS2, which enhances the built-in electric field and photo-carriers transmission driving force for Ni1-xCoxS2-CdS heterojunction, resulting in an evidently promoted activity toward H2 evolution reaction (HER). Under visible-light (λ > 400 nm) irradiation, the Ni1-xCoxS2-CdS composite with 10 mol% Co doping and 80 wt.% CdS (NC0.10S-80% CdS) achieved an outstanding HER rate up to 35.94 mmol·g-1·h-1 (corresponding to the apparent quantum efficiency of 34.7% at 420 nm), approximately 76.4 times that of 3 wt.% Pt-loaded CdS and it is much superior to that of most CdS-based photocatalysts ever reported. Moreover, the good photocatalytic durability of Ni1-xCoxS2-CdS heterostructures was validated by cycling and long-term HER tests. This work could inspire the development of high-performance Z-scheme heterojunction via optimizing the morphology and interfacial charge transmission. [ABSTRACT FROM AUTHOR]

There are few reports relating non-clay bricks with high compressive strength made from waste materials. In this research, secondary aluminum dross (SAD) and waste glass are explored as materials for non-clay bricks, to protect the raw clay resource, consume the generated wastes, and seek high-quality products. The influence of different raw materials and preparation conditions on the physical, mechanical, and environmental properties of fired bricks was examined carefully. It was detected that bricks made from SAD and glass performed better than SAD and clay bricks. The brick sample incorporating 80 wt.% SAD and 20 wt.% waste glass fired at 950 °C possessed excellent physical properties and reached the peak of compressive strength at 93.7 MPa, much higher than the criteria of ASTM C 62, showing great potential in practical application. A majority of hazardous materials were removed during the firing process so that the harmlessness and utilization of SAD were realized at the same time. This study provided the strategy and analysis of non-clay bricks with high compressive strength made from wastes, promoting material cycles and waste management. [ABSTRACT FROM AUTHOR]

Arl1 is an Arf-like (Arl) GTP-binding protein that interacts with the guanine nucleotide exchange factor Gea2 to recruit the golgin Imh1 to the Golgi. The Arl1–Gea2 complex also binds and activates the phosphatidylserine flippase Drs2 and these functions may be related, although the underlying molecular mechanism is unclear. Here we report high-resolution cryo-EM structures of the full-length Gea2 and the Arl1–Gea2 complex. Gea2 is a large protein with 1459 residues and is composed of six domains (DCB, HUS, SEC7, HDS1-3). We show that Gea2 assembles a stable dimer via an extensive interface involving hydrophobic and electrostatic interactions in the DCB and HUS region. Contrary to the previous report on a Gea2 homolog in which Arl1 binds to the dimerization surface of the DCB domain, implying a disrupted dimer upon Arl1 binding, we find that Arl1 binds to the outside surface of the Gea2 DCB domain, leaving the Gea2 dimer intact. The interaction between Arl1 and Gea2 involves the classic FWY aromatic residue triad as well as two Arl1-specific residues. We show that key mutations that disrupt the Arl1–Gea2 interaction abrogate Imh1 Golgi association. This work clarifies the Arl1–Gea2 interaction and improves our understanding of molecular events in the membrane trafficking. Arl1 is a GTP-binding protein that interacts with the guanine nucleotide exchange factor Gea2 to recruit the golgin Imh1 to the Golgi. Here, the authors report structures of the full-length Gea2 and the Arl1–Gea2 complex, with insights into the mechanism of their function in membrane trafficking. [ABSTRACT FROM AUTHOR]

Objectives: The previous studies have reported that adverse childhood experiences (ACEs) can have detrimental effects on victims' attachment styles, emotion regulation strategies and depression. How the insecure attachment styles and emotion dysregulation strategies play a role in the relationship between ACEs and depression among Chinese university students remains unclear. Methods: The research was made known to students studying at universities in China. Five hundred and eighty-nine college students completed questionnaires measuring ACEs, insecure attachment styles, emotion dysregulation strategies and depression. Sequential chain mediation model was built by Mplus. Results: The model showed that insecure attachment styles and emotion dysregulation strategies mediated the relationship between ACEs and depression respectively. Moreover, the sequential chain mediation showed an indirect path (ACEs - insecure attachment styles - emotion dysregulation strategies - depression). Conclusion: Following childhood adversities, students can experience elevated depression which is influenced by attachment styles and emotion regulation strategies. [ABSTRACT FROM AUTHOR]

The molecular chaperone DnaK is essential for viability of Mycobacterium tuberculosis (Mtb). DnaK hydrolyzes ATP to fold substrates, and the resulting ADP is exchanged for ATP by the nucleotide exchange factor GrpE. It has been unclear how GrpE couples DnaK's nucleotide exchange with substrate release. Here we report a cryo-EM analysis of GrpE bound to an intact Mtb DnaK, revealing an asymmetric 1:2 DnaK−GrpE complex. The GrpE dimer ratchets to modulate both DnaK nucleotide-binding domain and the substrate-binding domain. We further show that the disordered GrpE N-terminus is critical for substrate release, and that the DnaK−GrpE interface is essential for protein folding activity both in vitro and in vivo. Therefore, the Mtb GrpE dimer allosterically regulates DnaK to concomitantly release ADP in the nucleotide-binding domain and substrate peptide in the substrate-binding domain. Cryo-EM analysis reveals that the GrpE dimer of M. tuberculosis undergoes ratcheting motions when bound to an intact DnaK, thereby allosterically regulating DnaK's nucleotide exchange and substrate release. [ABSTRACT FROM AUTHOR]

The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6A117D with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6A117D. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance. The proteasome of Plasmodium falciparum (Pf20S) is a promising multi-stage drug target. Using CryoEM Hsu et al. report the structures of parasite and human proteasome in complex with the recently developed inhibitor TDI-8304 to gain insights into its species selectivity. [ABSTRACT FROM AUTHOR]

Deep hydrolysis for removing hazardous aluminum nitride (AlN) from secondary aluminum dross (SAD) remains a challenge nowadays. Enhanced hydrolysis of AlN from SAD through a combination of wet-stirred milling and alkaline leaching is investigated in the present study, which has not been reported before. SAD is activated during wet-stirred milling with water by reducing the grain size and increasing the active surface area. Leaching with NaOH dissolves the hydrolysis products (AlOOH, Al(OH)3) to expose reactive sites of unhydrolyzed AlN, contributing to the enhanced hydrolysis process. Results indicate that by utilizing optimized conditions (10 min wet milling, 5 wt.% NaOH solution, L/S ratio of 2, 75 ℃ temperature, and 120 min duration), 98.3% of AlN is removed from SAD. The kinetic analysis indicates that the hydrolysis process is controlled by both diffusion and chemical reactions, with the activation energy calculated to be 31.0 kJ/mol. After undergoing this enhanced hydrolysis process, the residue, which consisted primarily of Al2O3 and Al(OH)3,can be recycled as Al concentrate. The technology has been already applied in a pilot plant and achieved a favorable effect in practical applications. [ABSTRACT FROM AUTHOR]

The T4 bacteriophage gp41 helicase and gp61 primase assemble into a primosome to couple DNA unwinding with RNA primer synthesis for DNA replication. How the primosome is assembled and how the primer length is defined are unclear. Here we report a series of cryo-EM structures of T4 primosome assembly intermediates. We show that gp41 alone is an open spiral, and ssDNA binding triggers a large-scale scissor-like conformational change that drives the ring closure and activates the helicase. Helicase activation exposes a cryptic hydrophobic surface to recruit the gp61 primase. The primase binds the helicase in a bipartite mode in which the N-terminal Zn-binding domain and the C-terminal RNA polymerase domain each contain a helicase-interacting motif that bind to separate gp41 N-terminal hairpin dimers, leading to the assembly of one primase on the helicase hexamer. Our study reveals the T4 primosome assembly process and sheds light on the RNA primer synthesis mechanism. Here the authors present a methodical cryo-EM analysis to show how a T4 bacteriophage gp41 helicase hexamer and a gp61 primase assemble with a template-primer into an active primosome. [ABSTRACT FROM AUTHOR]

The eukaryotic polymerase α (Pol α) synthesizes an RNA-DNA hybrid primer of 20–30 nucleotides. Pol α is composed of Pol1, Pol12, Primase 1 (Pri1), and Pri2. Pol1 and Pri1 contain the DNA polymerase and RNA primase activities, respectively. It has been unclear how Pol α hands over an RNA primer from Pri1 to Pol1 for DNA primer extension, and how the primer length is defined. Here we report the cryo-EM analysis of yeast Pol α in the apo, primer initiation, primer elongation, RNA primer hand-off from Pri1 to Pol1, and DNA extension states, revealing a series of very large movements. We reveal a critical point at which Pol1-core moves to take over the 3'-end of the RNA from Pri1. DNA extension is limited by a spiral motion of Pol1-core. Since both Pri1 and Pol1-core are flexibly attached to a stable platform, primer growth produces stress that limits the primer length. DNA Polymerase α has separate RNA and DNA Polymerase subunits to form a hybrid RNA-DNA primer of unique length. Cryo-EM structures of each stage in primer synthesis reveal large movements among the four subunits and explain how primer length may be limited. [ABSTRACT FROM AUTHOR]

Purpose: Fine-needle aspiration (FNA) biopsy is an effective method to discriminate malignant thyroid nodules but reaches indeterminate results in approximately 30% of cases. Molecular testing can improve the diagnostic accuracy of FNA. This study aimed to investigate the real-life utility of the five-gene panel testing in thyroid FNAs. Methods: 759 thyroid nodules from 740 patients under FNAs were retrospectively enrolled. Gene mutation information and clinical parameters, including age, gender, tumor size, and lymph node metastasis, were respectively recorded. Cytological results were classified based on The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We analyzed mutational hotspots in BRAF, KRAS, NRAS, HRAS, and TERT genes from FNA specimens. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess diagnostic performance. Results: We identified 549 five-gene mutations in 759 nodules (72.3%), and the mutation frequency increased from the lower TBSRTC category to the upper category. BRAF.p.V600E showed the highest mutation incidence (71.3%) in the five-gene panel, correlated with the small to medium diameter (p = 0.008, p = 0.012) and high cytological categories (p < 0.001). The sensitivity, specificity, PPV, NPV, and accuracy of the combination of FNA cytology and five-gene detection were 96.83%, 100%, 100%, 42.86%, and 96.90%, respectively. Conclusions: The mutation frequency of the five-gene panel is 72.3% in thyroid FNAs. BRAF.p.V600E has the highest alteration rate, which is closely associated with tumor size and cytological results. The five-gene panel can improve the sensitivity and accuracy of FNA cytology, which may represent a valid adjunct technique in distinguishing thyroid nodules. [ABSTRACT FROM AUTHOR]

Background: The biomechanics generated by the clear aligner (CA) material changes continuously during orthodontic tooth movement, but this factor remains unknown during the computer-aid design process and the predictability of molars movement is not as expected. Therefore, the purpose of this study was to propose an iterative finite element method to simulate the long-term biomechanical effects of mandibular molar mesialization (MM) in CA therapy under dual-mechanical systems. Methods: Three groups including CA alone, CA with a button, and CA with a modified lever arm (MLA) were created. Material properties of CA were obtained by in vitro mechanical experiments. MM was conducted by the rebound force exerted by CA material and the mesial elastic force (2N, 30° to the occlusal plane) applied to the auxiliary devices. Stress intensity and distribution on periodontal ligament (PDL), attachment, button and MLA, and displacement of the second molar (M2) during the iterations were recorded. Results: There was a significant difference between the initial and cumulative long-term displacement. Specifically, compared to the beginning, the maximum stress of PDL decreased by 90% on average in the intermediate and final steps. The aligner was the main mechanical system at first, and then, the additional system exerted by the button and MLA dominated gradually. The stress of attachments and auxiliary devices is mainly concentrated on their interfaces with the tooth. Additionally, MLA provided a distal tipping and extrusive moment, which was the only group that manifested a total mesial displacement of the root. Conclusions: The innovatively designed MLA was more effective in reducing undesigned mesial tipping and rotation of M2 than the traditional button and CA alone, which provided a therapeutic method for MM. The proposed iterative method simulated tooth movement by considering the mechanical characteristic of CA and its long-term mechanical force changes, which will facilitate better movement prediction and minimize the failure rate. [ABSTRACT FROM AUTHOR]

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases. ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson's disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle. [ABSTRACT FROM AUTHOR]

Biclustering is a powerful data mining technique that allows simultaneously clustering rows (observations) and columns (features) in a matrix-format data set, which can provide results in a checkerboard-like pattern for visualization and exploratory analysis in a wide array of domains. Multiple biclustering algorithms have been developed in the past two decades, among which the convex biclustering can guarantee a global optimum by formulating in as a convex optimization problem. On the other hand, the application of biclustering has not progressed in parallel with the algorithm techniques. For example, biclustering for increasingly popular microbiome research data is under-applied possibly due to its compositional constraints for each sample. In this manuscript, we propose a new convex biclustering algorithm, called the bi-ADMM, under general setups based on the ADMM algorithm, which is free of extra smoothing steps to visualize informative biclusters required by existing convex biclustering algorithms. Furthermore, we tailor it to the algorithm named biC-ADMM specifically to tackle compositional constraints confronted in microbiome data. The key step of our methods is to utilize the Sylvester Equation to derive the ADMM algorithm, which is new to the clustering research. The effectiveness of the proposed methods is examined through a variety of numerical experiments and a microbiome data application. [ABSTRACT FROM AUTHOR]

Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr−/− mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr−/− mice, male Ldlr−/−Diaph1−/− mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr−/−Diaph1−/− mice displayed significantly less atherosclerosis compared to Ldlr−/− mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1. Male and female mice deficient in DIAPH1 are protected from the development of experimental atherosclerosis and display reduced cholesterol levels; these changes are linked to the regulation of SREBP1 subcellular localization. [ABSTRACT FROM AUTHOR]

Introduction: Hip fracture is one of the leading causes of death and disability in the elderly. We analyzed the risk factors of mortality and second fracture within 2 years after hip fracture surgery in elderly Chinese patients.Materials and Methods: A total of 613 elderly patients after hip fracture surgery were selected, including 181 males and 432 females, and the patients were followed for at least 24 months. Information about patients and surgery was collected from medical records. Information on death, secondary fracture, and postoperative activities of daily living (ADL) was obtained by telephone follow-up. Cox regression was performed to identify risk factors associated with mortality and second fracture, measured by hazard ratio (HR).Results: The 1-year and 2-year mortality rates after hip fracture were 13.4% and 20.7%, respectively. The second fracture rate within 2 years was 9.5%. Male gender (HR 1.51, P = 0.035), increased age (HR 1.07, P < 0.001), preoperative hypoalbuminemia (HR 1.79, P = 0.004), preoperative pneumonia (HR 2.60, P = 0.005) and poor ADL (P = 0.048) were independent risk factors for 2-year mortality, while high preoperative hemoglobin (HR 0.98, P = 0.002), high preoperative eGFR (HR 0.99, P = 0.031), high preoperative LVEF (HR 0.92, P = 0.048) were protective factors for 2-year mortality. Poor ADL (P = 0.002) was the independent risk factor for second fracture within 2 years.Conclusions: The 2-year mortality rate and second fracture rate after hip fracture in elderly remained high, which was related to old age and complications exists. Postoperative rehabilitation and improving ADL were very important to reduce mortality and second fracture. [ABSTRACT FROM AUTHOR]

Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKIIδ expression and increases BMAL1 activity via eliciting CaMKIIδ-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKIIδ-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders. Circadian modulators that exert amplitude-enhancing activity using highthroughput compound screening of small molecules identifies ISX-9, which is shown to augment CaMKIIδ expression, increasing BMAL1 activity via CaMKIIδ-dependent phosphorylation. [ABSTRACT FROM AUTHOR]

Many aspects of plant photoperception are mediated by the phytochrome (Phy) family of bilin-containing photoreceptors that reversibly interconvert between inactive Pr and active Pfr conformers1,2. Despite extensive biochemical studies, full understanding of plant Phy signalling has remained unclear due to the absence of relevant 3D models. Here we report a cryo-electron microscopy structure of Arabidopsis PhyB in the Pr state that reveals a topologically complex dimeric organization that is substantially distinct from its prokaryotic relatives. Instead of an anticipated parallel architecture, the C-terminal histidine-kinase-related domains (HKRDs) associate head-to-head, whereas the N-terminal photosensory regions associate head-to-tail to form a parallelogram-shaped platform with near two-fold symmetry. The platform is internally linked by the second of two internal Per/Arnt/Sim domains that binds to the photosensory module of the opposing protomer and a preceding ‘modulator’ loop that assembles tightly with the photosensory module of its own protomer. Both connections accelerate the thermal reversion of Pfr back to Pr, consistent with an inverse relationship between dimer assembly and Pfr stability. Lopsided contacts between the HKRDs and the platform create profound asymmetry to PhyB that might imbue distinct signalling potentials to the protomers. We propose that this unique structural dynamism creates an extensive photostate-sensitive surface for conformation-dependent interactions between plant Phy photoreceptors and their signalling partners.The inactive Pr conformer of Arabidopsis phytochrome B shows a topologically complex dimeric organization that is distinct from its prokaryotic relatives. [ABSTRACT FROM AUTHOR]

Essential oils (EOs), as unique natural products, are promising resources for the discovery of green agrochemicals. The main ingredient geraniol of citronella oil was found to exhibit substantial antifungal activities in this study. Therefore, a series of novel geranyl aromatic sulfonamide compounds were synthesized and found to display considerable antifungal activities. Two geranyl thiofuran-sulfonamide compounds 4c-1 (median effective concentration (EC50) against Rhizoctonia solani: 24.97 mg/L and EC50 against Sclerotinia sclerotiorum: 27.26 mg/L), 4c-2 (EC50 against S. sclerotiorum: 18.53 mg/L) and one geranyl pyridine-sulfonamide compound 4d-2 (EC50 against R. solani: 29.31 mg/L and EC50 against S. sclerotiorum: 29.98 mg/L) were screened as "star molecules" due to their excellent antifungal activities. The preliminary structure-activity relationship (SAR) study revealed that the introduction of various aromatic heterocycles maybe an efficient protocol to improve the fungicidal activities of geranyl aromatic sulfonamide compounds. The molecular mechanisms of the geranyl aromatic sulfonamide compounds were clarified by performing molecular docking and molecular dynamics (MD) simulations. Three "star molecules" of these geranyl aromatic sulfonamide compounds were found to bind to Complex III through several hydrogen bonds and π-interactions with crucial residues TRP17, GLY20 etc. Their binding free energies were calculated to be strong ranging from −50.60 to −39.44 kcal/mol by MM/GBSA method, which suggested the geranyl aromatic sulfonamide compounds were potential Complex III inhibitors. The main component originating from the natural plant EOs ought to be studied in the future to discover novel pathogenic fungicidal candidates. [ABSTRACT FROM AUTHOR]

An excellent organolead halide perovskite film is important for the good performance of perovskite solar cells (PSCs). However, defects in perovskite crystals can affect the photovoltaic properties and stability of solar cells. To solve this problem, this study incorporated a complex of CdS and Cd(SCN2H4)2Cl2 into the CH3NH3PbI3 active layer. The effects of different doping concentrations of CdS and Cd(SCN2H4)2Cl2 on the performance and stability of PSCs were analyzed. Results showed that doping appropriate incorporation concentrations of CdS and Cd(SCN2H4)2Cl2 in CH3NH3PbI3 can improve the performance of the prepared solar cells. In specific, CdS and Cd(SCN2H4)2Cl2 can effectively passivate the defects in perovskite crystals, thereby suppressing the charge recombination in PSCs and promoting the charge extraction at the TiO2/perovskite interface. Due to the reduction of perovskite crystal defects and the enhancement of compactness of the CdS:Cd(SCN2H4)2Cl2:CH3NH3PbI3 composite film, the stability of PSCs is significantly improved. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. [ABSTRACT FROM AUTHOR]

The S. cerevisiae plasma membrane H+-ATPase, Pma1, is a P3A-type ATPase and the primary protein component of the membrane compartment of Pma1 (MCP). Like other plasma membrane H+-ATPases, Pma1 assembles and functions as a hexamer, a property unique to this subfamily among the larger family of P-type ATPases. It has been unclear how Pma1 organizes the yeast membrane into MCP microdomains, or why it is that Pma1 needs to assemble into a hexamer to establish the membrane electrochemical proton gradient. Here we report a high-resolution cryo-EM study of native Pma1 hexamers embedded in endogenous lipids. Remarkably, we found that the Pma1 hexamer encircles a liquid-crystalline membrane domain composed of 57 ordered lipid molecules. The Pma1-encircled lipid patch structure likely serves as the building block of the MCP. At pH 7.4, the carboxyl-terminal regulatory α-helix binds to the phosphorylation domains of two neighboring Pma1 subunits, locking the hexamer in the autoinhibited state. The regulatory helix becomes disordered at lower pH, leading to activation of the Pma1 hexamer. The activation process is accompanied by a 6.7 Å downward shift and a 40° rotation of transmembrane helices 1 and 2 that line the proton translocation path. The conformational changes have enabled us to propose a detailed mechanism for ATP-hydrolysis-driven proton pumping across the plasma membrane. Our structures will facilitate the development of antifungal drugs that target this essential protein. The plasma membrane H+ -ATPase is responsible for maintenance of the plasma membrane potential, which provides energy for the transport of nutrients, and the plasma membrane H+ -ATPase in S. cerevisiae (Pma1) is a P3A-type ATPase that assembles and functions as a hexamer. Here, the authors present the cryo-EM structures of autoinhibited and activated native Pma1 hexamers purified with endogenous lipids and they propose a mechanism for proton pumping across the membrane by this family of H+ -ATPases. [ABSTRACT FROM AUTHOR]

P4 ATPases are lipid flippases that are phylogenetically grouped into P4A, P4B and P4C clades. The P4A ATPases are heterodimers composed of a catalytic α-subunit and accessory β-subunit, and the structures of several heterodimeric flippases have been reported. The S. cerevisiae Neo1 and its orthologs represent the P4B ATPases, which function as monomeric flippases without a β-subunit. It has been unclear whether monomeric flippases retain the architecture and transport mechanism of the dimeric flippases. Here we report the structure of a P4B ATPase, Neo1, in its E1-ATP, E2P-transition, and E2P states. The structure reveals a conserved architecture as well as highly similar functional intermediate states relative to dimeric flippases. Consistently, structure-guided mutagenesis of residues in the proposed substrate translocation path disrupted Neo1's ability to establish membrane asymmetry. These observations indicate that evolutionarily distant P4 ATPases use a structurally conserved mechanism for substrate transport. The P4 ATPase lipid flippases play a crucial role in membrane biogenesis. Here the authors report the structure of the monomeric P4B ATPase Neo1 in several states, clarifying the mechanism of substrate transport. [ABSTRACT FROM AUTHOR]

Uropathogenic Escherichia coli assemble surface structures termed pili or fimbriae to initiate infection of the urinary tract. P pili facilitate bacterial colonization of the kidney and pyelonephritis. P pili are assembled through the conserved chaperone-usher pathway. Much of the structural and functional understanding of the chaperone-usher pathway has been gained through investigations of type 1 pili, which promote binding to the bladder and cystitis. In contrast, the structural basis for P pilus biogenesis at the usher has remained elusive. This is in part due to the flexible and variable-length P pilus tip fiber, creating structural heterogeneity, and difficulties isolating stable P pilus assembly intermediates. Here, we circumvent these hindrances and determine cryo-electron microscopy structures of the activated PapC usher in the process of secreting two- and three-subunit P pilus assembly intermediates, revealing processive steps in P pilus biogenesis and capturing new conformational dynamics of the usher assembly machine. Escherichia coli form pili structures in order to initiate infection of the urinary tract. Here, Thanassi et al., have solved the structures of pili assembly intermediates and provided insights into their biogenesis and assembly. [ABSTRACT FROM AUTHOR]

The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults. [ABSTRACT FROM AUTHOR]

Gut microbiota, especially human pathogens, has been shown to be involved in the occurrence and development of cancer. Esophageal squamous cell carcinoma and lung cancer are two malignant cancers, and their relationship with gut microbiota is still unclear. Virulence factor database (VFDB) is an integrated and comprehensive online resource for curating information about human pathogens. Here, based on VFDB database, we analyzed the differences of bacteria at genus level in the gut of patients with esophageal squamous cell carcinoma, lung cancer, and healthy controls. We proposed the possible cancer-associated bacteria in gut and put forward their possible effects. Apart from this, principal coordinate analysis (PCoA) and analysis of similarities (ANSOIM) suggested that some bacteria in the gut can be used as potential biomarkers to screen esophageal squamous cell carcinoma and lung cancer, and their effectiveness was preliminary verified. The relative abundance of Klebsiella and Streptococcus can be used to distinguish patients with esophageal squamous cell carcinoma and lung cancer from healthy controls. The absolute abundance of Klebsiella can further distinguish patients with esophageal squamous cell carcinoma from patients with lung cancer. In particular, the relative abundance of Fusobacterium can directly distinguish between patients with esophageal squamous cell carcinoma and healthy controls. Additionally, the absolute abundance of Haemophilus can distinguish lung cancer from healthy controls. Our study provided a new way based on VFDB database to explore the relationship between gut microbiota and cancer, and initially proposed a feasible cancer screening method. [ABSTRACT FROM AUTHOR]

These authors contributed equally: Hongjun Yu, Dominik K. Haja. The original version of this Article omitted the following from the Acknowledgements: The EPR spectrometer was funded by an instrument award (CHE-1827968) from the National Science Foundation. [Extracted from the article]

Prostate-specific antigen (PSA)-based prostate cancer screening is a preference-sensitive decision for which experts recommend a shared decision making (SDM) approach. This study aimed to examine PSA screening SDM in primary care. Methods included qualitative analysis of audio-recorded patient-provider interactions supplemented by quantitative description. Participants included 5 clinic providers and 13 patients who were: (1) 40–69 years old, (2) Black, (3) male, and (4) attending clinic for routine primary care. Main measures were SDM element themes and “observing patient involvement in decision making” (OPTION) scoring. Some discussions addressed advantages, disadvantages, and/or scientific uncertainty of screening, however, few patients received all SDM elements. Nearly all providers recommended screening, however, only 3 patients were directly asked about screening preferences. Few patients were asked about prostate cancer knowledge (2), urological symptoms (3), or family history (6). Most providers discussed disadvantages (80%) and advantages (80%) of PSA screening. Average OPTION score was 25/100 (range 0–67) per provider. Our study found limited SDM during PSA screening consultations. The counseling that did take place utilized components of SDM but inconsistently and incompletely. We must improve SDM for PSA screening for diverse patient populations to promote health equity. This study highlights the need to improve SDM for PSA screening. [ABSTRACT FROM AUTHOR]