A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly.

Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation. Simultaneous expression of mutant proteins lacking these residues results in complete uncoupling from the cell cycle. Consequently, CENP-A assembly is fully recapitulated under high Cdk activities, indistinguishable from G1 assembly. We find that Cdk-mediated inhibition is exerted by sequestering active factors away from the centromere. Finally, we show that displacement of M18BP1 from the centromere is critical for the assembly mechanism of CENP-A.

Cluster-Level Heterostructure of PMo12/Cu for Efficient and Selective Electrocatalytic Hydrogenation of High-Concentration 5-Hydroxymethylfurfural.

Electrochemical hydrogenation of aldehyde molecules, exemplified by 5-hydroxymethylfurfural (HMF), offers a sustainable approach for synthesizing higher value-added alcohols. However, severe coupling side reactions impede its practical implementation at high concentrations. In this work, a cluster-level heterostructure of a PMo12/Cu catalyst is synthesized by loading Keggin-type phosphomolybdic acid (H3PMo12O40, PMo12) onto Cu nanowires. The catalyst exhibits high selectivity in electrocatalytic hydrogenation (ECH) of HMF to 2,5-bishydroxymethylfuran (BHMF) under an unprecedentedly high substrate concentration of 1.0 M. Under -0.3 V (vs RHE) with 1.0 M HMF, PMo12/Cu shows a Faradaic efficiency as high as 98% with an excellent productivity of 4.35 mmol cm-2 h-1 toward BHMF, much higher than those on the pristine Cu nanowires. Mechanism studies and density functional theory calculations demonstrate that the heterostructural interface of PMo12/Cu serves as an active reaction center for the ECH. The unique electronic properties and geometric structure promote the dissociative reduction of water molecules to generate H* and reduce HMF with a decreased reaction energy barrier, which is responsible for exceptional reactivity and selectivity.

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Lily LlHSFC2 coordinates with HSFAs to balance heat stress response and improve thermotolerance.

Heat stress transcription factors (HSFs) are core regulators of plant heat stress response. Much research has focused on class A and B HSFs, leaving those of class C relatively understudied. Here, we reported a lily (Lilium longiflorum) heat-inducible HSFC2 homology involved in thermotolerance. LlHSFC2 was located in the nucleus and cytoplasm and exhibited a repression ability by binding heat stress element. Overexpression of LlHSFC2 in Arabidopsis, tobacco (Nicotiana benthamiana), and lily, all increased the thermotolerance. Conversely, silencing of LlHSFC2 in lily reduced its thermotolerance. LlHSFC2 could interact with itself, or interact with LlHSFA1, LlHSFA2, LlHSFA3A, and LlHSFA3B of lily, AtHSFA1e and AtHSFA2 of Arabidopsis, and NbHSFA2 of tobacco. LlHSFC2 interacted with HSFAs to accelerate their transactivation ability and act as a transcriptional coactivator. Notably, compared with the separate LlHSFA3A overexpression, co-overexpression of LlHSFC2/LlHSFA3A further enhanced thermotolerance of transgenic plants. In addition, after suffering HS, the homologous interaction of LlHSFC2 was repressed, but its heterologous interaction with the heat-inducible HSFAs was promoted, enabling it to exert its co-activation effect for thermotolerance establishment and maintenance. Taken together, we identified that LlHSFC2 plays an active role in the general balance and maintenance of heat stress response by cooperating with HSFAs, and provided an important candidate for the enhanced thermotolerance breeding of crops and horticulture plants.

Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling.

Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR-driven cancers. We find that inhibiting the palmitoyltransferase DHHC20 creates a dependence on EGFR signaling for cancer cell survival. The loss of palmitoylation increases sustained EGFR signal activation and sensitizes cells to EGFR tyrosine kinase inhibition. Our work shows that the reversible modification of EGFR with palmitate "pins" the unstructured C-terminal tail to the plasma membrane, impeding EGFR activation. We identify by mass spectrometry palmitoylated cysteine residues within the C-terminal tail where mutation of the cysteine residues to alanine is sufficient to activate EGFR signaling promoting cell migration and transformation. Our results reveal that the targeting of a peripheral modulator of EGFR signaling, DHHC20, causes a loss of signal regulation and susceptibility to EGFR inhibitor-induced cell death.

Medical waste incineration fly ash-based magnesium potassium phosphate cement: Calcium-reinforced chlorine solidification/stabilization mechanism and optimized carbon reduction process strategy.

The traditional solidification/stabilization (S/S) technology, Ordinary Portland Cement (OPC), has been widely criticized due to its poor resistance to chloride and significant carbon emissions. Herein, a S/S strategy based on magnesium potassium phosphate cement (MKPC) was developed for the medical waste incineration fly ash (MFA) disposal, which harmonized the chlorine stabilization rate and potential carbon emissions. The in-situ XRD results indicated that the Cl- was efficiently immobilized in the MKPC system with coexisting Ca2+ by the formation of stable Ca5(PO4)3Cl through direct precipitation or intermediate transformation (the Cl- immobilization rate was up to 77.29%). Additionally, the MFA-based MKPC also demonstrated a compressive strength of up to 39.6 MPa, along with an immobilization rate exceeding 90% for heavy metals. Notably, despite the deterioration of the aforementioned S/S performances with increasing MFA incorporation, the potential carbon emissions associated with the entire S/S process were significantly reduced. According to the Life Cycle Assessment, the potential carbon emissions decreased to 8.35 × 102 kg CO2-eq when the MFA reached the blending equilibrium point (17.68 wt.%), while the Cl- immobilization rate still remained above 65%, achieving an acceptable equilibrium. This work proposes a low-carbon preparation strategy for MKPC that realizes chlorine stabilization, which is instructive for the design of S/S materials.

Investigating the network structure and causal relationships among bridge symptoms of comorbid depression and anxiety: A Bayesian network analysis.

BACKGROUND: The network analysis method emphasizes the interaction between individual symptoms to identify shared or bridging symptoms between depression and anxiety to understand comorbidity. However, the network analysis and community detection approach have limitations in identifying causal relationships among symptoms. This study aims to address this gap by applying Bayesian network (BN) analysis to investigate potential causal relationships. METHOD: Data were collected from a sample of newly enrolled college students. The network structure of depression and anxiety was estimated using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) Scale measures, respectively. Shared symptoms between depression and anxiety were identified through network analysis and clique percolation (CP) method. The causal relationships among symptoms were estimated using BN. RESULTS: The strongest bridge symptoms, as indicated by bridge strength, include sad mood (PHQ2), motor (PHQ8), suicide (PHQ9), restlessness (GAD5), and irritability (GAD6). These bridge symptoms formed a distinct community using the CP algorithm. Sad mood (PHQ2) played an activating role, influencing other symptoms. Meanwhile, restlessness (GAD5) played a mediating role with reciprocal influences on both anxiety and depression symptoms. Motor (PHQ8), suicide (PHQ9), and irritability (GAD6) assumed recipient positions. CONCLUSION: BN analysis presents a valuable approach for investigating the complex interplay between symptoms in the context of comorbid depression and anxiety. It identifies two activating symptoms (i.e., sadness and worry), which serve to underscore the fundamental differences between these two disorders. Additionally, psychomotor symptoms and suicidal ideations are recognized as recipient roles, being influenced by other symptoms within the network.

Biomechanical effects of clear aligners with different thicknesses and gingival-margin morphology for appliance design optimization.

INTRODUCTION: The objectives of this study were to investigate the biomechanical effects of clear aligners (CAs) with various thermoplastic material thicknesses and gingival-margin designs for space closure in extraction treatment and to propose a computer-aided procedure to optimize CA design. METHODS: The radiologic and intraoral scanning technology, in vitro mechanical experiment, viscoelastic modeling, and finite element analysis (FEA) were integrated to establish an orthodontic simulation model. Twelve FEA models of CA were created, comprising combinations of 2 kinds of thicknesses (0.75 and 0.50 mm), 2 forms of gingival-margin shape (scalloped and straight), and 3 types of margin height (-2, 0, and 2 mm). In vitro testing was carried out to determine the actual properties of material thickness. RESULTS: A 0.75-mm-thick aligner resulted in greater periodontal ligament (PDL) stress than 0.50 mm, and there was no clear correlation between the control ability of tooth movement and the thickness. For different margin designs, PDL stress at -2 mm height was significantly lower than those with a higher border. Aligners with straight margins had higher stress than the scalloped aligners, whereas the differences were unnoticeable at 2 mm height. The optimized aligner with differential margin designs was recommended on the basis of biomechanical calculations, which facilitated the efficiency and control of tooth movement for multiple teeth. CONCLUSIONS: The effect of material thickness and margin design of CA on the force and movement differed in different teeth. Preferable CA designs of each tooth during different movement stages should be presented personalized under the guidance of precise biomechanics instead of pure morphologic analysis.

Highly Efficient Biomass Upgrading by a Ni-Cu Electrocatalyst Featuring Passivation of Water Oxidation Activity.

Electricity-driven organo-oxidations have shown an increasing potential recently. However, oxygen evolution reaction (OER) is the primary competitive reaction, especially under high current densities, which leads to low Faradaic efficiency (FE) of the product and catalyst detachment from the electrode. Here, we report a bimetallic Ni-Cu electrocatalyst supported on Ni foam (Ni-Cu/NF) to passivate the OER process while the oxidation of 5-hydroxymethylfurfural (HMF) is significantly enhanced. A current density of 1000 mA cm-2 can be achieved at 1.50 V vs. reversible hydrogen electrode, and both FE and yield keep close to 100 % over a wide range of potentials. Both experimental results and theoretical calculations reveal that Cu doping impedes the OH* deprotonation to O* and hereby OER process is greatly passivated. Those instructive results provide a new approach to realizing highly efficient biomass upgrading by regulating the OER activity.

Photosynthesis of Benzonitriles on BiOBr Nanosheets Promoted by Vacancy Associates.

Photocatalytic organic functionalization reactions represent a green, cost-effective, and sustainable synthesis route for value-added chemicals. However, heterogeneous photocatalysis is inefficient in directly activating ammonia molecules for the production of high-value-added nitrogenous organic products when compared with oxygen activation in the formation of related oxygenated compounds. In this study, we report the heterogeneous photosynthesis of benzonitriles by the ammoxidation of benzyl alcohols (99 % conversion, 93 % selectivity) promoted using BiOBr nanosheets with surface vacancy associates. In contrast, the main reaction of catalysts with other types of vacancy sites is the oxidation of benzyl alcohol to benzaldehyde or benzoic acid. Experimental measurements and theoretical calculations have demonstrated a specificity of vacancy type with respect to product selectivity, which arises from the adsorption and activation of NH3 and O2 that is required to promote subsequent C-N coupling and oxidation to nitrile. This study provides a better understanding of the role of vacancies as catalytic sites in heterogeneous photocatalysis.

Engineering Lattice Disorder on a Photocatalyst: Photochromic BiOBr Nanosheets Enhance Activation of Aromatic C-H Bonds via Water Oxidation.

Solar-driven photocatalytic reactions can mildly activate hydrocarbon C-H bonds to produce value-added chemicals. However, the inefficient utilization of photogenerated carriers hinders the application. Here, we report reversible photochromic BiOBr (denoted as p-BiOBr) nanosheets that were colored by trapping photogenerated holes upon visible light irradiation and bleached by water oxidation to generate hydroxyl radicals, demonstrating enhanced carrier separation and water oxidation. The photocatalytic coupling and oxidation reactions of ethylbenzene were efficiently realized by p-BiOBr in a water-based medium under ambient temperature and pressure (apparent quantum yield is 14 times that of pristine BiOBr). The p-BiOBr nanosheets feature lattice disordered defects on the surface, providing rich uncoordinated catalytic sites and inducing structural distortions and lattice strain, which further leads to an altered band structure and significantly enhanced photocatalytic performances. These hole-trapping materials open up the possibility of substantially elevating the utilization efficiency of photogenerated holes for high-efficiency photocatalytic activation of various saturated C-H bonds.

Well-Defined Materials for Heterogeneous Catalysis: From Nanoparticles to Isolated Single-Atom Sites.

The use of well-defined materials in heterogeneous catalysis will open up numerous new opportunities for the development of advanced catalysts to address the global challenges in energy and the environment. This review surveys the roles of nanoparticles and isolated single atom sites in catalytic reactions. In the second section, the effects of size, shape, and metal-support interactions are discussed for nanostructured catalysts. Case studies are summarized to illustrate the dynamics of structure evolution of well-defined nanoparticles under certain reaction conditions. In the third section, we review the syntheses and catalytic applications of isolated single atomic sites anchored on different types of supports. In the final part, we conclude by highlighting the challenges and opportunities of well-defined materials for catalyst development and gaining a fundamental understanding of their active sites.

Health-related quality of life and associated factors in Chinese menstrual migraine patients: a cross-sectional study.

BACKGROUND: Menstrual migraine is a particular form of migraine with a significant impact on the quality of life for women afflicted. Presently, no study has reported the quality of life in menstrual migraine patients. This work aims to assess the health-related quality of life and identify its associated factors among Chinese menstrual migraine patients. METHODS: The cross-sectional study group consisted of 109 patients with menstrual migraine, and the control group consisted of 397 female patients with non-menstrual migraine. In total, 506 patients completed questionnaires for demographic and clinical information, the Self-rating Idea of Suicide Scale, the Hamilton Depression Scale, the Hamilton Anxiety Scale, the Headache Impact Test-6, the Perceived Social Support Scale, the Pittsburgh Sleep Quality Index. Health-related quality of life was measured using the 36-Item Short Form Survey. RESULTS: Compared with non-menstrual migraine patients, five dimensions of health-related quality of life were all found to be significantly impaired in menstrual migraine patients. Headache frequency (ß = - 0.218, P = 0.014), the impact of headache on daily life (ß = - 0.270, P = 0.002), depression symptoms (ß = - 0.345, P < 0.001) were significantly associated with physical component summary, depression symptoms (ß = - 0.379, P < 0.001), social support (ß = 0.270, P < 0.001), suicidal ideation (ß = - 0.344, P < 0.001) were closely related to mental component summary. CONCLUSION: Menstrual migraine patients had a significantly poorer health-related quality of life in many domains than non-menstrual migraine patients. Headache frequency, the impact of headache on daily life, depression symptoms, social support, and suicidal ideation were significantly associated with health-related quality of life in menstrual migraine patients. TRIAL REGISTRATION: ChiCTR1800014343. This study was registered prospectively on 7 January 2018 at Chinese Clinical Trial registry. http://www.chictr.org.cn/showproj.aspx?proj=24526.

Comparable outcomes among unmanipulated haploidentical, matched unrelated, and matched sibling donors in BU-based myeloablative hematopoietic stem cell transplantation for intermediate and adverse risk acute myeloid leukemia in complete remission: a single-center study.

There are a limited number of studies comparing outcomes of busulfan (BU)-based myeloablative hematopoietic stem cell transplantation using unmanipulated haploidentical donors (HIDs), HLA-matched unrelated donors (MUDs), and HLA-matched sibling related donors (MSDs) in acute myeloid leukemia (AML) patients with complete remission (CR) status. With this background, we compared outcomes among 377 cases of CR following consecutive HID-HSCT for AML (CR) to 86 MUD and 92 MSD-HSCT cases. All patients received BU-based myeloablative conditioning and an unmanipulated graft within the same period. The median patient age was 23 years (range 1.1 to 65 years), and 230 patients (41.4%) were under age18. Among the 555 patients, 432 (77.8%) were of intermediate cytogenetic risk and 123 (22.2%) were of adverse risk. A total of 113 patients (20.5%) had FLT3-ITD+ AML, 425 patients (76.6%) were in first complete remission (CR1) post-transplant, and 130 (23.4%) patients were in second CR (CR2). GVHD prophylaxis included mycophenolate mofetil (MMF), cyclosporine-A (CSA) with short-term methotrexate (MTX) for HID, and MUD-HSCT. MMF is not used for MSD-HSCT. The median survival follow-up time was 42 months (range 18-91 months). The 3-year leukemia-free survival (LFS) among the HID, MUD, and MSD cohorts was 73.8% ± 4.8%, 66.4% ± 8.5%, 74.5% ± 2.4%, respectively (P = 0.637). Three-year overall survival (OS) was 74.9% ± 2.4%, 81.8% ± 4.3%, and 77.5% ± 4.5% among the HID, MUD, and MSD cohorts, respectively (P = 0.322). There were no difference among the relapse rate among the HID, MUD, and MSD donor cohorts (14.3% ± 4.0% vs 20.3% ± 6.4% vs 14.5% ± 2.2, respectively; P = 0.851) or the non-relapse mortality (NRM) (12.3% ± 3.5% vs 9.5% ± 3.2% vs 14.0% ± 1.8%, respectively; P = 0.441). Multivariate analyses showed that MRD-positive pre-HSCT was the only risk factor associated with a lower OS and LFS and higher risk of relapse among all 555 patients. Compared with the use of a MUD or MSD, an HID for HSCT had similar outcomes among AML patients with CR states who underwent an allo-HSCT with BU-based myeloablative conditioning. MFC-MRD-positive pre-HSCT was an independent negative factor impact on outcomes for AML patients in CR. We conclude that for AML patients who do not have a MSD or if an urgent transplant is required, HSCT from an HID is a valid option.

Impact of the Surface and Microstructure on the Lubricative Properties of MoS2 Aging under Different Environments.

Molybdenum disulfide (MoS2) with a hydrophobic property and layered structure possesses an excellent lubricative property and has been widely used as a lubricant in various areas, including satellites, aircraft, and new energy vehicles. Aging is a ubiquitous phenomenon in MoS2 and plays a key role in its tribological application for shortening its service life. The effect of the surface and microstructure on the lubricative properties of MoS2 aging under different environments, including deionized water (DI water), ultraviolet/ozone (UV/Ozone), and high-temperature, was investigated. First, the lubrication of MoS2 transiently degrades because of physical adsorption and recovers after mechanical removal. The lubrication of MoS2 also degrades slightly when its surface becomes hydrophilic, thereby enhancing the adhesion energy due to atomic oxygen interaction under UV/Ozone exposure. Second, the lubrication of MoS2 degrades irreversibly because of the formation of stripes with the destroyed structures under accelerated aging. The lubrication of MoS2 further degrades with the formation of small triangular pits under high-temperature annealing. Finally, the lubrication of MoS2 deteriorates due to the destroyed structure and complete oxidation. The severe aging of MoS2 is accompanied with large triangular pits due to anisotropic oxidation etching of MoS2. The lubrication failure of MoS2 was determined on the basis of structural defect formation and surface property degradation induced by the extent of oxygen diffusion. The enhanced out-of-plane deformation due to the reduced out-of-plane stiffness and the increased energy barriers of defects are fundamentally responsible for the lubrication degradation of MoS2 at the atomic scale. These findings can provide new insights into the atomic-scale mechanism underlying the lubrication failure of MoS2 and pave the way for the realization of MoS2-based lubrication application under various environments.

A de novo nonsense mutation of STXBP1 causes early-onset epileptic encephalopathy.

Mutations in syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to multiple neurodevelopmental disorders, including severe early-onset epileptic encephalopathies (EOEEs). A de novo nonsense mutation of STXBP1 (c. 863G > A, p. W288X) was found in a patient diagnosed with EOEE at the age of 17 days. The electroencephalogram (EEG) showed sharp waves and spikes, while brain magnetic resonance imaging was normal. We generated a zebrafish EOEE model by overexpressing mutant STXBP1(W288X) and studied the behavioral changes further to understand the mechanism of W288X mutation in epileptogenesis. In addition, effective antiepileptic drugs were screened in the zebrafish model. Zebrafish STXBP1 homologs were highly conserved and prominently expressed in the larval zebrafish brain. The Tg(hSTXBP1W288X) zebrafish larvae exhibited hyperactivity compared with the wild-type (WT) controls. The expression of STXBP1 decreased during the development course from 1 to 5 days post fertilization. Spontaneous seizures and increased c-fos expression were observed in the mutant zebrafish larvae. The susceptibility of Tg(hSTXBP1W288X) zebrafish to pentylenetetrazol challenge also dramatically increased. Levetiracetam, clonazepam, and topiramate showed antiepileptic effects in the Tg(hSTXBP1W288X) larvae to different extents. Our findings in the newly generated mutant line of zebrafish suggested that zebrafish recapitulated clinical phenotypes associated with human STXBP1 mutation, which provided an appropriate in vivo model for epilepsy research.

Management of Sonographically Suspicious Thyroid Nodules 1 cm or Smaller and Candidacy for Active Surveillance: Experience of a Tertiary Center in China.

OBJECTIVE: Our objective was to investigate the management of patients with asymptomatic suspicious thyroid nodules ≤1 cm. METHODS: We retrospectively reviewed medical records of patients with sonographically suspicious thyroid nodules ≤1 cm and without distant metastases, suspicious lymph node metastasis (LNM), or extrathyroidal extension (ETE). RESULTS: Of the 386 enrolled patients, 174 (45.1%) had immediate surgery (IS), while 212 (54.9%) underwent active surveillance (AS). In the IS group, 166 (95.4%) patients were confirmed as having papillary thyroid microcarcinoma. LNM and ETE were observed in 24.7% and 2.4% cases, respectively. In the AS group, nodule size increased by ≥3 mm in 11 (5.2%) patients and 39 (18.4%) had a >50% increase in nodule volume after a median follow-up of 12 months. Nodules with smaller volume at diagnosis were more likely to increase in volume later. Newly suspicious LNM was detected in 23 (10.8%) patients. Delayed surgery (DS) was performed in 101 patients, with 27 showing disease progression. ETE and LNM were detected in 3% and 36%, respectively, of patients with papillary thyroid microcarcinoma. Compared with IS, tumors in the DS group more frequently showed lateral LNM and capsular invasion (P < .05). No patient had recurrence or died of thyroid cancer during postoperative follow-up (median 26 [4-60] months). CONCLUSIONS: IS or DS of patients with asymptomatic suspicious thyroid nodules ≤1 cm was relatively high in China. The inertia of low-risk nodules and the effectiveness of DS for those that progressed make AS a feasible strategy.

Diazepam Monotherapy or Diazepam-Ketamine Dual Therapy at Different Time Points Terminates Seizures and Reduces Mortality in a Status Epilepticus Animal Model.

BACKGROUND Being refractory to drugs remains an urgent treatment problem in status epilepticus (SE). The fact that γ-aminobutyric acid A receptors (GABAARs) become internalized and inactive, N-methyl-D-aspartate receptors (NMDARs) become externalized and active during SE may explain the refractoriness to benzodiazepine. However, the real-time dynamic efficacy of antiepileptic drugs remains unclear. Therefore, we propose a hypothesis that diazepam monotherapy or diazepam-ketamine dual therapy could terminate seizures and reduce mortality in the SE model at different time points during ongoing SE. MATERIAL AND METHODS An SE model was established in adult Sprague-Dawley rats with lithium and pilocarpine. The GABAAR agonist diazepam was injected at 5, 10, 20, or 30 min when SE continued. In addition, diazepam and the NMDAR antagonist ketamine were injected at 10 to 60 min at 6 different time points. We measured seizure-free rates, seizure duration, degree of behavioral seizure, and mortality. RESULTS Diazepam monotherapy at 5 min and 10 min from the beginning of SE was able to terminate seizures and improved survival rates. Diazepam-ketamine dual therapy at 10 min, 20 min, and 30 min from the beginning of SE terminated seizures and achieved high survival rates. CONCLUSIONS In this parallel randomized controlled trial with a rat model, we found that diazepam monotherapy was an effective antiepileptic strategy at the early stage of SE less than 10 min after SE onset. If SE lasts more than 10 min but less than 30 min, the diazepam-ketamine dual therapy strategy may be an appropriate choice.

Percardiac closure of large apical ventricular septal defects in infants: Novel modifications and mid-term results.

BACKGROUND/AIM: Both open heart surgery and percutaneous approaches retain several limitations in closing large apical muscular ventricular septal defects (AmVSD) in infants. We present probe-assisted percardiac device closure (PDC), an exclusively transoesophageal-echocardiography guided technique, as an alternative with midterm results. METHODS: Thirty-six infants with large AmVSDs (single or multiple-holed) underwent PDC in our department. Mean AmVSD for single and multiple-holed measured 7.2 ± 2.4 mm and 6.3 ± 3.4 mm, respectively. Subjects presented with a spectrum of cardiopulmonary sequelae and growth retardation, either alone or combined. Some were ventilator dependent and re-do cases. In addition, AmVSDs were categorized: cylindrical, tunnel and cave-like shaped as per color Doppler interrogation. Pursuant to cardiac access and deployment technique, subjects were apportioned: group A; inferior median sternotomy (perventricular), B; right mini-thoracotomy (peratrial) and C; complete median sternotomy (perventricular). Under exclusive echocardiography, the Z- or J probe-assisted delivery system was utilized to access AmVSDs and implant device(s) via aforementioned techniques. RESULTS: Forty-two muscular ventricular septal devices (8.4 ± 2.6 mm) were implanted in 36 subjects uneventfully. Seventeen "complex," and 10 cylindrical or straight tunnel-shapedAmVSDs (including 2 re-do patients) suited perventricular and peratrial techniques respectively. Comparatively, group B exhibited shorter procedural indices than A (p < .01). Five of 15 multiple-holed AmVSDs (four Swiss cheese) required two or three devices for a satisfactory occlusion. Nevertheless, post occlusion insignificant residual shunts( ≤ 2 mm) seldom achieved spontaneous closure, and at 36-month follow-up complete closure was 67%. Residual shunt persisted amongst multiple-holed. All patients improved during follow up. CONCLUSION: PDC is feasible, safe and effective alternative technique for AmVSD in infants.

Atomic site electrocatalysts for water splitting, oxygen reduction and selective oxidation.

Electrocatalysis plays a central role in clean energy conversion, enabling a number of processes for future sustainable technologies. Atomic site electrocatalysts (ASCs), including single-atomic site catalysts (SASCs) and diatomic site catalysis (DASCs), are being pursued as economical alternatives to noble-metal-based catalysts for these reactions by virtue of their exceptionally high atom utilization efficiencies, well-defined active sites and high selectivities. In this review, we start from a systematic review on the fabrication routes of ASCs followed by an overview of some new and effective characterization methods to precisely probe the atomic structure. Then we give a comprehensive summary on the current advances in some typical clean energy reactions: water splitting, including hydrogen evolution reaction (HER) and oxygen evolution reaction (OER); oxygen reduction reaction (ORR), including selective 4e- - ORR toward H2O/OH- and 2e- - ORR toward H2O2/HO2-; selective electrooxidation of formic acid, methanol and ethanol (FAOR, MOR and EOR). At the end of this paper, we present a brief conclusion, and discuss the challenges and opportunities on the further development of more selective, active, stable and less expensive ASCs.