Tailoring amorphous boron nitride for high-performance two-dimensional electronics.

Two-dimensional (2D) materials have garnered significant attention in recent years due to their atomically thin structure and unique electronic and optoelectronic properties. To harness their full potential for applications in next-generation electronics and photonics, precise control over the dielectric environment surrounding the 2D material is critical. The lack of nucleation sites on 2D surfaces to form thin, uniform dielectric layers often leads to interfacial defects that degrade the device performance, posing a major roadblock in the realization of 2D-based devices. Here, we demonstrate a wafer-scale, low-temperature process (<250 °C) using atomic layer deposition (ALD) for the synthesis of uniform, conformal amorphous boron nitride (aBN) thin films. ALD deposition temperatures between 125 and 250 °C result in stoichiometric films with high oxidative stability, yielding a dielectric strength of 8.2 MV/cm. Utilizing a seed-free ALD approach, we form uniform aBN dielectric layers on 2D surfaces and fabricate multiple quantum well structures of aBN/MoS2 and aBN-encapsulated double-gated monolayer (ML) MoS2 field-effect transistors to evaluate the impact of aBN dielectric environment on MoS2 optoelectronic and electronic properties. Our work in scalable aBN dielectric integration paves a way towards realizing the theoretical performance of 2D materials for next-generation electronics.

Treatment Patterns, Acute Healthcare Resource Use, and Costs of Patients with Treatment-Resistant Depression Completing Induction Phase of Esketamine in the United States.

BACKGROUND: This study aimed to understand treatment patterns, acute healthcare use, and cost patterns among adults with treatment-resistant depression (TRD) who completed induction treatment with esketamine nasal spray in the United States (US). Per label, induction is defined as administration twice a week for 4 weeks, after which maintenance is started on a weekly basis for 4 weeks, and thereafter, patients are treated weekly or bimonthly. METHODS: Adults with one or more esketamine claim (index date) on or after March 5, 2019 were selected from Optum's de-identified Clinformatics® Data Mart Database (January 2016-June 2022). Before the index date, patients had evidence of TRD and ≥ 12 months of continuous insurance eligibility (baseline period). Patients with eight or more esketamine treatment sessions were included in the main cohort. A subgroup included patients with one or more baseline mental health (MH)-related inpatient (IP) admission or emergency department (ED) visit (i.e., prior acute healthcare users). Treatment patterns were described during the follow-up period (index date until earliest of end of insurance eligibility or data); acute healthcare (i.e., IP and ED) resource use and costs (2021 US dollars) were reported during the baseline and follow-up periods. RESULTS: Of the 322 patients in the main cohort, 111 comprised the subgroup of prior acute healthcare users. During the follow-up period, mean time from index date to eighth esketamine session was 73.2 days in the main cohort and 78.8 days in the subgroup (per label, 28 days). Further, 75.2% of the main cohort and 73.9% of the subgroup completed four or more esketamine maintenance sessions following induction. In the main cohort, mean all-cause acute healthcare costs per patient per month (PPPM) decreased from baseline ($837) to follow-up ($770). Similar reductions were observed for mean MH-related acute healthcare costs PPPM (baseline $648, follow-up $577). In the subgroup, mean all-cause acute healthcare costs PPPM also decreased (baseline $2323, follow-up $1423), driven by mean MH-related acute healthcare costs PPPM (baseline $1880, follow-up $1139). Mean all-cause acute healthcare use per ten patients per month remained largely stable from baseline to follow-up in the main cohort (IP days: baseline 2.24, follow-up 2.13; ED visits: baseline 1.33, follow-up 1.45) and decreased in the subgroup (IP days: baseline 6.38, follow-up 4.56; ED visits: baseline 2.58, follow-up 2.41). Trends in mean MH-related acute healthcare use were similar. CONCLUSION: Patients generally required more time than label recommendation to complete esketamine induction treatment, and most went on to have 12 or more esketamine sessions. Completion of induction treatment correlated with reductions in mean all-cause and MH-related acute healthcare costs. Larger reductions were seen in the subgroup of prior acute healthcare users.

Learning and memory function preserved by delayed A1 adenosine receptor agonist treatment following soman intoxication in rats and a humanized esterase mouse model.

Exposure to organophosphorus compounds, such as soman (GD), cause widespread toxic effects, sustained status epilepticus, neuropathology, and death. The A1 adenosine receptor agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA), when given 1 min after GD exposure, provides neuroprotection and prevents behavioral impairments. Here, we tested the ability of ENBA at delayed treatment times to improve behavioral outcomes via a two-way active avoidance task in two male animal models, each consisting of saline and GD exposure groups. In a rat model, animals received medical treatments (atropine sulfate [A], 2-PAM [P], and midazolam [MDZ]) or AP + MDZ + ENBA at 15 or 30 min after seizure onset and were subjected to behavioral testing for up to 14 days. In a human acetylcholinesterase knock-in serum carboxylesterase knock-out mouse model, animals received AP, AP + MDZ, AP + ENBA, or AP + MDZ + ENBA at 15 min post seizure onset and were subjected to the behavioral task on days 7 and 14. In rats, the GD/AP + MDZ + ENBA group recovered to saline-exposed avoidance levels while the GD/AP + MDZ group did not. In mice, in comparison with GD/AP + MDZ group, the GD/AP + MDZ + ENBA showed decreases in escape latency, response latency, and pre-session crossings, as well as increases in avoidances. In both models, only ENBA-treated groups showed control level inter-trial interval crossings by day 14. Our findings suggest that ENBA, alone and as an adjunct to medical treatments, can improve behavioral and cognitive outcomes when given at delayed time points after GD intoxication.

Hypothermia as potential therapeutic approach to attenuating soman-induced seizure, neuropathology, and mortality with an adenosine A1 receptor agonist and body cooling.

Organophosphorus nerve agents, such as soman (GD), produce excitotoxic effects resulting in sustained status epilepticus (SSE) and brain damage. Previous work shows that neuronal inhibitory effects of A1 adenosine receptor (A1AR) agonists, such as N6- Bicyclo (2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (Cl-ENBA), suppresses GD-induced SSE and improves neuropathology. Some other physiologic effects of these agonists are hypothermia, hypotension, and sedation. Hypothermia may also shield the brain from injury by slowing down chemical insults, lessening inflammation, and contributing to improved neurological outcomes. Therefore, we attempted to isolate the hypothermic effect from ENBA by assessing the neuroprotective efficacy of direct surface body cooling in a rat GD-induced SSE model, and comparing the effects on seizure termination, neuropathology, and survival. Male rats implanted with a body temperature (Tb) transponder and electroencephalographic (EEG) electrodes were primed with asoxime (HI-6), exposed to GD 30 min later, and then treated with Cl-ENBA or had Tb lowered directly via body cooling at 30 min after the onset of seizure activity. Afterwards, they were either allowed to develop hypothermia as expected, or received thermal support to maintain normothermic Tb for a period of 6-h. Neuropathology was assessed at 24 h. Regardless of Cl-ENBA or surface cooling, all hypothermic GD-exposed groups had significantly improved 24-h survival compared to rats with normothermic Tb (81% vs. 39%, p < 0.001). Cl-ENBA offered neuroprotection independently of hypothermic Tb. While hypothermia enhanced the overall efficacy of Cl-ENBA by improving survival outcomes, body cooling didn't reduce seizure activity or neuropathology following GD-induced SSE.

Prediction of cardiovascular and renal risk among patients with apparent treatment-resistant hypertension in the United States using machine learning methods.

Apparent treatment-resistant hypertension (aTRH), defined as blood pressure (BP) that remains uncontrolled despite unconfirmed concurrent treatment with three antihypertensives, is associated with an increased risk of developing cardiovascular and renal complications compared with controlled hypertension. We aimed to identify the characteristics of aTRH patients with an elevated risk of major adverse cardiovascular events plus (MACE+; defined as stroke, myocardial infarction, or heart failure hospitalization) and end stage renal disease (ESRD). This retrospective cohort study included aTRH patients (BP ≥140/90 mmHg and taking ≥3 antihypertensives) from the United States-based Optum® de-identified Electronic Health Record dataset and used machine learning models to identify risk factors of MACE+ or ESRD. Patients had claims for ≥3 antihypertensive classes within 30 days between January 1, 2015 and June 30, 2021, and two office BP measures recorded 1-90 days apart within 30 days to 11 months after the index regimen date. Of a total 18 797 070 patients identified with any hypertension, 71 100 patients had aTRH. During the study period (mean 25.5 months), 4944 (7.0%) patients had a MACE+ and 2403 (3.4%) developed ESRD. In total, 22 risk factors were included in the MACE+ model and 16 in the ESRD model, and most were significantly associated with study outcomes. The risk factors with the largest impact on MACE+ risk were congestive heart failure, stages 4 and 5 chronic kidney disease (CKD), age ≥80 years, and living in the Southern region of the United States. The risk factors with the largest impact on ESRD risk, other than pre-existing CKD, were anemia, congestive heart failure, and type 2 diabetes. The overall study cohort had a 5-year predicted MACE+ risk of 13.4%; this risk was increased in those in the top 50% and 25% high-risk groups (21.2% and 29.5%, respectively). The overall study cohort had a predicted 5-year risk of ESRD of 6.8%, which was increased in the top 50% and 25% high-risk groups (10.9% and 17.1%, respectively). We conclude that risk models developed in our study can reliably identify patients with aTRH at risk of MACE+ and ESRD based on information available in electronic health records; such models may be used to identify aTRH patients at high risk of adverse outcomes who may benefit from novel treatment interventions.

Real-World Impact of Blood Pressure Control in Patients With Apparent Treatment-Resistant or Difficult-to-Control Hypertension and Stages 3 and 4 Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is a common comorbidity in patients with apparent treatment-resistant hypertension (aTRH). We assessed clinical outcomes, healthcare resource utilization events, and costs in patients with aTRH or difficult-to-control hypertension and stage 3-4 CKD with uncontrolled vs. controlled BP. METHODS: This retrospective cohort study used linked IQVIA Ambulatory EMR-US and IQVIA PharMetrics Plus claims databases. Adult patients had claims for ≥3 antihypertensive medication classes within 30 days between 01/01/2015 and 06/30/2021, 2 office BP measures recorded 1-90 days apart, ≥1 claim with ICD-9/10-CM diagnosis codes for CKD 3/4, and ≥1 year of continuous enrollment. Baseline BP was defined as uncontrolled (≥130/80 mm Hg) or controlled (<130/80 mm Hg) BP. Outcomes included risk of major adverse cardiovascular events plus (MACE+; stroke, myocardial infarction, heart failure hospitalization), end-stage renal disease (ESRD), healthcare resource utilization events, and costs during follow-up. RESULTS: Of 3,966 patients with stage 3-4 CKD using ≥3 antihypertensive medications, 2,479 had uncontrolled BP and 1,487 had controlled BP. After adjusting for baseline differences, patients with uncontrolled vs. controlled BP had a higher risk of MACE+ (HR [95% CI]: 1.18 [1.03-1.36]), ESRD (1.85 [1.44-2.39]), inpatient hospitalization (rate ratio [95% CI]: 1.35 [1.28-1.43]), and outpatient visits (1.12 [1.11-1.12]) and incurred higher total medical and pharmacy costs (mean difference [95% CI]: $10,055 [$6,741-$13,646] per patient per year). CONCLUSIONS: Patients with aTRH and stage 3-4 CKD and uncontrolled BP despite treatment with ≥3 antihypertensive classes had an increased risk of MACE+ and ESRD and incurred greater healthcare resource utilization and medical expenditures compared with patients taking ≥3 antihypertensive classes with controlled BP.

Metalloradical Catalysis: General Approach for Controlling Reactivity and Selectivity of Homolytic Radical Reactions.

Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two-electron heterolytic ionic chemistry. While one-electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high-energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal-centered radicals present in open-shell metal complexes as one-electron catalysts for homolytic activation of substrates to generate metal-entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two-electron catalysis by transition metal complexes, MRC operates through one-electron chemistry utilizing stepwise radical mechanisms.

High-density stable glasses formed on soft substrates.

Enabled by surface-mediated equilibration, physical vapour deposition can create high-density stable glasses comparable with liquid-quenched glasses aged for millions of years. Deposition is often performed at various rates and temperatures on rigid substrates to control the glass properties. Here we demonstrate that on soft, rubbery substrates, surface-mediated equilibration is enhanced up to 170 nm away from the interface, forming stable glasses with densities up to 2.5% higher than liquid-quenched glasses within 2.5 h of deposition. Gaining similar properties on rigid substrates would require 10 million times slower deposition, taking ~3,000 years. Controlling the modulus of the rubbery substrate provides control over the glass structure and density at constant deposition conditions. These results underscore the significance of substrate elasticity in manipulating the properties of the mobile surface layer and thus the glass structure and properties, allowing access to deeper states of the energy landscape without prohibitively slow deposition rates.

Combined Experimental and Computational Insight into the Role of Substrate in the Synthesis of Two-Dimensional WSe2.

Synthesis of large-area transition-metal dichalcogenides (TMDs) with controlled orientation is a significant challenge to their industrial applications. Substrate plays a vital role in determining the final quality of monolayer materials grown via the chemical vapor deposition process by controlling their orientation, crystal structure, and grain boundary. This study determined the binding energy and equilibrium distance for tungsten diselenide (WSe2) monolayers on crystalline and amorphous silicon dioxide and aluminum dioxide substrates. Differently oriented WSe2 monolayers are considered to investigate the role of the substrate in the orientation, binding strength, and equilibrium distance. This study can pave the way to synthesizing high-quality two-dimensional (2D) materials for electronic and chemical applications.

Rapid and Quantitative Functional Interrogation of Human Enhancer Variant Activity in Live Mice.

Functional analysis of non-coding variants associated with human congenital disorders remains challenging due to the lack of efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison of enhancer allele activities in live mice of any genetic background. We use this new technology to examine and measure the gain- and loss-of-function effects of enhancer variants linked to limb polydactyly, autism, and craniofacial malformation. By combining dual-enSERT with single-cell transcriptomics, we characterize variant enhancer alleles at cellular resolution, thereby implicating candidate molecular pathways in pathogenic enhancer misregulation. We further show that independent, polydactyly-linked enhancer variants lead to ectopic expression in the same cell populations, indicating shared genetic mechanisms underlying non-coding variant pathogenesis. Finally, we streamline dual-enSERT for analysis in F0 animals by placing both reporters on the same transgene separated by a synthetic insulator. Dual-enSERT allows researchers to go from identifying candidate enhancer variants to analysis of comparative enhancer activity in live embryos in under two weeks.

Functional analysis of Salix purpurea genes support roles for ARR17 and GATA15 as master regulators of sex determination.

The Salicaceae family is of growing interest in the study of dioecy in plants because the sex determination region (SDR) has been shown to be highly dynamic, with differing locations and heterogametic systems between species. Without the ability to transform and regenerate Salix in tissue culture, previous studies investigating the mechanisms regulating sex in the genus Salix have been limited to genome resequencing and differential gene expression, which are mostly descriptive in nature, and functional validation of candidate sex determination genes has not yet been conducted. Here, we used Arabidopsis to functionally characterize a suite of previously identified candidate genes involved in sex determination and sex dimorphism in the bioenergy shrub willow Salix purpurea. Six candidate master regulator genes for sex determination were heterologously expressed in Arabidopsis, followed by floral proteome analysis. In addition, 11 transcription factors with predicted roles in mediating sex dimorphism downstream of the SDR were tested using DAP-Seq in both male and female S. purpurea DNA. The results of this study provide further evidence to support models for the roles of ARR17 and GATA15 as master regulator genes of sex determination in S. purpurea, contributing to a regulatory system that is notably different from that of its sister genus Populus. Evidence was also obtained for the roles of two transcription factors, an AP2/ERF family gene and a homeodomain-like transcription factor, in downstream regulation of sex dimorphism.

Poor Sleep Quality Increases Gestational Weight Gain Rate in Pregnant People: Findings from the MADRES Study.

Background: Poor sleep quality is associated with weight gain in non-pregnant populations, but evidence in pregnant people is lacking. Our study examined the association between early-to-mid pregnancy sleep quality and weekly gestational weight gain (GWG) rate during mid-to-late pregnancy by pre-pregnancy body mass index (BMI). Method: Participants were 316 pregnant participants from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) study. During early-to-mid pregnancy, participants reported their sleep quality which was used to construct four categories: very poor, poor, good, and very good. Linear growth curve models examined the association between early-to-mid pregnancy sleep quality and weekly rate of GWG (kg/week) during mid-to-late pregnancy (> 20 weeks gestation), with a three-way cross-level interaction between gestational age, sleep quality, and pre-pregnancy BMI category. Models adjusted for ethnicity by birthplace, hypertensive disorders, perceived stress score, and physical activity level. Results: Overall, poorer early-to-mid pregnancy sleep quality was associated with increased weekly weight gain during mid-to-late pregnancy. For example, amongst normal weight participants, mid-to-late pregnancy weight gain was, on average, 0.39 kg (95% CI: 0.29, 0.48) per week for those with very good sleep quality, 0.53 kg (95% CI: 0.44, 0.61) per week for those with poor sleep quality, and 0.54 kg (95% CI: 0.46, 0.62) per week for those with very poor sleep quality during early-to-mid pregnancy. This difference in GWG rate was statistically significantly comparing very good to poor sleep (0.14 kg/week, 95% CI: 0.01, 0.26) and very good to very poor sleep (0.15kg/week, 85% CI: 0.02, 0.27). This association between sleep quality and GWG rate did not statistically differ by pre-pregnancy BMI. Conclusion: Our study found very poor early-to-mid pregnancy sleep quality was associated with higher mid-to-late pregnancy GWG rate. Incorporating pregnancy-specific sleep recommendations into routine obstetric care may be a critical next step in promoting healthy GWG.

A marmoset brain cell census reveals regional specialization of cellular identities.

The mammalian brain is composed of many brain structures, each with its own ontogenetic and developmental history. We used single-nucleus RNA sequencing to sample over 2.4 million brain cells across 18 locations in the common marmoset, a New World monkey primed for genetic engineering, and examined gene expression patterns of cell types within and across brain structures. The adult transcriptomic identity of most neuronal types is shaped more by developmental origin than by neurotransmitter signaling repertoire. Quantitative mapping of GABAergic types with single-molecule FISH (smFISH) reveals that interneurons in the striatum and neocortex follow distinct spatial principles, and that lateral prefrontal and other higher-order cortical association areas are distinguished by high proportions of VIP+ neurons. We use cell type-specific enhancers to drive AAV-GFP and reconstruct the morphologies of molecularly resolved interneuron types in neocortex and striatum. Our analyses highlight how lineage, local context, and functional class contribute to the transcriptional identity and biodistribution of primate brain cell types.

Genome-scale phylogeny and comparative genomics of the fungal order Sordariales.

The order Sordariales is taxonomically diverse, and harbours many species with different lifestyles and large economic importance. Despite its importance, a robust genome-scale phylogeny, and associated comparative genomic analysis of the order is lacking. In this study, we examined whole-genome data from 99 Sordariales, including 52 newly sequenced genomes, and seven outgroup taxa. We inferred a comprehensive phylogeny that resolved several contentious relationships amongst families in the order, and cleared-up intrafamily relationships within the Podosporaceae. Extensive comparative genomics showed that genomes from the three largest families in the dataset (Chaetomiaceae, Podosporaceae and Sordariaceae) differ greatly in GC content, genome size, gene number, repeat percentage, evolutionary rate, and genome content affected by repeat-induced point mutations (RIP). All genomic traits showed phylogenetic signal, and ancestral state reconstruction revealed that the variation of the properties stems primarily from within-family evolution. Together, the results provide a thorough framework for understanding genome evolution in this important group of fungi.

Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism.

Metalloradical catalysis (MRC) exploits the metal-centred radicals present in open-shell metal complexes as one-electron catalysts for the generation of metal-stabilized organic radicals-key intermediates that control subsequent one-electron homolytic reactions. Cobalt(II) complexes of porphyrins, as stable 15e-metalloradicals with a well-defined low-spin d7 configuration, have dominated the ongoing development of MRC. Here, to broaden MRC beyond the use of Co(II)-based metalloradical catalysts, we describe systematic studies that establish the operation of Fe(III)-based MRC and demonstrate an initial application for asymmetric radical transformations. Specifically, we report that five-coordinate iron(III) complexes of porphyrins with an axial ligand, which represent another family of stable 15e-metalloradicals with a d5 configuration, are potent metalloradical catalysts for olefin cyclopropanation with different classes of diazo compounds via a stepwise radical mechanism. This work lays a foundation and mechanistic blueprint for future exploration of Fe(III)-based MRC towards the discovery of diverse stereoselective radical reactions.

Fabrication of p-type 2D single-crystalline transistor arrays with Fermi-level-tuned van der Waals semimetal electrodes.

High-performance p-type two-dimensional (2D) transistors are fundamental for 2D nanoelectronics. However, the lack of a reliable method for creating high-quality, large-scale p-type 2D semiconductors and a suitable metallization process represents important challenges that need to be addressed for future developments of the field. Here, we report the fabrication of scalable p-type 2D single-crystalline 2H-MoTe2 transistor arrays with Fermi-level-tuned 1T'-phase semimetal contact electrodes. By transforming polycrystalline 1T'-MoTe2 to 2H polymorph via abnormal grain growth, we fabricated 4-inch 2H-MoTe2 wafers with ultra-large single-crystalline domains and spatially-controlled single-crystalline arrays at a low temperature (~500 °C). Furthermore, we demonstrate on-chip transistors by lithographic patterning and layer-by-layer integration of 1T' semimetals and 2H semiconductors. Work function modulation of 1T'-MoTe2 electrodes was achieved by depositing 3D metal (Au) pads, resulting in minimal contact resistance (~0.7 kΩ·µm) and near-zero Schottky barrier height (~14 meV) of the junction interface, and leading to high on-state current (~7.8 µA/µm) and on/off current ratio (~105) in the 2H-MoTe2 transistors.

Biophysical Profiling of Sickle Cell Disease Using Holographic Cytometry and Deep Learning.

Sickle cell disease (SCD) is an inherited hematological disorder associated with high mortality rates, particularly in sub-Saharan Africa. SCD arises due to the polymerization of sickle hemoglobin, which reduces flexibility of red blood cells (RBCs), causing blood vessel occlusion and leading to severe morbidity and early mortality rates if untreated. While sickle solubility tests are available to sub-Saharan African population as a means for detecting sickle hemoglobin (HbS), the test falls short in assessing the severity of the disease and visualizing the degree of cellular deformation. Here, we propose use of holographic cytometry (HC), a high throughput, label-free imaging modality, for comprehensive morphological profiling of RBCs as a means to detect SCD. For this study, more than 2.5 million single-cell holographic images from normal and SCD patient samples were collected using the HC system. We have developed an approach for specially defining training data to improve machine learning classification. Here, we demonstrate the deep learning classifier developed using this approach can produce highly accurate classification, even on unknown patient samples.

Association of uncontrolled blood pressure in apparent treatment-resistant hypertension with increased risk of major adverse cardiovascular events plus.

Patients with apparent treatment-resistant hypertension (aTRH) are at increased risk of end-organ damage and cardiovascular events. Little is known about the effects of blood pressure (BP) control in this population. Using a national claims database integrated with electronic medical records, the authors evaluated the relationships between uncontrolled BP (UBP; ≥130/80 mmHg) or controlled BP (CBP; <130/80 mmHg) and risk of major adverse cardiovascular events plus (MACE+; stroke, myocardial infarction, heart failure requiring hospitalization) and end-stage renal disease (ESRD) in adult patients with aTRH (taking ≥3 antihypertensive medication classes concurrently within 30 days between January 1, 2015 and June 30, 2021). MACE+ components were also evaluated separately. Multivariable regression models were used to adjust for baseline differences in demographic and clinical characteristics, and sensitivity analyses using CBP <140/90 mmHg were conducted. Patients with UBP (n = 22 333) were younger and had fewer comorbidities at baseline than those with CBP (n = 11 427). In the primary analysis, which adjusted for these baseline differences, UBP versus CBP patients were at an 8% increased risk of MACE+ (driven by a 31% increased risk of stroke) and a 53% increased risk of ESRD after 2.7 years of follow-up. Greater MACE+ (22%) and ESRD (98%) risk increases with UBP versus CBP were seen in the sensitivity analysis. These real-world data showed an association between suboptimal BP control in patients with aTRH and higher incidence of MACE+ and ESRD linked with UBP despite the use of multidrug regimens. Thus, there remains a need for improved aTRH management.

Degradation of amyloid beta species by multi-copper oxidases.

Reduction of the production of amyloid beta (Aß) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aß species, another potential beneficial approach, has been far less explored. In this study, we discovered that ceruloplasmin (CP), an important multi-copper oxidase (MCO) in human blood, could degrade Aß peptides. We also found that the presence of Vitamin C could enhance the degrading effect in a concentration-dependent manner. We then validated the CP-Aß interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer, and fluorescence polarization measurement. Based on the above discovery, we hypothesized that other MCOs had similar Aß-degrading functions. Indeed, we found that other MCOs could induce Aß degradation as well. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect among the tested MCOs. Using induced pluripotent stem (iPS) neuron cells, we observed that AO could rescue neuron toxicity which induced by Aß oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Ab-induced deficit in synaptic transmission in the hippocampus. To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.

The Evolution of MXenes Conductivity and Optical Properties Upon Heating in Air.

MXenes, a family of 2D transition-metal carbides and nitrides, have excellent electrical conductivity and unique optical properties. However, MXenes oxidize in ambient conditions, which is accelerated upon heating. Intercalation of water also causes hydrolysis accelerating oxidation. Developing new tools to readily characterize MXenes' thermal stability can enable deeper insights into their structure-property relationships. Here, in situ spectroscopic ellipsometry (SE) is employed to characterize the optical properties of three types of MXenes (Ti3 C2 Tx , Mo2 TiC2 Tx , and Ti2 CTx ) with varied composition and atomistic structures to investigate their thermal degradation upon heating under ambient environment. It is demonstrated that changes in MXene extinction and optical conductivity in the visible and near-IR regions correlate well with the amount of intercalated water and hydroxyl termination groups and the degree of oxidation, measured using thermogravimetric analysis. Among the three MXenes, Ti3 C2 Tx and Ti2 CTx , respectively, have the highest and lowest thermal stability, indicating the role of transition-metal type, synthesis route, and the number of atomic layers in MXene flakes. These findings demonstrate the utility of SE as a powerful in situ technique for rapid structure-property relationship studies paving the way for the further design, fabrication, and property optimization of novel MXene materials.