Three-atom-wide gold quantum rods with periodic elongation and strongly polarized excitons.

Atomically precise control over anisotropic nanoclusters constitutes a grand challenge in nanoscience. In this work, we report our success in achieving a periodic series of atomically precise gold quantum rods (abbrev. Au QRs) with unusual excitonic properties. These QRs possess hexagonal close-packed kernels with a constant three-atom diameter but increasing aspect ratios (ARs) from 6.3 to 18.7, all being protected by the same thiolate (SR) ligand. The kernels of the QRs are in a Au1-(Au3)n-Au1 configuration (where n is the number of Au3 layers) and follow a periodic elongation with a uniform Au18(SR)12 increment consisting of four Au3 layers. These Au QRs possess distinct HOMO-LUMO gaps (Eg = 0.6 to 1.3 eV) and exhibit strongly polarized excitonic transition along the longitudinal direction, resulting in very intense absorption in the near-infrared (800 to 1,700 nm). While excitons in gapped systems and plasmons in gapless systems are distinctly different types of excitations, the strongly polarized excitons in Au QRs surprisingly exhibit plasmon-like behaviors manifested in the shape-induced polarization, very intense absorption (~106 M-1 cm-1), and linear scaling relations with the AR, all of which resemble the behaviors of conventional metallic-state Au nanorods (i.e., gapless systems), but the QRs possess distinct gaps and very long excited-state lifetimes (10 to 2,122 ns), which hold promise in applications such as near-infrared solar energy utilization, hot carrier generation and transfer. The observation of plasmon-like behaviors from single-electron transitions in Au QRs elegantly bridges the distinct realms of single-electron and collective-electron excitations and may stimulate more research on excitonics and plasmonics.

hP-MSCs attenuate severe acute pancreatitis in mice via inhibiting NLRP3 inflammasome-mediated acinar cell pyroptosis.

BACKGROUND: Severe acute pancreatitis (SAP) is a serious gastrointestinal disease that is facilitated by pancreatic acinar cell death. The protective role of human placental mesenchymal stem cells (hP-MSCs) in SAP has been demonstrated in our previous studies. However, the underlying mechanisms of this therapy remain unclear. Herein, we investigated the regularity of acinar cell pyroptosis during SAP and investigated whether the protective effect of hP-MSCs was associated with the inhibition of acinar cell pyroptosis. METHODS: A mouse model of SAP was established by the retrograde injection of sodium taurocholate (NaTC) solution in the pancreatic duct. For the hP-MSCs group, hP-MSCs were injected via the tail vein and were monitored in vivo. Transmission electron microscopy (TEM) was used to observe the pyroptosis-associated ultramorphology of acinar cells. Immunofluorescence and Western blotting were subsequently used to assess the localization and expression of pyroptosis-associated proteins in acinar cells. Systemic inflammation and local injury-associated parameters were evaluated. RESULTS: Acinar cell pyroptosis was observed during SAP, and the expression of pyroptosis-associated proteins initially increased, peaked at 24 h, and subsequently showed a decreasing trend. hP-MSCs effectively attenuated systemic inflammation and local injury in the SAP model mice. Importantly, hP-MSCs decreased the expression of pyroptosis-associated proteins and the activity of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in acinar cells. CONCLUSIONS: Our study demonstrates the regularity and important role of acinar cell pyroptosis during SAP. hP-MSCs attenuate inflammation and inhibit acinar cell pyroptosis via suppressing NLRP3 inflammasome activation, thereby exerting a protective effect against SAP.

A nomogram to predict the risk of proliferative lupus nephritis in patients with systemic lupus erythematosus involving the kidneys.

Proliferative lupus nephritis (PLN) is a serious organ-threatening manifestation of systemic lupus erythematosus (SLE) that is associated with high mortality and renal failure. Here, we analyzed data from 1287 SLE patients with renal manifestations, including 780 of which were confirmed as proliferative or non-proliferative LN patients by renal biopsy, divided into a training cohort (547 patients) and a validation cohort (233 patients). By applying a least absolute shrinkage and selection operator (LASSO) regression approach combined with multivariate logistic regression analysis to build a nomogram for prediction of PLN that was then assessed by receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curves (DCA) in both the training and validation cohorts. The area under the ROC curve (AUC) of the model in the training cohort was 0.921 (95% confidence interval (CI): 0.895-0.946), the AUC of internal validation in the training cohort was 0.909 and the AUC of external validation was 0.848 (95% CI: 0.796-0.900). The nomogram showed good performance as evaluated using calibration and DCA curves. Taken together, our results indicate that our nomogram that comprises 12 significantly relevant variables could be clinically valuable to prognosticate on the risk of PLN in SLE, so as to improve patient prognoses.

Specialized cis-Acting RNA Elements Balance Genome Cyclization to Ensure Efficient Replication of Yellow Fever Virus.

Genome cyclization is essential for viral RNA (vRNA) replication of the vertebrate-infecting flaviviruses, and yet its regulatory mechanisms are not fully understood. Yellow fever virus (YFV) is a notorious pathogenic flavivirus. Here, we demonstrated that a group of cis-acting RNA elements in YFV balance genome cyclization to govern efficient vRNA replication. It was shown that the downstream of the 5'-cyclization sequence hairpin (DCS-HP) is conserved in the YFV clade and is important for efficient YFV propagation. By using two different replicon systems, we found that the function of the DCS-HP is determined primarily by its secondary structure and, to a lesser extent, by its base-pair composition. By combining in vitro RNA binding and chemical probing assays, we found that the DCS-HP orchestrates the balance of genome cyclization through two different mechanisms, as follows: the DCS-HP assists the correct folding of the 5' end in a linear vRNA to promote genome cyclization, and it also limits the overstabilization of the circular form through a potential crowding effect, which is influenced by the size and shape of the DCS-HP structure. We also provided evidence that an A-rich sequence downstream of the DCS-HP enhances vRNA replication and contributes to the regulation of genome cyclization. Interestingly, diversified regulatory mechanisms of genome cyclization, involving both the downstream of the 5'-cyclization sequence (CS) and the upstream of the 3'-CS elements, were identified among different subgroups of the mosquito-borne flaviviruses. In summary, our work highlighted how YFV precisely controls the balance of genome cyclization to ensure viral replication. IMPORTANCE Yellow fever virus (YFV), the prototype of the Flavivirus genus, can cause devastating yellow fever disease. Although it is preventable by vaccination, there are still tens of thousands of yellow fever cases per year, and no approved antiviral medicine is available. However, the understandings about the regulatory mechanisms of YFV replication are obscure. In this study, by a combination of bioinformatics, reverse genetics, and biochemical approaches, it was shown that the downstream of the 5'-cyclization sequence hairpin (DCS-HP) promotes efficient YFV replication by modulating the conformational balance of viral RNA. Interestingly, we found specialized combinations for the downstream of the 5'-cyclization sequence (CS) and upstream of the 3'-CS elements in different groups of the mosquito-borne flaviviruses. Moreover, possible evolutionary relationships among the various downstream of the 5'-CS elements were implied. This work highlighted the complexity of RNA-based regulatory mechanisms in the flaviviruses and will facilitate the design of RNA structure-targeted antiviral therapies.

Differential distribution of ivacaftor and its metabolites in plasma and human airway epithelia.

Ivacaftor is the first clinically approved monotherapy potentiator to treat CFTR channel dysfunction in people with cystic fibrosis. Ivacaftor (Iva) is a critical component for all current modulator therapies, including highly effective modulator therapies. Clinical studies show that CF patients on ivacaftor-containing therapies present various clinical responses, off-target effects, and adverse reactions, which could be related to metabolites of the compound. In this study, we reported the concentrations of Iva and two of its major metabolites (M1-Iva and M6-Iva) in capillary plasma and estimated M1-Iva and M6-Iva metabolic activity via the metabolite parent ratio in capillary plasma over 12 hours. We also used the ratio of capillary plasma versus human nasal epithelial cell concentrations to evaluate entry into epithelial cells in vivo. M6-Iva was rarely detected by LC-MS/MS in epithelial cells from participants taking ivacaftor, although it was detected in plasma. To further explore this discrepancy, we performed in vitro studies, which showed that M1-Iva, but not M6-Iva, readily crossed 16HBE cell membranes. Our studies also suggest that metabolism of these compounds is unlikely to occur in airway epithelia despite evidence of expression of metabolism enzymes. Overall, our data provide evidence that there are differences between capillary and cellular concentrations of these compounds that may inform future studies of clinical response and off-target effects.

Elucidating the Near-Infrared Photoluminescence Mechanism of Homometal and Doped M25(SR)18 Nanoclusters.

More than a decade of research on the photoluminescence (PL) of classic Au25(SR)18 and its doped nanoclusters (NCs) still leaves many fundamental questions unanswered due to the complex electron dynamics. Here, we revisit the homogold Au25 (ligands omitted hereafter) and doped NCs, as well as the Ag25 and doped ones, for a comparative study to disentangle the influencing factors and elucidate the PL mechanism. We find that the strong electron-vibration coupling in Au25 leads to weak PL in the near-infrared region (∼1000 nm, quantum yield QY = 1% in solution at room temperature). Heteroatom doping of Au25 with a single Cd or Hg atom strengthens the coupling of the exciton with staple vibrations but reduces the coupling with the core breathing and quadrupolar modes. The QYs of the three MAu24 NCs (M = Hg, Au, and Cd) follow a linear relation with their PL lifetimes, suggesting a mechanism of suppressed nonradiative decay in PL enhancement. In contrast, the weaker electron-vibration coupling in Ag25 leads to higher PL (QY = 3.5%), and single Au atom doping further leads to a 5× enhancement of the radiative rate and a suppression of nonradiative decay rate (i.e., twice the PL lifetime of Ag25) in AuAg24 (hence, QY 35%), but doping more Au atoms results in gold distribution to staple motifs and thus triggering of strong electron-vibration coupling as in the MAu24 NCs, hence, counteracting the radiative enhancement effect and giving rise to only 5% QY for AuxAg25-x (x = 3-10). The obtained insights will provide guidance for the design of metal NCs with high PL for lighting, sensing, and optoelectronic applications.

Tailoring Carbon Tails of Ligands on Au52(SR)32 Nanoclusters Enhances the Near-Infrared Photoluminescence Quantum Yield from 3.8 to 18.3.

One of the important factors that determine the photoluminescence (PL) properties of gold nanoclusters pertain to the surface. In this study, four Au52(SR)32 nanoclusters that feature a series of aromatic thiolate ligands (-SR) with different bulkiness at the para-position are synthesized and investigated. The near-infrared (NIR) photoluminescence (peaks at 900-940 nm) quantum yield (QY) is largely enhanced with a decrease in the ligand's para-bulkiness. Specifically, the Au52(SR)32 capped with the least bulky p-methylbenzenethiolate (p-MBT) exhibits the highest PLQY (18.3% at room temperature in non-degassed dichloromethane), while Au52 with the bulkiest tert-butylbenzenethiolate (TBBT) only gives 3.8%. The large enhancement of QY with fewer methyl groups on the ligands implies a nonradiative decay via the multiphonon process mediated by C-H bonds. Furthermore, single-crystal X-ray diffraction (SCXRD) comparison of Au52(p-MBT)32 and Au52(TBBT)32 reveals that fewer methyl groups at the para-position lead to a stronger interligand π···π stacking on the Au52 core, thus restricting ligand vibrations and rotations. The emission nature is identified to be phosphorescence and thermally activated delayed fluorescence (TADF) based on the PL lifetime, 3O2 quenching, and temperature-dependent PL and absorption studies. The 1O2 generation efficiencies for the four Au52(SR)32 NCs follow the same trend as the observed PL performance. Overall, the highly NIR-luminescent Au52(p-MBT)32 nanocluster and the revealed mechanisms are expected to find future applications.

Pathogenicity and Structural Basis of Zika Variants with Glycan Loop Deletions in the Envelope Protein.

The glycan loop of Zika virus (ZIKV) envelope protein (E) contains the glycosylation site and has been well documented to be important for viral pathogenesis and transmission. In the present study, we report that deletions in the E glycan loop, which were recorded in African ZIKV strains previously, have re-emerged in their contemporary Asian lineages. Here, we generated recombinant ZIKV containing specific deletions in the E glycan loop by reverse genetics. Extensive in vitro and in vivo characterization of these deletion mutants demonstrated an attenuated phenotype in an adult A129 mouse model and reduced oral infections in mosquitoes. Surprisingly, these glycan loop deletion mutants exhibited an enhanced neurovirulence phenotype, and resulted in a more severe microcephalic brain in neonatal mouse models. Crystal structures of the ZIKV E protein and a deletion mutant at 2.5 and 2.6 Å, respectively, revealed that deletion of the glycan loop induces encephalitic flavivirus-like conformational alterations, including the appearance of perforations on the surface and a clear change in the topology of the loops. Overall, our results demonstrate that the E glycan loop deletions represent neonatal mouse neurovirulence markers of ZIKV. IMPORTANCE Zika virus (ZIKV) has been identified as a cause of microcephaly and acquired evolutionary mutations since its discovery. Previously deletions in the E glycan loop were recorded in African ZIKV strains, which have re-emerged in the contemporary Asian lineages recently. The glycan loop deletion mutants are not glycosylated, which are attenuated in adult A129 mouse model and reduced oral infections in mosquitoes. More importantly, the glycan loop deletion mutants induce an encephalitic flavivirus-like conformational alteration in the E homodimer, resulting in a significant enhancement of neonatal mouse neurovirulence. This study underscores the critical role of glycan loop deletion mutants in ZIKV pathogenesis, highlighting a need for global virological surveillance for such ZIKV variants.

Comparison of heterologous prime-boost immunization strategies with DNA and recombinant vaccinia virus co-expressing GP3 and GP5 of European type porcine reproductive and respiratory syndrome virus in pigs.

Vaccination is principally used to control and treat porcine reproductive and respiratory syndrome virus (PRRSV) infection. This study investigated immunogenicity and protective efficacy of heterologous prime-boost regimens in pigs, including recombinant DNA and vaccinia virus vectors coexpressing PRRSV European genotype (EU) isolate GP3 and GP5: group A, pVAX1-EU-GP3-GP5 prime and rddVTT-EU-GP3-GP5 boost; group B, rddVTT-EU-GP3-GP5 prime and pVAX1-EU-GP3-GP5 boost; group C, empty vector pVAX1; group D, E3L gene-deleted vaccinia virus E3L- VTT. Vaccine efficacy was tested in an EU-type PRRSV (Lelystad virus strain) challenge pig model based on evaluating PRRSV-specific antibody responses, neutralizing antibodies, cytokines, T lymphocyte proliferation, CD4+ and CD8+ T lymphocytes, clinical symptoms, viremia and tissue virus loads. Plasmid DNA was delivered as chitosan-DNA nanoparticles, and Quil A (Quillaja) was used to increase vaccine efficiency. All piglets were boosted 21 days post the initial inoculation (dpi) and then challenged 14 days later. At 14, 21, 28 and 35 dpi, groups A and B developed significantly higher PRRSV-specific antibody responses compared with control groups C and D. Two weeks after the boost, significant differences in neutralizing antibody and IFN-γ levels were observed between groups A, C, D and B. At 49 dpi, groups A and B had markedly increased peripheral blood CD3+CD4+ T cell levels. Following virus challenge, group A showed viremia, but organ virus loads were lower than those in other groups. Thus, a heterologous prime-boost vaccine regimen (rddVTT-EU-GP3-GP5 prime, pVAX1-EU-GP3-GP5 boost) can improve humoral- and cell-mediated immune responses to provide resistance to EU-type PRRSV infection in vivo.

Gut microbiota-derived melatonin from Puerariae Lobatae Radix-resistant starch supplementation attenuates ischemic stroke injury via a positive microbial co-occurrence pattern.

Ischemic stroke is closely associated with gut microbiota dysbiosis and intestinal barrier dysfunction. Prebiotic intervention could modulate the intestinal microbiota, thus considered a practical strategy for neurological disorders. Puerariae Lobatae Radix-resistant starch (PLR-RS) is a potential novel prebiotic; however, its role in ischemic stroke remains unknown. This study aimed to clarify the effects and underlying mechanisms of PLR-RS in ischemic stroke. Middle cerebral artery occlusion surgery was performed to establish a model of ischemic stroke in rats. After gavage for 14 days, PLR-RS attenuated ischemic stroke-induced brain impairment and gut barrier dysfunction. Moreover, PLR-RS rescued gut microbiota dysbiosis and enriched Akkermansia and Bifidobacterium. We transplanted the fecal microbiota from PLR-RS-treated rats into rats with ischemic stroke and found that the brain and colon damage were also ameliorated. Notably, we found that PLR-RS promoted the gut microbiota to produce a higher level of melatonin. Intriguingly, exogenous gavage of melatonin attenuated ischemic stroke injury. In particular, melatonin attenuated brain impairment via a positive co-occurrence pattern in the intestinal microecology. Specific beneficial bacteria served as leaders or keystone species to promoted gut homeostasis, such as Enterobacter, Bacteroidales_S24-7_group, Prevotella_9, Ruminococcaceae and Lachnospiraceae. Thus, this new underlying mechanism could explain that the therapeutic efficacy of PLR-RS on ischemic stroke at least partly attributed to gut microbiota-derived melatonin. In summary, improving intestinal microecology by prebiotic intervention and melatonin supplementation in the gut were found to be effective therapies for ischemic stroke.

Size-Dependent Electrocatalytic Water Oxidation Activity for a Series of Atomically Precise Nickel-Thiolate Clusters.

The development of renewable energy technologies is critical for reducing global carbon emissions. Water splitting offers a promising renewable energy mechanism by converting water into H2 and O2 gas, which can directly power fuel cells or be utilized as chemical feedstocks. To increase the efficiency of water splitting, catalysts must be developed for the water reduction and water oxidation half-reactions. To promote rational catalyst design, atomically precise metal clusters (APMCs) with earth-abundant metals provide a framework for developing both structure-activity relationships and cost-effective catalysts. Previous reports on the water oxidation activity of nickel-thiolate clusters [Nin(SR)2n] have not developed a systematic description of a possible size-activity relationship. Utilizing recent advancements in preparative chromatography for isolating APMCs, we have synthesized a series of Nin(SR)2n (n = 4, 5, or 6) clusters as electrocatalysts for the oxygen evolution reaction. We discovered a clear size-activity and size-stability trend, with intrinsic activity and stability increasing with cluster size. Using density functional theory, we found that intrinsic activity is inversely correlated to intermediate binding energy, and by extension the oxidation potential of each cluster. Our work demonstrates the ability of APMCs to uncover previously unknown structure-activity relationships that can guide future catalyst design.

Near-Infrared Dual Emission from the Au42(SR)32 Nanocluster and Tailoring of Intersystem Crossing.

This work presents the synthesis and intriguing photoluminescence of the Au42(PET)32 (PET = 2-phenylethanethiolate) nanocluster (NC). The Au42(PET)32 NC exhibits dual emission at 875 and 1040 nm, which are revealed to be fluorescence and phosphorescence, respectively. The emission quantum yield (QY) of Au42(PET)32 in dichloromethane is 11.9% at room temperature in air, which is quite rare for thiolate-protected Au NCs. When Au42(PET)32 NCs are embedded in polystyrene films (solid state), the fluorescence was dramatically suppressed while the phosphorescence was significantly enhanced. This divergent behavior is explained by dipolar interaction-induced enhancement of intersystem crossing from singlet to triplet excited state.

Circ_0128846/miR-140-3p/JAK2 Network in Osteoarthritis Development.

Circular RNAs (circRNAs) titrate the function of microRNAs (miRNAs), regulate transcription, and interfere with splicing. This study attempted to confirm the role of a novel circRNA circ_0128846 during osteoarthritis (OA) progression. Tissues and chondrocytes were isolated from OA patients. Overexpression and knockdown of target genes were generated using cell transfection and siRNA interference. Expression levels of genes were measured by qRT-PCR, Western blot, and immunohistochemistry, respectively. The interactions among circ_0128846, miR-140-3p, and JAK2 were verified by bioinformatics prediction, a dual-luciferase reporter assay, and RNA immunoprecipitation assay. The role of circ_0128846 in vivo was confirmed by the construction of experimental OA rats. Pathological changes were evaluated by hematoxylin and eosin and Safranin O staining. In OA patients, the level of circ_0128846 and JAK2 were up-regulated with down-regulated level of miR-140-3p. Circ_0128846 was principally located in the cytoplasm. Circ_0128846 silence enhanced cells viability, but reduced apoptosis rate and inflammatory response, which was obviously reversed by miR-140-3p knockdown. The overexpression of JAK2 reversed the effects of miR-140-3p on cell phenotypes. Circ_0128846 silence suppressed the level of MMP-13 and promoted the expression of collagen II by up-regulating miR-140-3p and down-regulating JAK2 in OA cells. Results of animal experiments demonstrated that circ_0128846 silence promoted collagen II expression and attenuated the OA progression by regulating the miR-140-3p/JAK2 axis. Circ_0128846 contributes to OA development through acting as a sponge RNA for miR-140-3p and thereby increasing JAK2 expression. Results indicated that targeting circ_0128846 may have the potential to alleviate OA progression.Abbreviations:circRNAs: Circular RNAs; miRNAs: microRNAs; OA: osteoarthritis; RIP: RNA immunoprecipitation; H&E: hematoxylin and eosin; ncRNAs: noncoding RNAs; ceRNA: competitive endogenous RNA; DMEM: Dulbecco's modified Eagle's medium; PBS: phosphate buffered saline; OE-circ_0128846: overexpression vector for circ_0128846; pcDNA3.1-JAK2: pcDNA3.1 overexpression vector for Janus kinase 2; NC: negative control; CCK-8: Cell Counting Kit-8; PI: propidium iodide; WT: Wild-type; mutants (MUT); SD rats: Sprague Dawley rats; DMM: destabilization of medial meniscus; IHC: immunohistochemistry; DAB: diaminobenzene; pre-Mrna: precursor mRNA.

Rule-based natural language processing for automation of stroke data extraction: a validation study.

PURPOSE: Data extraction from radiology free-text reports is time consuming when performed manually. Recently, more automated extraction methods using natural language processing (NLP) are proposed. A previously developed rule-based NLP algorithm showed promise in its ability to extract stroke-related data from radiology reports. We aimed to externally validate the accuracy of CHARTextract, a rule-based NLP algorithm, to extract stroke-related data from free-text radiology reports. METHODS: Free-text reports of CT angiography (CTA) and perfusion (CTP) studies of consecutive patients with acute ischemic stroke admitted to a regional stroke center for endovascular thrombectomy were analyzed from January 2015 to 2021. Stroke-related variables were manually extracted as reference standard from clinical reports, including proximal and distal anterior circulation occlusion, posterior circulation occlusion, presence of ischemia or hemorrhage, Alberta stroke program early CT score (ASPECTS), and collateral status. These variables were simultaneously extracted using a rule-based NLP algorithm. The NLP algorithm's accuracy, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were assessed. RESULTS: The NLP algorithm's accuracy was > 90% for identifying distal anterior occlusion, posterior circulation occlusion, hemorrhage, and ASPECTS. Accuracy was 85%, 74%, and 79% for proximal anterior circulation occlusion, presence of ischemia, and collateral status respectively. The algorithm confirmed the absence of variables from radiology reports with an 87-100% accuracy. CONCLUSIONS: Rule-based NLP has a moderate to good performance for stroke-related data extraction from free-text imaging reports. The algorithm's accuracy was affected by inconsistent report styles and lexicon among reporting radiologists.

A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation.

Long noncoding RNAs (lncRNAs) participate in various biological processes such as apoptosis. The function of lncRNAs is closely correlated with their localization within the cell. While regulatory potential of many lncRNAs has been revealed at specific subcellular location, the biological significance of discrete distribution of an lncRNA in different cellular compartments remains largely unexplored. Here, we identified an lncRNA antisense to the pro-apoptotic gene PYCARD, named PYCARD-AS1, which exhibits a dual nuclear and cytoplasmic distribution and is required for the PYCARD silencing in breast cancer cells. The PYCARD-regulated apoptosis is controlled by PYCARD-AS1; moreover, PYCARD-AS1 regulates apoptosis in a PYCARD-dependent manner, indicating that PYCARD is a critical downstream target of PYCARD-AS1. Mechanistically, PYCARD-AS1 can localize to the PYCARD promoter, where it facilitates DNA methylation and H3K9me2 modification by recruiting the chromatin-suppressor proteins DNMT1 and G9a. Moreover, PYCARD-AS1 and PYCARD mRNA can interact with each other via their 5' overlapping region, leading to inhibition of ribosome assembly in the cytoplasm for PYCARD translation. This study reveals a mechanism whereby an lncRNA works at different cellular compartments to regulate the pro-apoptotic gene PYCARD at both the epigenetic and translational levels, contributing to the PYCARD-regulated apoptosis, and also sheds new light on the role of discretely distributed lncRNAs in diverse biological processes.

Dissecting Critical Factors for Electrochemical CO2 Reduction on Atomically Precise Au Nanoclusters.

This work investigates the critical factors impacting electrochemical CO2 reduction reaction (CO2 RR) using atomically precise Au nanoclusters (NCs) as electrocatalysts. First, the influence of size on CO2 RR is studied by precisely controlling NC size in the 1-2.5 nm regime. We find that the electrocatalytic CO partial current density increases for smaller NCs, but the CO Faradaic efficiency (FE) is not directly associated with the NC size. This indicates that the surface-to-volume ratio, i.e. the population of active sites, is the dominant factor for determining the catalytic activity, but the selectivity is not directly impacted by size. Second, we compare the CO2 RR performance of Au38 isomers (Au38 Q and Au38 T) to reveal that structural rearrangement of identical size NCs can lead to significant changes in both CO2 RR activity and selectivity. Au38 Q shows higher activity and selectivity towards CO than Au38 T, and density functional theory (DFT) calculations reveal that the average formation energy of the key *COOH intermediate on the proposed active sites is significantly lower on Au38 Q than Au38 T. These results demonstrate how the structural isomerism can impact stabilization of reaction intermediates as well as the overall CO2 RR performance of identical size Au NCs. Overall, this work provides important structure-property relationships for tailoring the NCs for CO2 RR.

Hydrogen Evolution Electrocatalyst Design: Turning Inert Gold into Active Catalyst by Atomically Precise Nanochemistry.

Electrocatalytic hydrogen evolution reaction (HER) holds promise in the renewable clean energy scheme. Crystalline Au and Ag are, however, poor in catalyzing HER, and the ligands on colloidal nanoparticles are generally another disadvantage. Herein, we report a thiolate (SR)-protected Au36Ag2(SR)18 nanocluster with low coverage of ligands and a core composed of three icosahedral (Ih) units for catalyzing HER efficiently. This trimeric structure, together with the monomeric Ih Au25(SR)18- and dimeric Ih Au38(SR)24, constitutes a unique series, providing an opportunity for revealing the correlation between the catalytic properties and the catalyst's structure. The Au36Ag2(SR)18 surprisingly exhibits high catalytic activity at lower overpotentials for HER due to its low ligand-to-metal ratio, low-coordinated Au atoms and unfilled superatomic orbitals. The current density of Au36Ag2(SR)18 at -0.3 V vs RHE is 3.8 and 5.1 times that of Au25(SR)18- and Au38(SR)24, respectively. Density functional theory (DFT) calculations reveal lower hydrogen binding energy and higher electron affinity of Au36Ag2(SR)18 for an energetically feasible HER pathway. Our findings provide a new strategy for constructing highly active catalysts from inert metals by pursuing atomically precise nanoclusters and controlling their geometrical and electronic structures.

CFTR function and clinical response to modulators parallel nasal epithelial organoid swelling.

In vitro biomarkers to assess cystic fibrosis transmembrane conductance regulator activity are desirable for precision modulator selection and as a tool for clinical trials. Here, we describe an organoid swelling assay derived from human nasal epithelia using commercially available reagents and equipment and an automated imaging process. Cells were collected in nasal brush biopsies, expanded in vitro, and cultured as spherical organoids or as monolayers. Organoids were used in a functional swelling assay with automated measurements and analysis, whereas monolayers were used for short-circuit current measurements to assess ion channel activity. Clinical data were collected from patients on modulators. Relationships between swelling data and short-circuit current, as well as between swelling data and clinical outcome measures, were assessed. The organoid assay measurements correlated with short-circuit current measurements for ion channel activity. The functional organoid assay distinguished individual responses as well as differences between groups. The organoid assay distinguished incremental drug responses to modulator monotherapy with ivacaftor and combination therapy with ivacaftor, tezacaftor, and elexacaftor. The swelling activity paralleled the clinical response. In conclusion, an in vitro biomarker derived from patients' cells can be used to predict responses to drugs and is likely to be useful as a preclinical tool to aid in the development of novel treatments and as a clinical trial outcome measure for a variety of applications, including gene therapy or editing.

COMRADES determines in vivo RNA structures and interactions.

The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs.

Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study.

BACKGROUND AIMS: Stem cell transplantation is a potential treatment for intractable spinal cord injury (SCI), and allogeneic human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate because of the advantages of immune privilege, paracrine effect, immunomodulatory function, convenient collection procedure and little ethical concern, and there is an urgent need to develop a safe and effective protocol regarding their clinical application. METHODS: A prospective, single-center, single-arm study in which subjects received four subarachnoid transplantations of hUC-MSCs (1 × 106 cells/kg) monthly and were seen in follow-up four times (1, 3, 6 and 12 months after final administration) was conducted. At each scheduled time point, safety and efficacy indicators were collected and analyzed accordingly. Adverse events (AEs) were used as a safety indicator. American Spinal Injury Association (ASIA) and SCI Functional Rating Scale of the International Association of Neurorestoratology (IANR-SCIFRS) total scores at the fourth follow-up were determined as primary efficacy outcomes, whereas these two indicators at the remaining time points as well as scores of pinprick, light touch, motor and sphincter, muscle spasticity and spasm, autonomic system, bladder and bowel functions, residual urine volume (RUV) and magnetic resonance imaging (MRI) were secondary efficacy outcomes. Subgroup analysis of primary efficacy indicators was also performed. RESULTS: Safety and efficacy assessments were performed on 102 and 41 subjects, respectively. Mild AEs involving fever (14.1%), headache (4.2%), transient increase in muscle tension (1.6%) and dizziness (1.3%) were observed following hUC-MSC transplantation and resolved thoroughly after conservative treatments. There was no serious AE. ASIA and IANR-SCIFRS total scores revealed statistical increases when compared with the baselines at different time points during the study, mainly reflected in the improvement of pinprick, light touch, motor and sphincter scores. Moreover, subjects showed a continuous and remarkable decrease in muscle spasticity. Regarding muscle spasm, autonomic system, bladder and bowel functions, RUV and MRI, data/imaging at final follow-up showed significant improvements compared with those at first collection. Subgroup analysis found that hUC-MSC transplantation improved neurological functions regardless of injury characteristics, including level, severity and chronicity. CONCLUSIONS: The authors' present protocol demonstrates that intrathecal administration of' allogeneic hUC-MSCs at a dose of 106 cells/kg once a month for 4 months is safe and effective and leads to significant improvement in neurological dysfunction and recovery of quality of life.