Concurrent Activation Research Articles

Individual and joint associations between sleep duration and physical activity with cognitive function: A longitudinal analysis among middle-aged and older adults in China.

Studies using cross-sectional data or with a short follow-up period fail to distinguish whether the associations between sleep duration and physical activity with cognitive function result from reverse causation. The longitudinal study examined the individual and joint associations, with specific temporality, between sleep duration and physical activity with cognitive function, using time-lagged linear mixed models and generalized additive mixed models. A total of 14,694 participants aged ≥ 50 years were included, with an average lagged time of 4.5 (standard deviation 1.3) years. Long sleep duration was independently associated with cognitive decline, while short sleep duration and physical activity were not. The analysis of joint effects showed that increased physical activity slowed the rate of cognitive decline among participants reporting long sleep duration, consistent with the results of the stratified analyses. Interventions on improving sleep should consider concurrent physical activity to maximize benefits for slowing cognitive decline. Long sleep duration was independently associated with worse cognitive function, while short sleep duration was not. Elevated levels of physical activity were not independently associated with better cognitive function. Increased physical activity appeared to mitigate the negative impact of long sleep duration on cognitive function.

Monetised sustainability impacts of integrated planning in the manufactured construction products industry: A transport perspective from New Zealand

<p style="text-align: justify;"><span style="font-size: 14pt; font-family: 'times new roman', times, serif;">The extensive, interdisciplinary nature of construction supply chains make them prone to inefficiencies at organisational interfaces. Inefficiencies are accentuated by the project-centric delivery paradigm, and complex logistics systems between multiple stakeholders. They manifest as a multitude of concurrent activities, processes, and systems both on and off-site. Transportation is the largest component of the logistics domain. Transport operations are inherently fragmented, intrinsic to every business, while vehicle ownership and deployment is typically externalised. Differentiated waste removal and materials delivery further disintegrate the already fragmented construction supply chain. Inefficiencies from the insularity of the planning process across segmental boundaries aggregate incrementally, with impacts visible at the macro level. Re-configuration of activities, resources and actors are acknowledged strategies for optimising logistics and transportation function. This paper investigates the impact of three integration strategies on a manufactured construction products supply chain efficiency. These strategies include vertical integration of distribution, integrated planning for transport operations, and integration of reverse logistics into operations. Sustainability impacts are evaluated according to domestically determined monetary parameters in order to benchmark performance at the business and national scale.</span></p>

A bioinspired sulfur–Fe–heme nanozyme with selective peroxidase-like activity for enhanced tumor chemotherapy

Iron-based nanozymes, recognized for their biocompatibility and peroxidase-like activities, hold promise as catalysts in tumor therapy. However, their concurrent catalase-like activity undermines therapeutic efficacy by converting hydrogen peroxide in tumor tissues into oxygen, thus diminishing hydroxyl radical production. Addressing this challenge, this study introduces the hemin–cysteine–Fe (HCFe) nanozyme, which exhibits exclusive peroxidase-like activity. Constructed through a supramolecular assembly approach involving Fmoc-l-cysteine, heme, and Fe²⁺ coordination, HCFe distinctly incorporates heme and [Fe–S] within its active center. Sulfur coordination to the central Fe atom of Hemin is crucial in modulating the catalytic preference of the HCFe nanozyme towards peroxidase-like activity. This unique mechanism distinguishes HCFe from other bifunctional iron-based nanozymes, enhancing its catalytic selectivity even beyond that of natural peroxidases. This selective activity allows HCFe to significantly elevate ROS production and exert cytotoxic effects, especially against cisplatin-resistant esophageal squamous cell carcinoma (ESCC) cells and their xenografts in female mice when combined with cisplatin. These findings underscore HCFe’s potential as a crucial component in multimodal cancer therapy, notably in augmenting chemotherapy efficacy.

Negative hemodynamic response in the visual cortex: Evidence supporting neuronal origin via hemodynamic observation and two-photon imaging

The positive hemodynamic response (PHR) during stimulation often co-occurs with a strong, sustained negative hemodynamic response (NHR). However, the characteristics and neurophysiological mechanisms of the NHR, especially in regions distal to the PHR, remain incompletely understood. Using intrinsic optical imaging (OI) and two-photon imaging, we observed that forelimb electrical stimulation evoked strong PHR signals in the forelimb region of the primary somatosensory cortex (S1FL). Meanwhile, NHR signals primarily appeared in the primary visual cortex (V1), with a delayed onset and lower amplitude relative to the PHR signals. Additionally, stimulation led to a reduction in cerebral blood flow (CBF) in the NHR region. Notably, there was an overall suppression of the calcium response in the NHR region, although a small proportion (14 %) of neurons exhibited concurrent activation. Axon tracing revealed cortico-cortical projections from S1FL to V1. These findings suggest that neuronal deactivation significantly contributes to the origin of the NHR, offering additional insights into the specific inhibitory mechanisms underlying the NHR.

Synthesis and characterization of Z-scheme based MoS2/ GQD/Ag nanocomposite for degradation of organic pollution

The constituent composition of heterojunction composite materials can be changed to effectively segregate photogenerated charge carriers and to significantly advance the process of photocatalytic destruction of resistant pollutants under visible light irradiation. This work presents the hydrothermal synthesis of a novel ternary heterojunction composite, MoS2/GQD/Ag NPs (MS/GQD/Ag) and its photocatalytic performance in the degradation of organic dyes. In the synthesized material, the Z-scheme heterojunction demonstrated enhanced visible light-driven catalytic activity by effectively separating electrons from holes (e−/h+) and producing reactive oxygen species. In addition to producing reactive radicals, a variety of surface-bound redox cycles are important in the transmission of photogenerated charge carriers. Rhodamin B (RhB) photocatalytic degradation by MS/GQD/Ag under visible light irradiation was investigated, and results demonstrated 99 % RhB was decomposed using 0.1 g/L of ternary composite during 75 min. Experiments using scavenging techniques verified the concurrent activity of hydroxyl and superoxide radical species in the direction of degradation. The structural stability, recyclability for four cycles, and the pH effect in degradation efficiency of the synthesized photocatalyst illuminate its potential application for the degradation of organic pollutants for water treatment.

Novel Multipoint-drive Rotary Actuator for Extraterrestrial Celestial Ultrasonic Driller

Ultrasonic drilling has emerged as a prominent technique in extraterrestrial environments due to its advantageous features. However, its application in extraterrestrial sampling missions is constrained by challenges such as drilling, chip removal efficiency, and high and low temperature adaptability. Addressing these limitations, this study introduces a novel multi-point driven rotary helical longitudinal torsion horn. The initial phase involved a detailed analysis of the actuator’s structure and operational principle. Subsequently, the actuator’s vibration mode and elliptical motion trajectory were validated through finite element simulation. The study further explores a methodology for adjusting the parameters of the helical groove and the displacement amplitude of the impact head. Following the theoretical analysis, prototypes of the actuator and drill were fabricated. Their adaptability to high and low temperatures, as well as their output characteristics, were rigorously tested. Experimental results demonstrate that with an increase in temperature, the dynamic impedance of the actuator initially rises before decreasing, while the mechanical quality factor exhibits the opposite trend. Notably, the concurrent activation of points P1 and P2 significantly enhances the no-load speed, achieving a maximum of 506 revolutions per minute (r/min). Under conditions of power below 35 W and a drilling pressure of 10 N, the drilling speed achieved in basalt is 6.2 millimeters per minute (mm/min). The proposed multipoint-driven actuator can effectively improve the drilling and chip removal efficiency of the driller, which is an important application prospect in future extraterrestrial drilling missions.

Tirzepatide – a new hope for type 2 diabetes mellitus and obesity management. A literature review.

INTRODUCTION AND PURPOSE. While obesity and type 2 diabetes mellitus (T2DM) are defined (according to WHO) as civilization diseases we are still searching for the ideal tool to fight them. Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes and weight reduction among obese and overweighted patients. This review evaluates the efficacy and safety of using tirzepatide based on GIP/GLP-1 agonists clinical trials. MATERAILS AND METHODS. Literature available in the PubMeb Database and Google Scholar Databases was reviewed using keywords. RESULTS AND CONCLUSIONS. Tirzepatide is a novel medicine which stands against type 2 diabetes and obesity pandemic. Combining two agonists of GIP and GLP-1 receptors helps decrease glycemic blood levels, HbA1c levels and reducing body weight in more efficient way than the GLP-1 receptor agonists. All these effects have also resulted in minimizing cardiovascular risk which is observed as an improvement in heart failure, hyperlipidemia and hypertension. Beyond that, the recent data present possible positive long-term effect of tirzepatide in such diseases as MAFLD (metabolic associated fatty liver disease) and OSA (obstructive sleep apnea). However, triagonists, achieving a concurrent activation of GLP-1, GIP, and glucagon receptors, normalize body weight in a manner superior to that of monoagonists and dual agonists. Therefore, the triple agonism or other than GIP/GLP-1 combinations could soon represent a new standard for pharmaceutical interventions. KEYWORDS: tirzepatide; obesity; type 2 diabetes; weight reduction; GIP; GLP-1.

PANoptosis Regulation in Reservoir Hosts of Zoonotic Viruses.

Zoonotic viruses originating from reservoir hosts, such as bats and birds, often cause severe illness and outbreaks amongst humans. Upon zoonotic virus transmission, infected cells mount innate immune responses that include the activation of programmed cell death pathways to recruit innate immune cells to the site of infection and eliminate viral replication niches. Different inflammatory and non-inflammatory cell death pathways, such as pyroptosis, apoptosis, necroptosis, and PANoptosis can undergo concurrent activation in humans leading to mortality and morbidity during zoonosis. While controlled activation of PANoptosis is vital for viral clearance during infection and restoring tissue homeostasis, uncontrolled PANoptosis activation results in immunopathology during zoonotic virus infections. Intriguingly, animal reservoirs of zoonotic viruses, such as bats and birds, appear to have a unique immune tolerance adaptation, allowing them to host viruses without succumbing to disease. The mechanisms facilitating high viral tolerance in bats and birds are poorly understood. In this perspective review, we discuss the regulation of PANoptotic pathways in bats and birds and indicate how they co-exist with viruses with mild clinical signs and no immunopathology. Understanding the PANoptotic machinery of bats and birds may thus assist us in devising strategies to contain zoonotic outbreaks amongst humans.

Small-scale Current Sheets and Associated Switchback Activity in the Inner Heliosphere

Several long-standing theories postulate that turbulent dissipation can heat solar wind protons in situ. Turbulent dissipation can occur via current sheets, which are small-scale structures embedded in the solar wind magnetic field. This study examines the role that switchbacks—intermediate-scale reversals in the interplanetary magnetic field—may play in heating the solar wind by generating current sheets. We explore this possible relationship by analyzing the characteristics of current sheets within and around switchback regions. Previous studies investigated current sheet properties during Parker Solar Probe's first solar encounter, analyzed current sheets using a wide range of statistics, and explored trends that switchbacks follow with radial distance from the Sun. The present study builds on these works by analyzing the distribution and maximum values of solar wind current sheets using the Partial Variance of Increments method and focusing on how these properties correlate with the presence of switchbacks to better understand how switchbacks contribute to current sheet activity. We conclude that there are no increased current sheet populations observed within and around switchbacks, with most current sheets being observed outside switchbacks. We find a consistent distribution of current sheets regardless of whether there is concurrent switchback activity. We also observe that current sheets follow a uniform occurrence rate with increased distance from the Sun, while switchback regions significantly evolve with larger radial distances. Our findings suggest that local turbulence may be responsible for generating solar wind current sheets and does so with the same efficiency inside and outside of switchback regions.

English Student-Teachers’ Awareness of Communication Strategies and Their Implementation During Internship Program

This study aims to examine the use of Communication Strategies (CSs) by English language student teachers within a classroom setting. To achieve this, a qualitative research method involving document analysis was utilized. The analyzed documents consisted of video lesson studies from English education students participating in a 2024 educational internship program. Data collection involved: 1) selecting videos of model lesson study teachers from the internship schools for analysis, 2) the model teacher and their team reviewing these videos, 3) the model teacher and team engaging in group reflections and analyzing the use of communication strategies using a predefined list of CS types while providing example quotes, and 4) the team questioning the model teacher about the rationale behind using these strategies. The data analysis process included three concurrent activities: data condensation, data display, and conclusion drawing/verifying. The study's findings indicate that English education student teachers employed 16 different types of CSs during the internship program for classroom communication. These strategies include Message Abandonment, Message Reduction, Message Replacement, Approximation, Restructuring, Literal Translation, Code-switching, Omission, Self-repair, Other-repair, Comprehension Check, Asking for Repetition, Asking for Clarification, Expressing Non-understanding, Interpretative Summary, and Repetitions.

How Culture and Musical Engagement Shape Musical Reward Sensitivity in Danish Teens: A Validation Study of the Danish Barcelona Musical Reward Questionnaire With 4641 Adolescents.

The ability to convey emotions and induce pleasure is one of the most important aspects of the way that music becomes meaningful to humans. Affective responses to music are specific to both cultural and personal preferences, but little is known about the individual variability in adolescence. The Barcelona Music Reward Questionnaire (BMRQ) is a psychometric measure that identifies five factors associated with musical pleasure: Musical Seeking, Emotional Evocation, Mood Regulation, Social Reward, and Sensory-Motor. With this study, we aimed to validate the BMRQ in Danish teens and to explore the differences in music reward experiences in relation to the amount of musical activity, between genders and over ages. Approximately 30,000 Danish adolescents participated in a mass experiment with a subset (N = 4641, 51.2% girls, age range = 13-19 years old) responding to (1) a Danish adaptation of the BMRQ and (2) the Concurrent Musical Activities (CCM) Questionnaire. Both exploratory and confirmatory factor analyses were applied, and a seven-factor model of the BMRQ was found to fit the Danish adolescent population. The seven-factor version of the Danish BMRQ was due to the split of the dimensions "Sensory-Motor" and "Social Reward" into two further subfactors. The students with a higher amount of musical engagement scored higher across all dimensions. In particular, the higher the musical engagement, the higher scores were found for the facet of musical pleasure related to the sharing of musical activities, especially in the earliest stages of adolescence. Furthermore, we found that sensitivity to music generally tends to increase with age, and that girls reported overall to be more sensitive to music than boys in the dimension related to evocation of emotions. A slightly different model of the BMRQ has to be taken into account when testing the Danish adolescent population. In addition to utilizing the Danish version of the BMRQ on a large sample of adolescents, this study may provide insight into the relationship between changes in the level of musical reward depending on amount of musical engagement and how musical reward unfolds within and between genders and across age groups during this developmental stage.

Song-like activation of syringeal and respiratory muscles during sleep in canaries.

Sleep replay activity involves the reactivation of brain structures with patterns similar to those observed during waking behavior. In this study, we demonstrate that adult male canaries exhibit spontaneous, song-like peripheral reactivation during night sleep. Our findings include: (1) the presence of activity in respiratory muscles, leading to song-like air sac pressure patterns of low amplitude, (2) the simultaneous occurrence of respiratory replay events and reactivation of syringeal muscles, and (3) the reactivation of syringeal muscles without concurrent respiratory system activity. This song-like reactivation of peripheral motor systems enables the identification of specific motor patterns, with replay events preserving individual morphological and temporal properties. The activation of peripheral motor systems in songbirds and the differences in activation patterns between species give unique insights into the fictive behavioral output of activation of a complex learned motor behavior during sleep, shedding light on the neural control mechanisms and potential functions.

Sonocatalysis Regulates Tumor Autophagy for Enhanced Immunotherapy.

Immunotherapy stands as a groundbreaking strategy for cancer treatment, due to its ability to precisely and safely detect and eradicate tumors. However, the efficacy of immunotherapy is often limited by tumor autophagy, a natural defense mechanism that tumors exploit to resist immune attacks. Herein, we introduce a spatiotemporally controlled method to modulate tumor autophagy via sonocatalysis, aiming to improve immunotherapeutic outcomes. Specifically, we synthesized a tumor-targeting nanocatalyst based on a semiconductor heterojunction composed of Barium Titanate (BTO), Black Phosphorus (BP) integrated with Hyaluronic Acid (HA), referred to as BTO/BP-HA. Compared to traditional catalysts, the heterojunction structure enhances energy band bending and rapid electron-hole separation under ultrasonic stimulation, splitting water to generate H2. This promotes tumor cell apoptosis by inhibiting mitochondrial respiration and induces immunogenic cell death, triggering immune responses to eliminate tumor cells. However, the concurrent activation of autophagy mitigates the cytotoxic effectiveness of nanocatalysts. Within the nanocatalyst, BP undergoes lysosomal degradation to generate PO43-, which subsequently interacts with H+ to generate a conjugated acidic anion, increasing the lysosomal pH. This research ingeniously combines sonocatalysis with tumor autophagy, disrupting the activity of acidic hydrolases to inhibit autophagy, thereby enhancing the immune response and improving the effectiveness of immunotherapy.

Ash deposits link Oceanic Anoxic Event 2 to High Arctic volcanism

Oceanic Anoxic Event 2 (OAE 2) was a major environmental perturbation that occurred ∼94 million years ago. It is associated with profound changes in global climate and carbon cycling, which are commonly attributed to large-scale carbon release from large igneous province (LIP) volcanism. However, the specific LIP(s) involved and the mechanisms of carbon release remain poorly understood, as indicated by discrepancies between carbon release rates suggested by numerical models and LIP degassing estimates. Our study refines the eruptive history of the High Arctic large igneous province (HALIP) by dating ashfall deposits in marine sediments from the Canadian High Arctic using an integrated stratigraphic approach. Our results show that silicic HALIP volcanism began tens of thousands of years before OAE 2, suggesting a strong causal link. Volcanic activity coincides with a marked shift in carbon isotope values, linked to the degassing of HALIP magmas and/or thermogenic gas release. We propose that the concurrent activity of two LIPs—the HALIP and the Kerguelen Plateau—could account for the high rates of carbon release inferred for OAE 2, providing a hypothesis for its pervasive environmental impact.

7972 A Shared Phenotype, Transcriptome, and Methylome in Turner Syndrome Across Various Karyotypes with Concurrent Chronic Neutrophil Activation

Abstract Disclosure: J. Just: None. L. Ridder: None. E. Johannsen: None. H. Christensen: None. A. Skakkebæk: None. C.H. Gravholt: None. Turner syndrome (TS) is a clinical diagnosis with a karyotype containing one X chromosome and complete or partial absence of the second X chromosome. TS is typically associated with clinical manifestations such as short stature, hypergonadotropic hypogonadism and metabolic conditions. The genome-wide changes in females with TS affect both transcriptome and methylome. Historically, genomic studies have primarily focused on the 45,X karyotype, leaving the impact of other karyotypes unexplored. Only 35-45% of the entire TS population has the 45,X karyotype, while the remaining TS women have a range of other karyotypes - i.e. 45,X/46,XX, 46,X,i(Xq), 46,X,i(Xp), 45,X/46,XY, ring X. This study aimed to bridge this gap by comparing TS individuals with the standard 45,X karyotype (TS 45,X) (n = 32) to those with alternative karyotypic forms (TS other karyotypes) (n = 24), alongside age-matched 46,XX controls (n = 33). Specifically, we analyzed the DNA methylation and gene expression profiles from whole-blood samples and explored the genetic and clinical similarities between these groups. Overall findings revealed a shared phenotype and an identical autosomal transcriptome and methylome between TS 45,X and TS other karyotypes. Furthermore, TS 45,X and TS other karyotypes shared the same expression profile for all pseudoautosomal 1 (PAR1) genes on the X chromosome. In addition, the expression of XIST from the q-arm of the X chromosome did not affect the autosomal transcriptome or methylome. Thus, the X chromosomal p-arm, and perhaps in particular PAR1, appear to be a main driver influencing the genome-wide transcriptome and methylome Combining DNA methylation, gene expression and white blood cell counts, we observed a higher neutrophil count (p < 0.01), and increased neutrophil activation in the combined TS group. The increased neutrophil activity, based on increased gene expression of neutrophil activation markers (myeloperoxidase, neutrophil elastase, S100A8/9, p < 0.01), suggested a pathological activation of neutrophils with concomitant release of pro-inflammatory mediators. We further validated the increase of neutrophils in TS women in an independent cohort using flow cytometry (p < 0.01). Emerging evidence has highlighted the substantial involvement of neutrophils in chronic inflammatory processes associated with metabolic diseases such as obesity and diabetes, which triggers a sustained low-grade inflammation partially driven by activated neutrophils. The neutrophil increase and activation in TS women may offer an explanation for this phenotypic trait observed in TS women. Therefore, identifying TS women with increased neutrophil activation in order to initiate anti-inflammatory treatment earlier could potentially mitigate the progression towards more severe metabolic disturbances and associated co-morbidities. Presentation: 6/1/2024

Sulfate Radical Based In Situ Vaccine Boosts Systemic Antitumor Immunity via Concurrent Activation of Necroptosis and STING Pathway.

In situ vaccine (ISV) can provoke systemic anti-tumor immunity through the induction of immunogenic cell death (ICD). The development of ISV technology has been restricted by the limited and suboptimal ICD driven tumor antigen production which are currently relying on chemo-drugs, photo-/radio-sensitizers, oncolytic-virus and immunostimulatory agents. Herein, a sulfate radical (SO4 ·-) based ISV is reported that accomplishes superior tumor immunotherapy dispense from conventional approaches. The ISV denoted as P-Mn-LDH is constructed by intercalating peroxydisulfate (PDS, a precursor of SO4 ·-) into manganese layered double hydroxide nanoparticles (Mn-LDH). This design allows the stabilization of PDS under ambient condition, but triggers a Mn2+ mediated PDS decomposition in acidic tumor microenvironment (TME) to generate in situ SO4 ·-. Importantly, it is found that the SO4 ·- radicals not only effectively kill cancer cells, but also induce a necroptotic cell death pathway, leading to robust ICD signaling for eliciting adaptive immunity. Further, the P-Mn-LDH can activate the stimulator of interferon genes (STING) pathway to further boost anti-tumor immunity. Collectively, the P-Mn-LDH based ISV exhibited potent activity in inhibiting tumor growth and lung metastasis. When combined with immune checkpoint inhibitor, significant inhibition of distant tumors is achieved. This study underpins the promise of SO4 ·- based vaccine technology for cancer immunotherapy.

Tectonic evolution and structural geology of the Jurassic succession in the Zubair oil field, southern Iraq

This study investigates the structural style and tectonic evolution of Jurassic succession in southern Iraq, within the Zubair oil field, which are crucial for charging oil to the Cretaceous reservoirs, utilized 3-D seismic reflection data to explore its complex geological history. The field is located in the Mesopotamian plain on the northeast Arabian Plate in southern Iraq. Four folds recognized: Hammar, Shuaiba, Rafdyia, and Safwan, each shaped by specific geodynamic processes. Hammar, Shuaiba, and Safwan are characterized as salt-related folds, influenced by salt tectonics. Rafdyia is identified as a compression-related fold formed due to the convergence of the Arabian and Eurasian plates. Forty-seven faults were identified, with diversity patterns and spatial distributions suggesting a tectonic history marked by three distinct phases: extensional tectonics, extensional with concurrent salt activity, and plate convergence. These phases have created a series of graben structures that, along with the identified folds, highlight the role of three primary tectonic processes: basement tectonics, salt dynamics, and plate interactions in shaping the structural style of the Zubair oil field during the Jurassic time.

Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity.

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

Palladium(0) and Brønsted Acid Co-Catalyzed Enantioselective Hydro-Cyclization of 2,4-Dienyl Hydrazones and Oximes.

The transition metal-catalyzed asymmetric hydro-functionalization of 1,3-dienes has been well explored, but most reactions focus on electron-neutral substrates in an intermolecular manner. Here we first demonstrate that readily available 2,4-dienyl hydrazones and oximes can be efficiently utilized in the hydro-cyclization reaction under co-catalysis of a Brønsted acid and a chiral palladium complex, furnishing multifunctional dihydropyrazones and dihydroisoxazoles, respectively. Diverse substitution patterns for both types of electron-deficient diene compounds are tolerated, and corresponding heterocycles were generally constructed with moderate to excellent enantioselectivity, which can be elaborated to access products with higher molecular complexity and diversity. Control experiments and density functional theory calculations support that α-regioselective protonation of dienyl substrates by acid and concurrent π-Lewis base activation of Pd0 complex is energetically favoured in the formation of active π-allylpalladium intermediates, and an outer-sphere allylic amination or etherification mode is adopted to deliver the observed cyclized products enantioselectively.

Atopic dermatitis and tobacco smoke exposure during childhood and adolescence

Tobacco smoke may affect atopic dermatitis (AD) because of its known effects on humoral and cellular immunity, but prior studies lack data on disease severity and biomarkers over time. We investigated the association between passive and active tobacco smoke exposure (TSE) during childhood and adolescence and the activity and severity of AD. A birth cohort of 10,521 individuals was followed through adolescence as part of the Avon Longitudinal Study of Parents and Children. We used mixed-effect models to determine the risk of AD (based on repeated assessments) with passive smoke exposure during childhood, active TSE during adolescence, and using a serum biomarker of tobacco exposure (cotinine) at 3 time points. After adjusting for confounding factors, there was no evidence of a relationship between passive TSE and concurrent AD activity in childhood (adjusted odds ratio, 0.95; 95% confidence interval, 0.83, 1.07) or of an increased risk between active smoking and AD activity in adolescence (adjusted odds ratio, 0.57; 95% confidence interval, 0.44, 0.75). Secondary analyses demonstrated no dose-response relationship and no increased severity of AD with passive or active TSE. Furthermore, we found no increased risk of AD with a cumulative measure of passive TSE across childhood (adjusted relative risk ratio, 0.98; 95% confidence interval, 0.96, 1.00). Neither active nor passive TSE was associated with AD during childhood and adolescence.