Initial Activity Research Articles

Monitoring the electrophysiological effects of hydroquinidine non-invasively in patients with Brugada syndrome

Abstract Background Quinidine and it’s derivative hydroquinidine are the only drugs shown to reduce arrhythmic events in patients with Brugada syndrome (BrS). There is currently no standardised approach to monitoring the effect of pharmacotherapy in BrS to guide dosing and evaluate an individual’s response to therapy. Purpose To investigate if the electrophysiological effects of Hydroquinidine can be detected on non-invasive testing and identify parameters that may be used to study a non-invasive strategy for monitoring pharmacotherapy in BrS. Methods Patients with a diagnosis of BrS underwent multimodality non-invasive assessment with electrocardiogram (ECG), signal averaged ECG, 24 hour 12-lead Holter monitor and electrocardiographic imaging (ECGi – a method of non-invasive electroanatomical mapping), at baseline and "on treatment" with hydroquinidine (300mg BD) therapy. A medication survey was used to recorded adverse drug reactions and serum hydroquinidine levels were determined using liquid chromatography mass spectrometry. Results Twelve patients with BrS (11 male, mean age 47.6±10.9 years) with spontaneous type 1 BrS pattern or drug inducible type 1 BrS pattern and resuscitated cardiac arrest participated in the study. The mean Shanghai score was 4.6±1.4 and two patients had disease-causing SCN5A variants. During hydroquinidine therapy, there was a significant increase in QRS duration (110.7msec vs 117.8msec, p=0.004) and in mean activation time in the area of late activation in the right ventricular outflow tract (RVOT, 90.9ms to 97.7ms, p=0.020). In nine (75%) patients, the area of late activation (defined as >80ms after initial activation) in the RVOT also increased with hydroquinidine. Repolarisation parameters were also affected by hydroquinidine with an increase in QT interval corrected for heart rate (369.5msec vs 434.8msec, p<0.0001) and T-wave width (232.8msec to 271.2msec p=0.003) and a significant reduction in T-wave amplitude (0.4mV to 0.2mV p=0.001) on treatment. The reduction in T-wave amplitude precluded computation of repolarisation time in the RVOT by ECGi on treatment. No difference in the burden of type 1 BrS ECG pattern over 24 hours was seen on 12-lead Holter monitor between baseline and on treatment assessment. No significant difference in serum hydroquinidine level was detected between those who experienced side effects and those who did not (2.9µmol vs 3.1µmol, p=0.790). Conclusion Hydroquinidine affects both ventricular activation and repolarisation in patients with BrS and these effects can be detected non-invasively. Further work is required to determine clinical significance of these observed effects and investigate the feasibility of non-invasive monitoring strategy of pharmacotherapy in BrS.ECGi activation maps

Carbonic anhydrase-magnetite nanocomposites with an RF field controlled enzymatic activity

A magnetic enzymatic composite was synthesized from non-toxic magnetite nanoparticles modified by biomimetic polymerization of modified dopamine and carbonic anhydrase enzyme, which has a significant role in neurodegenerative processes. The mass fraction of the enzyme in the composite was 10% wt, which corresponded to about 120 enzyme molecules per nanoparticle. The composite showed Km about 10 folds higher compared to free enzyme (0.22 and 0.019 mmol/L respectively) and Vmax four times lower (0.17 and 0.69 mmol/min). The enzymatic composite had 17% higher thermal stability compared to free enzyme and retained 95% of its initial activity after seven consecutive reuse cycles. In a colloidal state, the composite showed no response to the RF field due to the ballistic mechanism of heat dissipation but in concentrated form, the material showed up to 155% enhanced catalytic activity under the influence of heating radio frequency magnetic fields. The observed results are discussed and explained.

Patients cancelled after initial activation for suspected STEMI via the ODiSEA APP, what happens to them?

Abstract Introduction The use of technological innovation in STEMI care networks has been shown to be effective in sharing diagnostic ECG tracing and clinical information with the cardiology department, reducing the number of inappropriate cases transferred to the cathlab. These inappropriate cases have been shown to be more likely to die than those undergoing urgent coronary angiography, but data on incidence, cause of cancellation and prognosis are limited1. Objective Our aim was to investigate the characteristics and prognosis of patients in whom transfer to the cathlab was cancelled, compared with those who underwent emergent coronary angiography (EC). Material and Methods Prospective study analysing all STEMI alert activations during the year 2022. Information on ECG pattern and clinical history was transmitted using an APP (ODiSEA2,3). Based on the ECG pattern and clinical history, cancellations were made. Patient characteristics, myocardial infarction, ECG activation pattern, angiography results and in-hospital mortality were studied. Results A total of 406 infarction codes were activated through the ODISEA APP, of which 284 (70%) underwent EC and 122 (30%) were cancelled. The cancelled patients had a higher comorbidity than the transferred patients. The reasons for cancellation based on ECG patterns are shown in Figure 1. The most common were ST depression (23%), concave ST elevation (18.8%) and intraventricular conduction disturbances (22.9%). In addition, coronary angiography was performed in 33% of the cancelled patients compared to 99% of the transferred patients (p<0.001). The number of patients with coronary arteries without lesions was significantly higher in the cancelled group (31.7% vs. 9.6% p<0.001). In the EC group, 90.5% of patients presented with a final diagnosis of ACS, whereas in the cancelled group this was 32.8% (final diagnosis of STEMI 2.5% in the cancelled group vs. 83.5% in the CE group, p<0.001). Discharge from the emergency department was 46% in the cancellation group versus 2.7% in the transfer group (p<0.001). Finally, the in-hospital mortality rate was significantly higher in the cancelled group: 14 patients (11.4%) vs. 12 patients (4.2%) in the transferred group (p<0.001). Discussion Compared to patients who are transferred to a centre with cathlab, the subgroup of patients initially activated as STEMI alerts and eventually cancelled have a high comorbidity, a low probability of a final diagnosis of ACS and a high in-hospital.Table 1.Patients characteristicsFigure 1.ECG pattern

DNA flexible chain modified MOFs as a versatile platform for chemoenzymatic cascade reactions in glucose catalysis

Glucose oxidase (GOD) is widely used in the pharmaceutical industry, fermentation products and glucose biosensors for its essential role in catalyzing the conversion of glucose to gluconic acid and hydrogen peroxide (H2O2). As H2O2 is the by-product and will have a toxic effect on glucose oxidase, so introducing another enzyme that could consume H2O2 to form an enzymatic cascade reaction is a practical solution. However, this decision will lead to extra expenses and complex condition optimization such as the specific mass ratio, temperature and pH to improve the activity, stability and recyclability. Herein, we describe a mild and versatile strategy by anchoring GOD on carboxyl-activated MOF (Cu-TCPP(Fe)) through DNA-directed immobilization (DDI) technology. Robust MOF nanosheets were utilized as not only the carrier for the immobilization of GOD, but also a peroxidase-like catalyst for the decomposition of H2O2 to reduce its harmful impacts. In this work, the immobilized GOD retained 55.78% of its initial activity after being used for 7 times. More than 60% of the immobilized enzyme's catalytic activity was still maintained after 96 h of being stored at 50 ℃. This study provides a new idea for preparing immobilized enzymes with enhanced stability, fast diffusion and high activity, which can be used in fields such as biocatalysis and biotechnology.

Antimicrobial Activity of Manganese(I) Tricarbonyl Complexes Bearing 1,2,3-Triazole Ligands.

Antimicrobial resistance is one of the most pressing health issues of our time. The increase in the number of antibiotic-resistant bacteria allied to the lack of new antibiotics has contributed to the current crisis. It has been predicted that if this situation is not dealt with, we will be facing 10 million deaths due to multidrug resistant infections per year by 2050, surpassing cancer-related deaths. This alarming scenario has refocused attention into researching alternative drugs to treat multidrug-resistant infections. In this study, the antimicrobial activities of four manganese complexes containing 1,2,3,-triazole and clotrimazole ligands have been evaluated. It is known that azole antibiotics coordinated to manganese tricarbonyl complexes display interesting antimicrobial activities against several microbes. In this work, the effect of the introduction of 1,2,3,-triazole-derived ligands in the [Mn(CO)3(clotrimazole)] fragment has been investigated against one Gram-positive bacterium and five Gram-negative bacteria. The initial antimicrobial activity of the above-mentioned complexes was assessed by determining the minimum inhibitory and bactericidal concentrations using the broth microdilution method. Growth curves in the presence and absence of the complexes were performed to determine the effects of these complexes on the growth of the selected bacteria. A possible impact on cellular viability was determined by conducting the MTS assay on human monocytes. Three of the Mn complexes investigated (4-6) had good antimicrobial activities against all the bacteria tested, with values ranging from 1.79 to 61.95 µM with minimal toxicity. Due to the increased problem of antibiotic resistance and a lack of new antibacterial drugs with no toxicity, these results are exciting and show that these types of complexes can be an avenue to pursue in the future.

A Recombinant Alginate Lyase Algt1 with Potential in Preparing Alginate Oligosaccharides at High-Concentration Substrate.

Alginate lyase has been demonstrated as an efficient tool in the preparation of functional oligosaccharides (AOS) from alginate. The high viscosity resulting from the high concentration of alginate poses a limiting factor affecting enzymatic hydrolysis, particularly in the preparation of the fragments with low degrees of polymerization (DP). Herein, a PL7 family alginate lyase Algt from Microbulbifer thermotolerans DSM 19189 was developed and expressed in Pichia pastoris. The recombinant alginate lyase Algt1 was constructed by adopting the structural domain truncation strategy, and the enzymatic activity towards the alginate was improved from 53.9 U/mg to 212.86 U/mg compared to Algt. Algt1 was stable when incubated at 40 °C for 90 min, remaining with approximately 80.9% of initial activity. The analyses of thin-layer chromatography (TLC), fast protein liquid chromatography (FPLC), and electrospray ionization mass spectrometry (ESI-MS) demonstrated that the DP of the minimum identifiable substrate of Algt1 was five, and the main hydrolysis products were AOS with DP 1-4. Additionally, 1-L the enzymatic hydrolysis system demonstrated that Algt1 exhibited an effective degradation at alginate concentrations of up to 20%, with the resulting products of monosaccharides (14.02%), disaccharides (21.10%), trisaccharides (37.08%), and tetrasaccharides (27.80%). These superior properties of Algt1 make it possible to efficiently generate functional AOS with low DP in industrial processing.

Insights into the influence of feed impurities on catalytic performance in the solvent-free dimerization of renewable levulinic acid

Bio-jet fuel precursors can be produced from the solvent-free aldol dimerization of levulinic acid. The influence of the most common impurities accompanying the levulinic acid produced in lignocellulosic biorefineries (sulfuric acid, water, formic acid, and furfural) has been studied on the catalytic performance of different kinds of heterogeneous acid catalysts: (i) sulfonic acid-based materials, such as propyl-sulfonic acid-modified SBA-15, and the sulfonic acid resin Amberlyst-70, and (ii) commercial acid zeolites, such as H-Beta-19 and H-Beta-75. Furfural is the impurity that produces the greatest detrimental effect on the performances of all the catalysts tested. Catalyst deactivation is observed due to the formation of organic deposits on the catalyst surface (identified by TGA and acid-base titration), phenomenon that is accentuated when furfural is present in the reaction medium. Amberlyst-70 can recover almost totally the initial catalytic activity with a regeneration step based on washing with an acid solution under reflux. For Beta zeolites, the original activity of the catalyst can be easily and totally recovered through a regeneration process by calcination. H-Beta-19 zeolite is shown as the most suitable catalyst for the aldol dimerization of renewable LA, as its activity is not significantly affected by the presence of most of the impurities in the levels herein analyzed. In addition, a simultaneous mixture of all the impurities produces a synergistic effect, even improving the initial activity of the H-Beta-19 zeolite as a consequence of the sulfuric acid contribution to the catalytic effect.

S-scheme heterojunction constructed by ZnCdS and CoWO4 nano-ions promotes photocatalytic hydrogen production

Low-cost and efficient photocatalyst is an important aspect of photocatalytic hydrogen production. In this study, a highly efficient and stable composite photocatalyst was synthesized by assembling ZnCdS nanoparticles and CoWO4 nanoparticles. Under the 5 W LED lamp, the hydrogen production of the composite catalyst ZCS/CW-10 is as high as 839.85 μmol in five hours, which is 5.2 times that of the pure ZnCdS photocatalyst, respectively. After four cycles, the hydrogen production still reaches 640.37 μmol, which is 76.3% of the initial activity. This is because the introduction of CoWO4 increases the absorption of visible light by ZnCdS, and effective interface contact with each other between nanoparticles can effectively accelerate the transfer of photo generated charges between semiconductors, increase the active sites of surface hydrogen production, and achieve efficient H2 production. The staggered band structure makes ZnCdS and CoWO4 follow the electron flow scheme of S-scheme heterojunction, which is proved by in-situ XPS. The S-scheme heterostructure of ZCS/CW retains high redox potential and prolongate the lifetime of electron-generated carriers, making it more conducive to proton reduction to produce H2. This work provides a novel and convenient way to construct an efficient S-scheme heterojunction scheme, which is helpful for the rapid and effective production of metal sulfide-based photocatalysts and the rapid construction of photocatalytic water splitting hydrogen production systems. It has important research value in the utilization of new energy hydrogen energy and environmental protection.

Mezigdomide Reverses T-Cell Exhaustion through Degradation of Aiolos/Ikaros and Reinvigoration of Cytokine Production Pathways

Introduction: T cell exhaustion (Tex) is characterized by progressive decline in activation and proliferation and has been implicated as a major resistance mechanism of T cell immunotherapies such as BCMA directed bispecifics approved for the treatment of multiple myeloma (MM). Understanding and overcoming Tex is key for relapsed patient populations facing drug resistance. Here, by using the next generation cereblon E3 ligase modulator (CELMoD) Mezigdomide (Mezi), a specific and potent Aiolos/Ikaros degrader to date, we revealed for the first time through comprehensive genomic/epigenomic and functional analyses that Aiolos/Ikaros are two major transcription factors that contribute to the regulation of the Tex phenotype and their degradation reverses the negative impact on activation, proliferation and tumor cell killing. Methods: Tex were generated ex vivo from normal donors through multiple rounds of anti-CD3/CD28 dynabead stimulations over the course of 14 days. Unstimulated (Tn) or transiently stimulated T cells (Tact) from the same donors were used for differential comparisons. Comprehensive genomic analyses were conducted to compare the three groups of T cells using RNAseq, ATACseq, whole genome bisulfite sequencing and ChIPseq for Aiolos/Ikaros and histone modifications (H3K27ac, H3K27me3, H3K4me3 H3K4me1), with and without Mezi treatment for 72 hrs. Cytokine/chemokines were measured by Luminex multiplex cytokine assays. Exhaustion markers were determined by flow cytometry. Mezi effects on Tex mediating tumor cell killing in combination with anti-CD3/BCMA bispecific antibody Alnuctamab (Alnuc) was also assessed via both incucyte and flow cytometry. Results: After multiple rounds of stimulation, the viability of Tex remained over 90%, with proliferation decreased from 3-6-fold in initial stimulation to 1-1.4-fold in the last stimulation, as well as 98% reduction in IL-2 secretion. RNAseq analysis showed more proinflammatory cytokine expression from Tex was significantly down-regulated compared to Tact, such IL-1/6/9/17/21/23 and TNF. Exhaustion markers CTLA4, PD1, TIM3, LAG3, TOX, PDL1, and ENTPD1 (CD39) were analyzed via flow cytometry and confirmed by RNAseq to be significantly increased in expression after initial activation, then maintained and/or increased further with subsequent re-stimulations. Treatment of Mezi significantly down regulated PD1, TIM3, TIGIT, and up-regulated proinflammatory cytokines/chemokines such as IL-1/23/3/6/7, CCL1/2/17/20, CXCL1/3/11/12 and TNF, as well as cell surface interaction related integrins, RAS signaling and proliferation related pathways, as revealed by both Luminex multiplex cytokine analysis and RNAseq (Fig.A). Using ATAC-seq, we found that the peaks gained or lost in Tex at promoters and distal sites were significantly correlated with gene expression changes from the RNAseq analysis, with the strongest effect seen at promoters. We identified that canonical RUNX1/2/3 binding motifs were significantly enriched in the gained peaks in Tex compared to Tact, with RUNX2/3 themselves also showing increased mRNA expression. After treatment of Mezi, Tex gained peaks were enriched with NFATC2 and RUNX3 binding sites whose gene expression levels were also increased (Fig. B). Enrichment analysis of the cis-regulated genes of the gained peaks in Tex after treatment highlights biological processes related to cell-cell adhesion, cytokine production and other T cell activation processes. Notably, TF analysis also showed that, after treatment, Ikaros motifs were enriched in the Tex gained peaks. Flow cytometry analysis revealed that Tex cells have the highest expression of Ikaros, especially in PD1 + TIM3 + CD4 subsets. To investigate the effect of Aiolos/Ikaros in Tex functionally, we set up co-culture assays using Tex cells with BCMA expressing tumor cells in the presence of Alnuc. We found that Mezi treatment to Tex significantly enhanced killing of tumor cells and reduced the EC 50 of Alnuc. 5-10 fold compared to DMSO controls. Conclusion: We demonstrated here that Aiolos/Ikaros regulate and maintain T cell exhaustion. Mezi mediated degradation of both transcription factors at the same time resulted in enhanced proinflammatory cytokine expression and reduction of exhaustion associated markers, as well as enhanced Tex killing of BCMA expressing tumor cells in combination with Alnuctamab.

A ten-year retrospective California Poison Control System experience with possible amatoxin mushroom calls

Introduction Mushrooms containing amatoxin are found worldwide and represent a challenging poisoning for the clinician and consulting poison center. This study evaluates the experience of a large poison system with possible amatoxin-containing mushroom ingestion calls. Methods A 10-year retrospective review of the California Poison Control System database was performed for amatoxin mushroom ingestion calls resulting in hospitalization. Cases found were abstracted and data statistically analyzed for association with a composite endpoint of death, liver transplant, and/or the need for dialysis. Results Amatoxin-containing mushroom calls are infrequent with the vast majority (98.4 percent) coming from Northern California during the rainier first and fourth quarters (October through March) of the year. Elevated initial aminotransferase activities and international normalized ratios were predictive of the composite negative outcome. The mortality plus liver transplant and hemodialysis composite rate was 8.2 percent, consistent with current literature. Conclusion The California Poison Control System has relatively few amatoxin-containing mushroom ingestion calls that result in hospitalization but those that are reported mostly occur in Northern California. Treatment bias towards the sickest patients may explain the association of intravenous fluid use or treatment with acetylcysteine or silibinin with meeting the composite outcome. The initial presence of elevated hepatic aminotransferase activity and international normalized ratios are poor prognostic indicators and are likely reflective of late presentation, an advanced toxic phase of amatoxin poisoning, and/or delays in time to obtain poison center consultation.

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Use of differential stimulation of the nucleus accumbens and anterior limb of the internal capsule to improve outcomes of obsessive-compulsive disorder.

Personalized stimulation is key to optimizing the outcomes of deep brain stimulation (DBS) for refractory obsessive-compulsive disorder (OCD). However, the contacts in a single conventional electrode cannot be programmed independently, which may affect the therapeutic efficacy of DBS for OCD. Therefore, a novel designed electrode and implantable pulse generator (IPG) that could achieve differential stimulation parameters for different contacts was implanted into the nucleus accumbens (NAc) and anterior limb of the internal capsule (ALIC) of a cohort of patients with OCD. Thirteen consecutive patients underwent bilateral DBS of the NAc-ALIC between January 2016 and May 2021. Differential stimulation of the NAc-ALIC was applied at initial activation. Primary effectiveness was assessed on the basis of change in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) from baseline to 6-month follow-up. Full-response was defined as a 35% decrease in Y-BOCS score. Secondary effectiveness measures were the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD). The local field potential of bilateral NAc-ALIC was recorded in 4 patients who were reimplanted with a sensing IPG after battery depletion of the previous IPG. The Y-BOCS, HAMA, and HAMD scores decreased remarkably during the first 6 months of DBS. Ten of 13 patients were categorized as responders (76.9%). Differential stimulation of the NAc-ALIC was favorable to optimization of the stimulation parameters by increasing the parameter configurations. Power spectral density analysis revealed pronounced delta-alpha frequency activity in the NAc-ALIC. Phase-amplitude coupling of the NAc-ALIC showed that strong coupling is present between the phase of delta-theta and broadband gamma amplitude. These preliminary findings indicate that differential stimulation of the NAc-ALIC can improve the efficacy of DBS for OCD. Clinical trial registration no.: NCT02398318 (ClinicalTrials.gov).

An analysis of placental chorionic villous and decidual basalis tissue immunoreactivity in patients after cesarean section due to a placenta accreta spectrum disorder and elective cesarean section followed by the depressed mood.

Over the past few years, interest in investigating immune dysfunction in patients with psychiatric disorders has increased. B7-H4 is a molecule with immunosuppressive properties that seems to play a key role in establishing maternal tolerance against fetal antigens. The aim of this study was to compare the B7-H4 immunoreactivity levels in patients after cesarean section. Placental and decidual tissue samples were obtained from 49 women who delivered at Bielański Hospital in Warsaw between 2009 and 2015. Fifteen of the patients developed postpartum depression and 14 had a diagnosis of placenta accreta spectrum. The control group consisted of 20 healthy patients on whom cesarean section was performed due to breech presentation at term. The highest levels of B7-H4 immunoreactivity were found in the placental chorionic villous and decidual basalis tissue samples of the patients who later developed postpartum depression, while the lowest levels were found in the samples of those patients with a placenta accreta spectrum disorder. The difference between the B7-H4 immunoreactivity levels of these two groups was statistically significant. The B7-H4 expression levels were statistically significantly higher in the women in the postpartum depression group than in the control group. Postpartum depression follows a disturbance of the suppressive milieu responsible for rebalancing the maternal immune system after the initial cytotoxic activation during labor.

Cellulase immobilization on zeolitic imidazolate frameworks for boosting cellulose hydrolysis at high solids loading

This study investigates the cellulase immobilization onto zeolitic imidazolate frameworks (ZIFs) to enable efficient cellulose hydrolysis at high solids loading. Different ZIF carriers (ZIF-8, ZIF-8-NH2, Fe3O4@ZIF-8, and Fe3O4@ZIF-8-NH2) were prepared and characterized. The resulting ZIF-immobilized cellulases were subsequently analyzed for their loading capacity and enzyme activity, as well as their biochemical properties such as temperature stability, pH stability, storage stability, enzyme leaching, and enzyme kinetics. Results revealed that the cellulase immobilized on Fe3O4@ZIF-8-NH2 exhibited an exceptional loading capacity of 359.89 mg/g and a relative enzyme activity of 69.39%. Remarkably, at a solid loading of 15% (w/w) and an enzyme dosage of 5 FPU/g cellulose, the Fe3O4@ZIF-8-NH2 immobilized cellulase demonstrated a 20.44% higher hydrolysis yield compared to the free cellulase. Furthermore, this immobilized enzyme system displayed robust reusability, retaining 71.03% of its initial activity even after 10 cycles of reuse. A proposed mechanism of enhanced enzymatic hydrolysis by ZIF-immobilized cellulases was also presented. These findings have significant implications for the future application of ZIF-immobilized cellulases in efficient and cost-effective lignocellulosic bioconversion.

On the clinical utility of on-scalp MEG: A modeling study of epileptic activity source estimation

ObjectiveEpilepsy surgery requires localization of the seizure onset zone (SOZ). Today this can only be achieved by intracranial electroencephalography (iEEG). The iEEG electrode placement is guided by findings from non-invasive modalities that cannot themselves detect SOZ-generated initial seizure activity. On scalp magnetoencephalography (osMEG), with sensors placed on the scalp, demonstrates higher sensitivity than conventional MEG (convMEG) and could potentially detect early seizure activity. Here, we modeled EEG, convMEG and osMEG to compare the modalities’ ability to localize SOZ activity and to detect epileptic spikes. MethodsWe modeled seizure propagation within ten epileptic networks located in the mesial and lateral temporal lobe; basal, dorsal, central and frontopolar frontal lobe; parietal and occipital lobe as well as insula and cingulum. The networks included brain regions often involved in focal epilepsy. 128-channel osMEG, convMEG, EEG and combined osMEG + EEG and convMEG + EEG were modeled, and the SOZ source estimation accuracy was quantified and compared using Student’s t-test. ResultsOsMEG was significantly (p-value <0.01) better than both convMEG and EEG at detecting the earliest SOZ-generated seizure activity and epileptic spikes, and better at localizing seizure activity from all epileptic networks (p < 0.01). ConclusionsOur modeling results clearly show that osMEG has an unsurpassed potential to detect both epileptic spikes and seizure activity from all simulated anatomical sites. SignificanceNo clinically available non-invasive technique can detect SOZ activity from all brain regions. Our study indicates that osMEG has the potential to become an important clinical tool, improving both non-invasive SOZ localization and iEEG electrode placement accuracy.

Unraveling the mechanism and kinetics of aerobic Baeyer–Villiger oxidation of cyclohexanone

AbstractThis study explores the aerobic Baeyer–Villiger oxidation of cyclohexanone into ε‐caprolactone using metalloporphyrin and benzaldehyde, a greener process to replace hazardous concentrated peroxyacid. The reaction mechanism involves a series of free radical reactions, identified through in situ EPR. In this complex three‐component reaction, we developed an intrinsic kinetic model based on the proposed mechanism. Utilizing a hyperbolic equation, the model well fits experimental data, describing biomimetic catalytic behavior of the aerobic Baeyer–Villiger oxidation. The reaction orders for the three reactants corroborate the kinetic model, with the activation energy of oxygen (130.27 kJ/mol) surpassing cyclohexanone (94.85 kJ/mol) and benzaldehyde (40.73 kJ/mol), implying slow initial oxygen activation while rapid subsequent benzaldehyde oxidation, making oxygen transfer and activation key steps. This unified approach to elementary reaction, mechanism, and intrinsic kinetics provides robust forecasts and lays the groundwork for additional studies, such as side reactions control and mass transfer enhancement and reactor design.

A104A virtual musculoskeletal case history simulation with service users for pre-registration physiotherapy students

Within health care provision many case history assessments are now performed online [1], with students expected to utilize a variety of virtual platforms in a safe, effective and professional manner. Aim: To approximate a real environment for students to practice virtual skills of case history assessment with service users. Objectives: Student development of: 1. Virtual communication skills (verbal, non-verbal, active listening, respect), 2. Clinical reasoning and interpretation, and 3. Reflective skills facilitated by debrief. Simulation preparation including revision of musculoskeletal assessment and familiarization with virtual ground rules linked to HCPC Guidance on Conduct and Ethics [2]. 42 students participated, split into groups of 14 for each virtual simulation session with a total of 5 service users briefed beforehand. Initial warm-up activities in breakout rooms were used to familiarize students with use of the online platform and to facilitate virtual communication skills. Groups of 4 students planned and undertook a virtual musculoskeletal case history with a service user. The Diamond structure for simulation debrief [3] was facilitated by Faculty staff involving the service users and peers; enabling further development of the students’ clinical reasoning and interpretation. Students reflected on their own performance using a simulation checklist as a resource, closing the loop by creating an action plan prior to their first practice placement. 25 students voluntarily completed an anonymous questionnaire linked to their virtual experiential learning activity. 75% strongly agreed and 21% agreed that the simulation was helpful in their development for placements (see Graph to show student response that virtual musculoskeletal simulation with service users was helpful in their development for placements Thematic analysis of good aspects of the activity identified 4 main themes: Benefits and realism of service user involvement compared to actors or peers Development of virtual communication and assessment skills Richness of involvement of service users in the debrief Usefulness of warm up activities using virtual technology Suggestions for improvement showed 2 main themes around increasing planning time and more opportunities for simulation with service users. Findings demonstrated the simulation aims and objectives were met with students positively reporting that the activity was helpful in their learning ahead of practice placements - enabling development of virtual communication, clinical reasoning/ interpretation and reflection through debrief. Approximation of a real environment for students to practice virtual case history assessment incorporating service users offers a rich educational example that aligns well with practice and sustainability in the current healthcare environment and is highly valued by students. Authors confirm that all relevant ethical standards for research conduct and dissemination have been met. The submitting author confirms that relevant ethical approval was granted, if applicable.

Reducible tungsten(VI) oxide-supported ruthenium(0) nanoparticles: highly active catalyst for hydrolytic dehydrogenation of ammonia borane.

Reducible WO3 powder with a mean diameter of 100 nm is used as support to stabilize ruthenium(0) nanoparticles. Ruthenium(0) nanoparticles are obtained by NaBH4 reduction of ruthenium(III) precursor on the surface of WO3 support at room temperature. Ruthenium(0) nanoparticles are uniformly dispersed on the surface of tungsten(VI) oxide. The obtained Ru0/WO3 nanoparticles are found to be active catalysts in hydrolytic dehydrogenation of ammonia borane. The turnover frequency (TOF) values of the Ru0/WO3 nanocatalysts with the metal loading of 1.0%, 2.0%, and 3.0% wt. Ru are 122, 106, and 83 min-1, respectively, in releasing hydrogen gas from the hydrolysis of ammonia borane at 25.0 °C. As the Ru0/WO3 (1.0% wt. Ru) nanocatalyst with an average particle size of 2.6 nm provides the highest activity among them, it is extensively investigated. Although the Ru0/WO3 (1.0% wt. Ru) nanocatalyst is not magnetically separable, it has extremely high reusability in the hydrolysis reaction as it preserves 100% of initial catalytic activity even after the 5th run of hydrolysis. The high activity and reusability of Ru0/WO3 (1.0% wt. Ru) nanocatalyst are attributed to the favorable metal-support interaction between the ruthenium(0) nanoparticles and the reducible tungsten(VI) oxide. The high catalytic activity and high stability of Ru0/WO3 nanoparticles increase the catalytic efficiency of precious ruthenium in hydrolytic dehydrogenation of ammonia borane.

Characterization of a Type II L-Asparaginase from the Halotolerant Bacillus subtilis CH11.

L-asparaginases from bacterial sources have been used in antineoplastic treatments and the food industry. A type II L-asparaginase encoded by the N-truncated gene ansZP21 of halotolerant Bacillus subtilis CH11 isolated from Chilca salterns in Peru was expressed using a heterologous system in Escherichia coli BL21 (DE3)pLysS. The recombinant protein was purified using one-step nickel affinity chromatography and exhibited an activity of 234.38 U mg-1 and a maximum catalytic activity at pH 9.0 and 60 °C. The enzyme showed a homotetrameric form with an estimated molecular weight of 155 kDa through gel filtration chromatography. The enzyme half-life at 60 °C was 3 h 48 min, and L-asparaginase retained 50% of its initial activity for 24 h at 37 °C. The activity was considerably enhanced by KCl, CaCl2, MgCl2, mercaptoethanol, and DL-dithiothreitol (p-value < 0.01). Moreover, the Vmax and Km were 145.2 µmol mL-1 min-1 and 4.75 mM, respectively. These findings evidence a promising novel type II L-asparaginase for future industrial applications.

Interfacial engineering design for one-dimensional cobalt-iron selenide nanomaterials as a high-efficiency catalyst for oxygen evolution reaction

One promising approach to improving the slow reaction dynamics of alkaline oxygen evolution reaction (OER) is to construct non-precious metal-based heterojunctions via interface engineering. In this work, the relationship between structure and activity for one-dimensional CoSe2/FeSe2 nanomaterials for OER is discussed in detail by experimental techniques, coupled with the density functional theory calculations. Capitalizing on the refined electronic structure layout and abundant heterogeneous interfaces, the hierarchical branched CoSe2/FeSe2 heterojunctions demonstrate the outstanding electrocatalytic activity for OER in 1 M KOH solution, and can achieve low overpotentials of 283 and 330 mV at current densities of 10 and 100 mA cm−2, respectively, as well as keeping 94.7 % of its initial activity after 100 h cycles.Furthermore, it is found that the enhanced inherent catalytic performance of CoSe2/FeSe2 electrocatalyst after standardizing the current density with electrochemically active surface area (ECSA) could be attributed to the robust interaction at the interface induced by the construction of the heterojunctions. This work presents the significance of manipulating the electronic structure of electrocatalysts utilizing interface design to enhance OER catalytic activity, and provides new insights for exploring the highly active electrocatalysts.