bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure‐Based Design of Ultrapotent Tricyclic Ligands for FK506‐Binding Proteins
Authors: Krajczy Patryk , Meyners Christian , Repity Maximilian L. , Hausch Felix
Published: June 2024

Access to small, rigid, and sp3‐rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506‐binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate‐mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14‐step gram‐scale synthesis featuring anodic oxidation, stereospecific vinylation, and N‐acyl iminium cyclization. Structure‐based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.
The ratio of intratumoral CD15+ neutrophils to CD8+ lymphocytes predicts recurrence in patients with gastric cancer after curative resection
Authors: Watanabe Junichiro , Kimura Takashi , Saze Zenichiro , Sato Naoya , Kofunato Yasuhide , Ishigame Teruhide , Okada Ryo , Kenjo Akira , Kono Koji , Marubashi Shigeru
Published: June 2024

Background

An elevated neutrophil‐to‐lymphocyte ratio (NLR) in peripheral blood is an independent prognostic indicator of various cancers.

Aims

In this study, we aimed to investigate the prognostic relevance of the intratumoral immune cell balance in gastric cancer.

Methods and Results

The study included 82 patients who underwent curative resection for gastric cancer. The intratumoral cluster of differentiation (CD) 15‐ and CD8‐positive cells were evaluated using immunohistochemical staining. Additionally, clinicopathological factors and prognoses were analyzed. Patients with high intratumoral CD15/CD8 ratios had significantly lower overall survival (OS) and relapse‐free survival (RFS) compared to those with low CD15/CD8 ratios (p = .0026 and p < .0001, respectively). Additionally, a high CD15/CD8 ratio was associated with lymph node metastasis (p = .019). Patients with high NLR had a significantly lower RFS than those with low NLR (p = .0050). Multivariate analysis revealed that the intratumoral CD15/CD8 ratio, NLR, and venous invasion were independent prognostic indicators of RFS (CD15/CD8 ratio: p < .001, hazard ratio (HR) = 14.7, 95% confidence interval (CI) = 3.8–56.8; NLR: p = .010, HR = 5.4, 95% CI = 1.5–19.6; venous invasion: p = .005, HR = 7.4, 95% CI = 1.8–29.7).

Conclusion

In summary, we found that the intratumoral CD15/CD8 ratio is an independent prognostic factor following gastric cancer resection and its increase is associated with lymph node metastasis and microscopic lymph vessel invasion. Immunological evaluation with additional aspects of innate immunity may be useful in predicting cancer prognosis.
Genetic and immune identification and functional analysis of TRPM8 as a potential biomarker for pancreatic adenocarcinoma proliferation
Authors: Qiao Sen , Wu Fengming , Wang Hongmei
Published: June 2024

Background

Pancreatic adenocarcinoma (PAAD), a member of highly lethal malignant tumors, has a poor outcome and extremely poor prognosis. The transient receptor potential (TRP) superfamily, a group of nonselective cation channels, is capable of influencing cellular functions by regulating calcium homeostasis. In addition, it has been shown that TRP channels can also affect various cellular phenotypes by regulating gene transcription levels and are involved in the development of a variety of malignant tumors.

Aims

In order to find new therapeutic targets and biomarkers to improve the clinical prognosis of pancreatic cancer, we performed genetic and immunological characterization of TRP channels in PAAD, as well as related functional and prognostic analyses.

Methods and Results

We investigated the expression, genetic alterations, methylation levels, and immune infiltration levels of TRP channels in PAAD, and further also analyzed the function of TRP channels in PAAD and their prognostic value for PAAD patients. Our results suggest that TRPM8 may contribute to tumor proliferation by controlling the PI3K‐AKT–mTOR signaling pathway in PAAD.

Conclusion

After careful evaluation of the accumulated data, we concluded that TRPM8 has potential as a prognostic indicator and prospective therapeutic target in PAAD.
IoT based sensor network clustering for intelligent transportation system using meta‐heuristic algorithm
Authors: Malik Aruna , Singh Samayveer , Manju  , Kumar Mohit , Gill Sukhpal Singh
Published: June 2024

Internet of Things (IoT) based sensor networks have been established as a pillar in intelligent communication systems for efficiently handling roadside congestion and accidents. These IoT networks sense, collect, and process data on a real‐time basis. However, IoT based sensor network clustering has various energy constraints such as inefficient routing due to long‐haul transmission, hot spot problem, network overhead, and unstable network whenever deployed along with the roadside that affect their architecture. In such networks, clustering techniques play a crucial role in extending the lifespan and optimizing the routes by integrating sensor devices through clusters. Therefore, a meta‐heuristic algorithm for clustering in IoT sensor networks for an intelligent transportation system is proposed. In this work, the seagull optimization algorithm is applied for clustering by considering residual and average energy, node spacing, and distance fitness parameters. Moreover, this work also considers the dynamic communication range of the cluster heads for increasing the stability period and lifetime of the proposed networks. The experiment results demonstrate that the proposed Seagull optimization algorithm for clustering in IoT networks (SOAC‐IoTNs) and Seagull optimization algorithm for clustering in IoT networks with dynamic communication range (SOAC‐IoTNs‐DR) achieve a significant increase in the stability period and network lifetime, with percentage increments of 55.68% and 71.47%, and 10.03% and 88.66% respectively, compared to the existing optimized genetic algorithm for cluster head selection with single static sink (OptiGACHS‐StSS).
Topology derivation and control method of high‐reliability buck‐boost double‐grounded transformerless three‐phase inverters
Authors: Yao Zhilei , Yang Mengwei
Published: June 2024

As the traditional transformerless three‐phase (TTP) inverters have the shoot‐through and common mode leakage current (CMLC) problems, as well as not being able to realize the buck‐boost conversion, topology derivation and control method of high‐reliability buck‐boost double‐grounded TTP inverters are proposed. These topologies consist of two‐port or three‐port converters with boost capability and three dual‐buck inverters. The two‐port or three‐port converters with boost capability provide the positive and negative bus voltages for the three dual‐buck inverters, realizing the boost conversion. The dual‐buck inverters address the shoot‐through problem. The double‐grounded structure is used to solve the CMLC problem. Dead time between switches is not needed, which reduces the complexity of the control system. Detailed topology derivation of the dual‐buck double grounded TTP inverters with boost capability is given. The operating principle, parameters design of the filters, and stability analysis of this inverter are analyzed in detail. Loss analysis of the inverter is given. The simulation and experimental results of a 750‐W TTP inverter are used to verify the theoretical analysis.
Potential diagnostic and distinguishing roles of microneedle‐based biosensors in bacterial and aseptic meningitis
Authors: Sadeghi Hamid , Gheibi Nematollah , Aslanimehr Masoumeh , Khoei Saeideh Gholamzadeh , Badri Milad
Published: June 2024

Meningitis, which is defined by inflammation of the meninges, is a major cause of death and morbidity worldwide. Traditional diagnostic approaches, such as imaging procedures and the study of cerebrospinal fluid, are intrusive, time consuming and sometimes non‐specific. The suggested approach entails creating a biosensor based on microneedles that can detect in real time without the requirement for labels. The biosensor uses highly sensitive detection techniques to detect changes in ionic current and modulation of impedance in response to biomolecules that are of interest, such as proteins and nucleic acids, which are linked to meningitis infections. Initial studies have shown that the microneedle‐based biosensor for meningitis diagnosis is both feasible and effective. When it comes to identifying bacterial and aseptic meningitis biomarkers from blood and cerebrospinal fluid (CSF) samples, the biosensor showed excellent sensitivity and specificity. This novel technique has the potential to enhance patient outcomes by facilitating prompt intervention and tailored therapy by offering a quick, safe and accurate way to distinguish between bacterial and aseptic meningitis. To maximise the biosensor's performance and confirm its therapeutic usefulness in various contexts, more investigations and advancements are necessary.
Polarization reconfigurable transmitarray antenna utilizing single‐layer Huygen element for Ku‐band satellite communication
Authors: Ahmad Ganie Javid , Saurav Kushmanda
Published: June 2024

This paper introduces a concept for designing a polarization reconfigurable transmitarray (PRT). The unit cell of the transmitarray utilizes Huygen elements, with dimensions measuring 0.6
(
corresponds to a frequency of 15 GHz). An equivalent circuit model is proposed for the unit cell based on the two‐port Z‐matrix. The proposed unit cells have a very low insertion loss of 0.5 dB at 15 GHz. The PRT is illuminated by a linearly polarized (LP) microstrip‐printed Yagi antenna. The transmitarray is designed using the
proposed unit cells with a two‐level phase quantization. The collimated LP radiation emitted by the transmitarray subsequently traverses a polarization reconfigurable converter (PRC). The resultant radiation from the PRC can be either LP or circularly polarized (CP), contingent on the configuration of the PIN diodes employed within the PRC. The proposed PRT demonstrates a measured gain of 16 dBi when operating in the LP mode while achieving a peak gain of 15 dBic in the CP mode. The overall size of the proposed PRT is compact owing to a small f/d ratio (0.58). The practicality of the design is validated through fabrication and measurement. This innovative antenna design holds potential applications in the realm of Ku‐band uplink satellite communication.
Sex differences in acute early life stress‐enhanced fear learning in adult rats
Authors: Minshall Brianna L. , Skipper Rachel A. , Riddle Collin A. , Wasylyshyn Catherine F. , Claflin Dragana I. , Quinn Jennifer J.
Published: June 2024

Patients diagnosed with posttraumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms resulting from exposure to trauma. Women are twice as likely to be diagnosed with anxiety and PTSD compared to men; however, the reason for this vulnerability remains unknown. We conducted four experiments where we first demonstrated a female vulnerability to stress‐enhanced fear learning (SEFL) with a moderate, acute early life stress (aELS) exposure (4 footshocks in a single session), compared to a more intense aELS exposure (15 footshocks in a single session) where males and females demonstrated comparable SEFL. Next, we demonstrated that this female vulnerability does not result from differences in footshock reactivity or contextual fear conditioning during the aELS exposure. Finally, using gonadectomy or sham surgeries in adult male and female rats, we showed that circulating levels of gonadal steroid hormones at the time of adult fear conditioning do not explain the female vulnerability to SEFL. Additional research is needed to determine whether this vulnerability can be explained by organizational effects of gonadal steroid hormones or differences in sex chromosome gene expression. Doing so is critical for a better understanding of increased female vulnerability to certain psychiatric diseases.
Associations between adversity in the family of origin and hair cortisol concentration in adulthood
Authors: Neppl Tricia K. , Diggs Olivia N. , Lohman Brenda J. , Lee Jeenkyoung , Russell Daniel , Bronikowski Anne M.
Published: June 2024

The current study examined associations between parental adversities as experienced in adolescence and hair cortisol concentration (HCC) 26 years later (n = 47). Specifically, bivariate correlations and linear regressions were used to examine harsh parenting as well as parental economic pressure, emotional distress, and body mass index (BMI) when their adolescent was between 15 and 16 years old (parent average age 43). HCC was measured when the adolescent was an adult (average 42 years old), at a similar age to when their parent(s) first participated in the study. We also assessed their economic pressure, emotional distress, obesity, and perceived stress in adulthood. For results across generations, parental economic pressure experienced during adolescence was significantly related to HCC when these adolescents were adults. None of the adult economic pressure, emotional distress, BMI, and perceived stress variables were associated with their HCC. Interestingly, there were significant associations among adult perceived stress, economic pressure, emotional distress, and obesity. Thus, the association between parental economic pressure and adult HCC is independent of adult adversities. Results highlight early economic adversity as a possible childhood stressor that has implications throughout the life course.
RSA instability in mothers of preschoolers and adolescents is related to observations of supportive parenting behaviors
Authors: Hale Molly E. , Morrow Kayley E. , Xu Jianjie , Han Zhuo Rachel , Oshri Assaf , Shaffer Anne , Caughy Margaret O. , Suveg Cynthia
Published: June 2024

Respiratory sinus arrhythmia (RSA; a measure of respiratory modulation of vagal control of heart rate) is a dynamic process. For mothers, RSA functioning has been associated with depressive symptoms and coincides with supportive parenting. However, research has largely focused on RSA suppression (i.e., difference score from rest to stress task). The present study examined depressive symptoms and supportive parenting with RSA instability—a dynamic measure of the magnitude of RSA change across a task. In two samples of mothers (N = 210), one with preschoolers (Study 1: n = 108, Mage = 30.68 years, SD = 6.06, 47.0% Black, 43.0% White) and one with adolescents (Study 2: n = 102, Mage = 35.51, SD = 6.51, 75.2% Black), RSA instability was calculated during an interaction task. In both studies, instrumental supportive parenting behaviors were negatively related to RSA instability. Findings provide preliminary support for RSA instability as an indicator of physiological dysregulation for mothers.
Understanding mental health in developmental dyslexia through a neurodiversity lens: The mediating effect of school‐connectedness on anxiety, depression and conduct problems
Authors: Wilmot Adrienne , Hasking Penelope , Leitão Suze , Hill Elizabeth , Boyes Mark
Published: June 2024

Dyslexia, a neurocognitive difference characterised by poor word‐reading, is associated with elevated risk for internalising (e.g., anxiety) and externalising (e.g., aggression) mental health concerns, the reasons are largely unknown. We took a neurodiversity perspective and explored whether school‐connectedness mediated these associations. A total of 283 primary school children (87 with dyslexia) and their caregivers (95.4% mothers) completed a battery of well‐validated connectedness and mental health measures. Two mediation models (one for child‐report and one for caregiver‐report) tested direct and indirect effects of dyslexia on anxiety, depression and conduct problems via several domains of school‐connectedness. After controlling for gender and neurodevelopmental conditions other than dyslexia, there were no direct effects of dyslexia on child‐ or caregiver‐reported internalising symptoms or child‐reported conduct problems. Dyslexia was associated with child and caregiver reported anxiety, depression and conduct problems via low levels of school (but not teacher, friend or peer) connectedness. Findings highlight school‐connectedness as an important intervention target for the mental health of children with dyslexia. Future research is needed to test associations between dyslexia, school‐connectedness and mental health over time.
Proactive cursorial and ambush predation risk avoidance in four African herbivore species
Authors: Bennitt Emily , Bartlam‐Brooks Hattie L. A. , Hubel Tatjana Y. , Jordan Neil R. , McNutt John W. , Wilson Alan M.
Published: June 2024

Most herbivores must balance demands to meet nutritional requirements, maintain stable thermoregulation and avoid predation. Species‐specific predator and prey characteristics determine the ability of prey to avoid predation and the ability of predators to maximize hunting success. Using GPS collar data from African wild dogs, lions, impala, tsessebes, wildebeest and zebra in the Okavango Delta, Botswana, we studied proactive predation risk avoidance by herbivores. We considered predator activity level in relation to prey movement, predator and prey habitat selection, and preferential use of areas by prey. We compared herbivore behaviour to lion and wild dog activity patterns and determined the effect of seasonal resource availability and prey body mass on anti‐predator behaviour. Herbivore movement patterns were more strongly correlated with lion than wild dog activity. Habitat selection by predators was not activity level dependent and, while prey and predators differed to some extent in their habitat selection, there were also overlaps, probably caused by predators seeking habitats with high prey abundance. Areas favoured by lions were used by herbivores more when lions were less active, whereas wild dog activity level was not correlated with prey use. Prey body mass was not a strong predictor of the strength of proactive predation avoidance behaviour. Herbivores showed stronger anti‐predator behaviours during the rainy season when resources were abundant. Reducing movement when top predators are most active and avoiding areas with a high likelihood of predator use during the same periods appear to be common strategies to minimize predation risk. Such valuable insights into predator–prey dynamics are only possible when using similar data from multiple sympatric species of predator and prey, an approach that should become more prevalent given the ongoing integration of technological methods into ecological studies.
Fabrication of a Highly Efficient and Reusable Pd/Al2O3/Al Monolithic Catalyst for the Suzuki‐Miyaura Reaction
Authors: Pan Shiguang , Hu Beibei , Liu Dan , Kuvarega Alex T. , Mamba Bhekie B. , Gui Jianzhou
Published: June 2024

Anodization was employed to treat the aluminum foil surface, leading to in situ the generation of Al2O3, consequently amplifying the specific surface area to aid in the dispersal of palladium nanoparticles. Through the anodic oxidation of aluminum followed by a precipitation‐deposition and calcination process, a highly efficient and reusable Pd/Al2O3/Al monolithic catalyst was synthesized. The effectiveness and reusability of the Pd/Al2O3/Al monolithic catalyst were evaluated in the Suzuki‐Miyaura reaction. The turnover number (TON) and turnover frequency (TOF) of the Pd/Al2O3/Al monolithic catalyst reached 73,880 and 0.86 s−1, respectively. Furthermore, the catalyst could be recovered and reused in reactions regardless of the used substrates.
Pomegranate seed as a novel source of plant protein: Optimization of protein extraction and evaluation of in vitro digestibility, functional, and thermal properties
Authors: Oroumei Souri , Rezaei Karamatollah , Chodar Moghadas Hooman
Published: June 2024

This research was carried out to optimize the extraction process of proteins from pomegranate seeds and characterize their in vitro digestibility as well as their thermal and functional properties. For this purpose, the study screened five parameters (liquid/solid ratio, pH, temperature, NaCl concentration, and time) that could potentially influence the extraction process. This screening was conducted using a two‐level Placket–Burman design (PBD). The significant parameters (pH and NaCl concentration) were subsequently optimized using a three‐level face‐centered central composite design (FCCD) to determine the optimum extraction conditions. A maximum protein recovery of 83.8% was obtained at pH 11.0 and NaCl concentration of 0.0 M. Pomegranate seed protein isolate (PSPI) with a protein content of 92.4% (w/w) was obtained through the isoelectric precipitation of pomegranate seed protein extracted under the optimized conditions. An emulsifying activity index of 14.1 m2 g−1 was observed at the isoelectric pH, where the emulsion stability index was at 8.2%. PSPI also showed high water‐ and oil‐holding capacities (3.7 and 4.3 g g−1, respectively). The essential amino acid levels in PSPI (except for valine and isoleucine) exceeded the recommended amounts set by WHO/FAO/UNU for adults, highlighting its high nutritional value. Based on thermal analysis data, denaturation of PSPI could occur at 89.5°C. The in vitro digestibility of PSPI was found to be 74.3%. PSPI shows a potential as a novel ingredient for substituting animal‐based proteins in various food applications.
Low rate hippocampal delay period activity encodes behavioral experience
Authors: Athanasiadis Markos , Masserini Stefano , Yuan Li , Fetterhoff Dustin , Leutgeb Jill K. , Leutgeb Stefan , Leibold Christian
Published: June 2024

Remembering what just happened is a crucial prerequisite to form long‐term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short‐term memory. Using a classifier‐based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low‐rate predictive patterns are present in both working memory and non‐working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory‐motor context.
Chemical hazard assessment toward safer electrolytes for lithium-ion batteries
Authors: Schwaebe Branden , He Haoyang , Glaubensklee Christopher , Ogunseitan Oladele A. , Schoenung Julie M.
Published: June 2024

Commercialization of rechargeable lithium-ion (Li-ion) batteries has revolutionized the design of portable electronic devices and is facilitating the current transition to electric vehicles. The technological specifications of Li-ion batteries continue to evolve through the introduction of various high-risk liquid electrolyte chemicals, yet critical evaluation of the physical, environmental, and human health hazards of these substances is lacking. Using the GreenScreen for Safer Chemicals approach, we conducted a chemical hazard assessment (CHA) of 103 electrolyte chemicals categorized into seven chemical groups: salts, carbonates, esters, ethers, sulfoxides–sulfites–sulfones, overcharge protection additives, and flame-retardant additives. To minimize data gaps, we focused on six toxicity and hazard data sources, including three empirical and three nonempirical predictive data sources. Furthermore, we investigated the structural similarities among selected electrolyte chemicals using the ChemMine tool and the simplified molecular input line entry system inputs from PubChem to evaluate whether chemicals with similar structures exhibit similar toxicity. The results demonstrate that salts, overcharge protection additives, and flame-retardant additives contain the most toxic components in the electrolyte solutions. Furthermore, carbonates, esters, and ethers account for most flammability hazards in Li-ion batteries. This study supports the complementary use of quantitative structure–activity relationship models to minimize data gaps and inconsistencies in CHA. Integr Environ Assess Manag 2024;20:2231–2244. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Key Points

Chemical hazard assessment was conducted for 103 electrolyte chemicals, categorized into seven groups, used in lithium-ion batteries. Most of the 103 electrolyte chemicals exhibited high levels of concern relative to human health and environmental hazard endpoints. Nonempirical predictive data sources are essential for filling data gaps commonly encountered in empirical data sources. Structure similarity analysis highlights that chemicals with structure similarity correlate with similar hazard endpoints, increasing the value of predictive data sources.
The scientific tale of the nexus between oil prices, macroeconomic uncertainty and Pakistan's exports to its major trading partners: Insights from advanced methods
Authors: Chishti Muhammad Zubair
Published: June 2024

The recent study aims to analyze the nonlinear dynamic effects of oil price shocks and macroeconomic uncertainty on exports. To achieve this, the study utilizes monthly data from July 2003 to December 2020 on oil prices and macroeconomic uncertainty, examining their impact on Pakistan's exports to its major trading partners. To ensure detailed and robust findings, the study employs various advanced econometric tools, including quantile unit root, cointegration, Granger causality tests, and quantile‐on‐quantile regression (QQR) and wavelet quantile correlation (WQC) techniques. The QQR and WQC estimates reveal diverse and nonlinear effects of oil price shocks and macroeconomic uncertainty on exports, reflecting the complexity of the relationship. While oil price shocks (OP) predominantly hinder exports in most cases, a significant and positive association between OP and exports is also observed. Similarly, macroeconomic uncertainty generally exhibits a significantly adverse influence on exports, but positive impacts are also evident. Furthermore, the quantile Granger causality test confirms the presence of a bidirectional causal relationship between the selected series. Based on the results mentioned above, the study argues that the effects of oil price shocks and economic uncertainty are nonlinear, diverse, and complex. As a result, the study suggests implementing phase‐wise policy recommendations to address these complexities.
Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open‐Label, Single‐Dose, Crossover Study in Healthy Adults
Authors: Hynes Scott M. , Goldsberry Angie , Henneghan Patrick D. , Murai Masako , Shinde Aparna , Wells Jason A. , Wu Lucy , Wu Tony , Zahir Hamim , Khan Seemi
Published: June 2024

Omaveloxolone (SKYCLARYS®) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50‐mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150‐mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (Cmax), AUC0‐t, and AUC0‐∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median tmax, 10 h) compared with sprinkled capsule contents over applesauce (median tmax, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4‐h difference in tmax is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information.
Reducing stigma and promoting HIV wellness/mental health of sexual and gender minorities: RCT results from a group‐based programme in Nigeria
Authors: Pulerwitz Julie , Gottert Ann , Tun Waimar , Eromhonsele Anita Fernandez , Oladimeji Progress Lanre , Shoyemi Elizabeth , Akoro Mauton , Ndeloa Columbus , Adedimeji Adebola
Published: June 2024

Introduction

High levels of HIV stigma as well as stigma directed towards sexual and/or gender minorities (SGMs) are well documented in the African setting. These intersecting stigmas impede psychosocial wellbeing and HIV prevention and care. Yet, there are few if any evidence‐based interventions that focus on reducing internalized stigma and promoting mental health and HIV wellness for SGMs in Africa. We developed and evaluated a group‐based intervention drawing on cognitive behavioural therapy (CBT) strategies for men who have sex with men (MSM) and transgender women (TGW) at risk for or living with HIV in Lagos, Nigeria.

Methods

The intervention comprised four weekly in‐person group sessions facilitated by community health workers. We conducted a delayed intervention group randomized controlled trial (April−September 2022), with pre‐post surveys plus 3‐month follow‐up (immediate group only), as well as qualitative research with participants and programme staff. Outcomes included internalized stigma related to SGM and HIV status, depression, resiliency/coping and pre‐exposure prophylaxis (PrEP)/HIV treatment use.

Results

Mean age of the 240 participants was 26 years (range 18−42). Seventy‐seven percent self‐identified as MSM and 23% TGW; 27% were people with HIV. Most (88%) participants attended all four sessions, and 98% expressed high intervention satisfaction. There was significant pre‐post improvement in each psychosocial outcome, in both the immediate and delayed arms. There were further positive changes for the immediate intervention group by 3‐month follow‐up (e.g. in intersectional internalized stigma, depression). While baseline levels of ever‐PrEP use were the same, 75% of immediate‐group participants reported currently using PrEP at 3 months post‐intervention versus 53% of delayed‐group participants right after the intervention (p<0.01). Participants post‐intervention described (in qualitative interviews) less self‐blame, and enhanced social support and resilience when facing stigma, as well as motivation to use PrEP, and indicated that positive pre‐intervention changes in psychosocial factors found in the delayed group mainly reflected perceived support from the study interviewers.

Conclusions

This study demonstrated the feasibility and acceptability of a group‐based CBT model for MSM and TGW in Nigeria. There were also some indications of positive shifts related to stigma, mental health and PrEP, despite issues with maintaining the randomized design in this challenging environment.
Unveiling the metabolic and coagulation disruptions in SARS‐CoV‐2‐associated acute macular neuroretinopathy: A case–control study
Authors: Xiong Xiaojing , Zheng Zheng , Liu Chunlin , Wang Xinyu , Luo Shuai , Xie Qinqin , Liu Yang , Chen Qingwei , Zheng Minming
Published: June 2024

SARS‐CoV‐2 infection has been associated with the increased incidence of acute macular neuroretinopathy (AMN), an infrequent ocular disorder. However, the precise mechanisms underpinning AMN in the context of SARS‐CoV‐2 infection (AMN‐SARS‐CoV‐2) remain elusive. In this case–control study, 14 patients diagnosed with AMN‐SARS‐CoV‐2 between 2022/12 and 2023/3 were enrolled and compared with 14 SARS‐CoV‐2‐infected individuals without AMN, who served as controls (SARS‐CoV‐2‐no AMN). Metabolomic profiling using ultrahigh‐performance liquid chromatography‐online electrospray mass spectrometry revealed significant alterations in serum metabolites in AMN‐SARS‐CoV‐2 patients. Coagulation abnormalities were observed in AMN‐SARS‐CoV‐2 patients, and their relationship with metabolic disorders was studied. Finally, a predictive model for AMN‐SARS‐CoV‐2 was established. Seventy‐six upregulated and 42 downregulated metabolites were identified in AMN‐SARS‐CoV‐2 cases. Notably, arginine metabolism within the urea cycle was significantly altered, evidenced by variations in ornithine, citrulline, 
l‐proline, and ADAM levels, correlating with abnormal coagulation markers like platelet crit, fibrinogen degradation product, and fibrinogen. Additionally, increased arginase 1 (AGR1) activity within the urea cycle and reduced nitric oxide synthase activity were observed in AMN‐SARS‐CoV‐2. The integration of urea cycle metabolite levels with coagulation parameters yielded a robust discriminatory model for AMN‐SARS‐CoV‐2, as evidenced by an area under the curve of 0.96. The findings of the present study enhance our comprehension of the underlying metabolic mechanisms associated with AMN‐SARS‐CoV‐2 and offer potential diagnostic markers for this uncommon ocular disorder within the context of SARS‐CoV‐2 infection.
Acute pancreatitis in children with inflammatory bowel disease: Risk factors, clinical course, and prognosis
Authors: Anafy Adi , Mirkin Yehoshua , Galai Tut , Ben‐Tov Amir , Moran‐Lev Hadar , Yerushalmy‐Feler Anat , Cohen Shlomi , Amir Achiya Z.
Published: June 2024

Objectives

To characterize the clinical course of acute pancreatitis (AP) in pediatric inflammatory bowel disease (IBD) patients compared to children with AP without IBD and to identify risk factors associated with AP among IBD patients.

Methods

This retrospective, single‐center study compared clinical characteristics of children (<19 years) with AP with and without concomitant IBD who were hospitalized 2005–2019. We also conducted a risk factor analysis of AP development in pediatric IBD.

Results

Sixty‐eight (54% males) patients with 120 episodes of AP were admitted at a median age of 15.3 years. Thirteen patients (14 episodes) had a co‐diagnosis of IBD, representing 4% of our IBD patient population. The AP‐IBD patients presented with lower amylase levels compared to the non‐IBD patients (160 [interquartile range, IQR: 83–231] vs. 418 [IQR: 176–874] U/L, p > 0.01), all had a mild pancreatitis, and none required invasive intervention. The presumed etiology for AP in all IBD patients was IBD‐related: IBD flare‐up in five, side effects of medications in two, and undetermined in seven. The only risk factor for AP development among IBD patients was IBD‐associated arthritis (23% vs. 3% for IBD‐non‐AP, p = 0.04), while extracolonic Crohn's disease and induction therapy with nutrition were negative risk factors (15% vs. 51%, p = 0.05, and 8% vs. 44%, p = 0.04, respectively). Other parameters, including disease type and medications, were nonsignificant.

Conclusion

The clinical course of AP in pediatric IBD patients is mild. Only IBD‐associated arthritis emerged as a risk factor for the development of AP, while, unexpectedly, IBD medication did not.
Maslinic acid alleviates alcoholic liver injury in mice and regulates intestinal microbiota via the gut–liver axis
Authors: Su Jingwen , Dai Yuan , Wu Xianyao , Zhou Xinhu , Fang Xianying , Ge Xiangyang , Zhao Linguo
Published: June 2024

BACKGROUND

Maslinic acid (MA), a pentacyclic triterpene acid, is widely distributed in natural plants and mainly found in the fruit and leaves of olives and hawthorn. MA has been reported as having many health‐promoting functions, such as anticancer, anti‐inflammation and neuroprotective activities. According to previous study, hawthorn extract has certain hepatoprotective effects. However, the detailed mechanism is still unclear, especially the effect of MA on gut microbiota.

RESULTS

Our study reveals that MA effectively counteracts alcohol‐induced liver injury and oxidative stress. It mitigates alcohol‐induced intestinal barrier damage, reverses increased permeability and reduces translocation of lipopolysaccharide (LPS). This prevents LPS/Toll‐like receptor 4 activation, leading to decreased TNF‐α and IL‐1β production. Furthermore, MA rebalances gut microbiota by reversing harmful bacterial abundance and enhancing beneficial bacteria post‐alcohol consumption.

CONCLUSION

MA, through modulation of gut microbiota, alleviates alcohol‐induced liver injury via the gut–liver axis. These findings support the potential use of MA as a functional food ingredient for preventing or treating alcoholic liver disease. © 2024 Society of Chemical Industry.
Color Duplex Ultrasonography for the Evaluation of Innominate, Subclavian, and Common Carotid Artery Stenosis
Authors: Zhang Jie , Wu Dianze , Wang Shaopeng , Bai Liyang , Meng Yan , Wang Lijuan
Published: June 2024

Objective

This study aimed to validate the efficiency of Doppler ultrasonography for predicting the innominate, subclavian, and common carotid artery stenosis.

Methods

This retrospective multicenter study between 2013 and 2022 enrolled 636 patients who underwent carotid Doppler ultrasonography and subsequent digital subtraction angiography. And 58 innominate artery stenosis, 147 common carotid artery stenosis, and 154 subclavian artery stenosis were included. The peak systolic velocity at innominate, subclavian, and common carotid artery, and velocity ratios of innominate artery to common carotid artery, innominate artery to subclavian artery, and common carotid artery to internal carotid artery were measured or calculated. The threshold values were determined using receiver operating characteristic analysis.

Results

The threshold values of innominate artery stenosis were peak systolic velocity >206 cm/s (sensitivity: 82.8%; specificity: 91.4%) to predict ≥50% stenosis and >285 cm/s (sensitivity: 89.2%; specificity: 94.9%) to predict ≥70% stenosis. The threshold values of common carotid artery stenosis were peak systolic velocity >175 cm/s (sensitivity: 78.2%; specificity: 91.9%) to predict ≥50% stenosis and >255 cm/s (sensitivity: 87.1%; specificity: 87.2%) to predict ≥70% stenosis. The threshold values of subclavian artery stenosis were peak systolic velocity >200 cm/s (sensitivity: 68.2%; specificity: 84.4%) to predict ≥50% stenosis and >305 cm/s (sensitivity: 57.9%; specificity: 91.4%) to predict ≥70% stenosis.

Conclusions

Symptomatic patients with ultrasonic parameters of velocity at innominate artery ≥206 cm/s, velocity at common carotid artery ≥175 cm/s, or velocity at subclavian artery ≥200 cm/s need to be considered for further verification and whether revascularization is necessary.
HMGB1 inhibition blocks ferroptosis and oxidative stress to ameliorate sepsis‐induced acute lung injury by activating the Nrf2 pathway
Authors: Jia Ya‐Jie , Xiong Sha , Yao Ming , Wei Yu , He Yan
Published: June 2024

The proinflammatory properties of high‐mobility group box protein 1 (HMGB1) in sepsis have been extensively studied. This study aimed to investigate the impact of HMGB1 on ferroptosis and its molecular mechanism in sepsis‐induced acute lung injury (ALI). A septic mouse model was established using the cecal ligation and puncture method. Blocking HMGB1 resulted in improved survival rates, reduced lung injury, decreased levels of ferroptosis markers (reactive oxygen species, malondialdehyde, and Fe2+), and enhanced antioxidant enzyme activities (superoxide dismutase and catalase) in septic mice. In addition, knockdown of HMGB1 reduced cellular permeability, ferroptosis markers, and raised antioxidant enzyme levels in lipopolysaccharide (LPS)‐stimulated MLE‐12 cells. Silencing of HMGB1 led to elevations in the expressions of ferroptosis core‐regulators in LPS‐treated MLE‐12 cells, such as solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member A2 (SLC3A2), and glutathione peroxidase 4. Furthermore, blocking HMGB1 did not alter ferroptosis, oxidative stress‐related changes, and permeability in LPS‐treated MLE‐12 cells that were pretreated with ferrostatin‐1 (a ferroptosis inhibitor). HMGB1 inhibition also led to elevated expressions of nuclear factor erythroid 2‐related factor 2 (Nrf2) and its downstream targets, heme oxygenase‐1 (HO‐1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in LPS‐treated MLE‐12 cells and lung tissues from septic mice. The Nrf2‐specific inhibitor ML385 reversed the effects of HMGB1 silencing on ferroptosis and cell permeability in LPS‐treated MLE‐12 cells. Our findings indicated that the inhibition of HMGB1 restrains ferroptosis and oxidative stress, thereby alleviating sepsis‐induced ALI through the activation of Nrf2 signaling.
Facile Modification of Propiolated Castor Oil via Nucleophilic Thiol‐Yne Click Reactions
Authors: Kalayci Damla , Akar Emre , Luleburgaz Serter , Çakmakçi Emrah , Gunay Ufuk Saim , Kumbaraci Volkan , Durmaz Hakan , Tunca Umit
Published: June 2024

The combination of modern click protocols and bio‐based building blocks is a great step toward energy‐efficient, and sustainable polymer production. Herein, thiol‐Michael addition (thiol‐yne) reactions from the toolbox of click chemistry protocols are chosen and propiolated castor oil (PCO) is used, a vegetable oil derivative, as the bio‐based building block for the facile functionalization of PCO with various thiols. In addition to the functionalization of PCO, hyperbranched and crosslinked polymers are also prepared. The thiol‐yne click functionalization reactions of the PCO are conducted at room temperature within 5 min and in the presence of an organic catalyst. The yields are found to change between 80% and 99% depending on the type of the thiol compound. The effect of various organic catalysts is investigated, and 1,8‐diazabicyclo(5.4.0)undec‐7‐ene (DBU) is found to be the most effective catalyst for the thiol‐yne modification reactions. The hyperbranched polymer reaches 23.8 kDa (Mw) within 5 min. The findings of this paper open up new horizons for polymer researchers who work in the field of sustainable polymers and click chemistry and the presented idea here is appealing because it offers a potential strategy for fast, reliable, modular, and functional macromolecule preparation from renewable vegetable oils.
What is to be expected? Optimizing the operationalization of consumer–brand relational norms
Authors: Makri Katerina , Bourdin David , Herz Marc
Published: June 2024

Consumers relate to brands in ways analogous to how they relate with people. And, just as consumers have norms that guide their interpersonal relationships, they also have norms that guide their relationships with brands. While such relational norms are essential in determining brand value, extant literature offers no measure to effectively operationalize the framework that governs consumer–brand relationships. Preliminary work offers important insight but suffers from several methodological shortcomings, rendering subsequent empirical applications problematic and hindering theoretical and practical advancements. In seven studies (ntotal = 3121), we revisit seminal work on the consumer–brand relational norms construct to refine and validate its measurement. Our findings reveal a unidimensional set of items that display strong psychometric properties, offering a parsimonious measure that promotes consistent operationalizations of the construct across studies and enables comparison and integration of empirical results.
Optionally green: The effect of hybrid product default policy on consumer response to hybrid products
Authors: Usrey Bryan , Saridakis Charalampos , Theotokis Aristeidis
Published: June 2024

In today's marketplace, products can feature both “green” and “non‐green” attributes and consumers, with the press of a button, can select their preferred operating mode (green vs. nongreen). In this research, we define such products as hybrid, arguing that their choice architecture design—specifically, the default operational mode—plays a pivotal role in influencing consumer evaluation and purchase behavior. In four experiments, we found that consumers view a hybrid product as more environmentally friendly when the green mode is the default setting and can be turned off (opt‐out), rather than when the green mode must be activated (opt‐in). Specifically, we show that, when efficiency (vs. effectiveness)—related attributes are valued, the opt‐out (vs. opt‐in) default policy enhances purchase behavior. Moreover, we find that this effect is mediated by green attribute centrality, in that consumers perceive the opt‐out (vs. opt‐in) default policy as more central. Finally, we find that the effect of default policy is stronger for consumers with an analytical, as opposed to a holistic, thinking style. This article contributes to both default policy and hybrid product literature and provides managerial implications for the design and promotion of hybrid products.
Economic evaluation of barriers to minimize reservoir sport fish escapement
Authors: Lewis Madeline C. , Tyndall John C. , Dodd Ben , Weber Michael J.
Published: June 2024

Objective

Barriers can be an effective method for reducing escapement of reservoir sport fish; however, whether the financial benefits of a barrier outweigh the costs of a barrier is unknown. We sought to quantify the costs and benefits associated with constructing barriers to reduce fish escapement while explicitly accounting for variability and uncertainty.

Methods

We developed a framework using simulation modeling and discounted cash flow techniques to quantify the costs and benefits of barrier construction on Brushy Creek Lake, Iowa, where a barrier was constructed in 2020 to reduce escapement of stocked Walleye Sander vitreus and Muskellunge Esox masquinongy. We then incorporated this framework into an interactive Shiny application to enable cost–benefit evaluations across a wide range of barrier types, system types, species, and escapement rates.

Result

The present value of the parallel-bar barrier on Brushy Creek Lake, Iowa, over 10 years was US$69,576 (range = $64,484–$73,976), whereas the present value of escaped fish was $316,416 ($253,459–$378,823), indicating a net benefit of $246,840 ($188,975–$304,847) associated with barrier construction. The benefit–cost ratio of barrier construction was 4.55 after 10 years, indicating that for every $1 in present value spent on barrier construction, we saved $4.55 by preventing fish escapement. There was a 99% probability of a positive mean net benefit of the barrier after 3 years.

Conclusion

Our results indicate that barriers can be a cost-effective option to minimize fish escapement, and barrier costs are more predictable compared with the cost of escapement. Quantifying the value of escaped fish and barrier construction on an economic scale enables the use of formal decision-making tools to address complicated and multifaceted issues associated with reservoir fisheries management.