bluuebunny/crossref_metadata_2025 huggingface dataset:
Phillyrin improves myocardial remodeling in salt-sensitive hypertensive mice by reducing endothelin1 signaling
Authors: Luo Qingman , Liu Qiao , Tang Kecheng , Zhong Bin , Yang Shengqian , Li Xiaohui
Published: March 2024

Objectives

Prolonged exposure to chronic hypertension places the heart under excessive strain, resulting in myocardial remodeling. Phillyrin, derived from the natural plant Forsythia suspensa, has been found to possess cardioprotective properties. The objective of this study is to investigate the role and mechanism of phillyrin in hypertension-induced myocardial remodeling in mice.

Methods

We constructed a mouse model of salt-sensitive hypertension. The mice were treated with varying doses of phillyrin, and their blood pressure, cardiac function, cardiac hypertrophy, fibrosis, inflammation, and other conditions were assessed.

Key findings

Our research findings demonstrated that phillyrin has the potential to lower blood pressure, enhance cardiac function, and mitigate cardiac hypertrophy, fibrosis, and inflammatory responses in deoxycorticosterone acetate-salt hypertension mice. In hypertensive mice, there was an elevated expression of endothelin1 (ET-1) in heart tissue, which can be reduced by phillyrin. Additionally, phillyrin effectively reduced the hypertrophy of H9c2 cells induced by ET-1 stimulation.

Conclusions

Our research highlights the therapeutic capabilities of phillyrin in the treatment of myocardial remodeling through the reduction of ET-1 signaling. These results contribute to the advancement of novel applications for phillyrin and establish a solid conceptual basis for future investigations in this area.
Safe testing
Authors: Grünwald Peter , de Heide Rianne , Koolen Wouter
Published: March 2024

We develop the theory of hypothesis testing based on the e-value, a notion of evidence that, unlike the p-value, allows for effortlessly combining results from several studies in the common scenario where the decision to perform a new study may depend on previous outcomes. Tests based on e-values are safe, i.e. they preserve type-I error guarantees, under such optional continuation. We define growth rate optimality (GRO) as an analogue of power in an optional continuation context, and we show how to construct GRO e-variables for general testing problems with composite null and alternative, emphasizing models with nuisance parameters. GRO e-values take the form of Bayes factors with special priors. We illustrate the theory using several classic examples including a 1-sample safe t-test and the 2×2 contingency table. Sharing Fisherian, Neymanian, and Jeffreys–Bayesian interpretations, e-values may provide a methodology acceptable to adherents of all three schools.
Usefulness of serial testing for the diagnosis of malaria in cases of fever upon return from travel
Authors: Lydia Slack , Blaise Genton
Published: March 2024

Background

When malaria is suspected in case of fever after travel in endemic areas, the current recommendation is to repeat the malaria test at 24-hour intervals, with up to two additional tests, as long as the test result is negative. A retrospective analysis was conducted to investigate the appropriateness of this recommendation by determining the proportion of tests with negative result at first and subsequently with a positive one at second or third attempt.

Methods

A retrospective study was conducted at the Centre for Primary Care and Public Health, Lausanne, covering a period of 15 years. All patients tested once for malaria were included. Testing included microscopy thick and thin films as well as malaria rapid diagnostic test used in combination. The main outcome measure was the proportion of patients with a first negative test result, subsequently positive on second or third test over the total patients with suspected malaria assessed. Demographic, travel, clinical, and laboratory variables were collected from patients’ records to identify potential predictors of an initially negative and then positive test result.

Results

Four thousand nine hundred seventy-two patients were included. Of those, 4557 (91.7%) had definitive negative test results, and 415 (8.3%) had a positive result on the first test [332/415 (80%) Plasmodium falciparum, 40/415 (9.6%) P. vivax, 21/415 (5.1%) P. ovale, 12/415 (2.9%) P. vivax/ovale, 9/415 (2.2%) P. malariae and 1/415 (0.2%) P. knowlesi], and 3/4972 (0.06%) had a positive result on the second test after a first negative result, 1/4972(0.02%) had a positive test result after 2 negative results, all with P. falciparum. One of the four patients that were positive after their initial negative test was pregnant. The very small number of patients with an initially negative test result and secondarily positive did not allow for risk factor analysis.

Conclusions

The current recommendation of serial malaria testing is not supported by the present study, a fortiori for those who do not present with a strong clinical or laboratory predictor of malaria.
Stress response membrane protein OsSMP2 negatively regulates rice tolerance to drought
Authors: Wang Wei , Li Yaqi , Yang Songjin , Wu Jiacheng , Ma Chuan , Chen Yulin , Sun Xingzhuo , Wu Lingli , Liang Xin , Fu Qiuping , Xu Zhengjun , Li Lihua , Huang Zhengjian , Zhu Jianqing , Jia Xiaomei , Ye Xiaoying , Chen Rongjun
Published: March 2024

In a gene chip analysis, rice (Oryza sativa) OsSMP2 gene expression was induced under various abiotic stresses, prompting an investigation into its role in drought resistance and abscisic acid signaling. Subsequent experiments, including qRT–PCR and β-glucuronidase activity detection, affirmed the OsSMP2 gene’s predominant induction by drought stress. Subcellular localization experiments indicated the OsSMP2 protein primarily localizes to the cell membrane system. Overexpressing OsSMP2 increased sensitivity to exogenous abscisic acid, reducing drought resistance and leading to reactive oxygen species accumulation under drought stress. Conversely, in simulated drought experiments, OsSMP2-silenced transgenic plants showed significantly longer roots compared with the wild-type Nipponbare. These results suggest that OsSMP2 overexpression negatively affects rice drought resistance, offering valuable insights into molecular mechanisms, and highlight OsSMP2 as a potential target for enhancing crop resilience to drought stress.
When synthetic biology meets medicine
Authors: Feng Yuge , Su Cong , Mao Guobin , Sun Baoting , Cai Yizhi , Dai Junbiao , Ma Yingxin
Published: March 2024

In recent years, the world has faced significant challenges with the coronavirus disease 2019 (COVID-19) pandemic, as well as other infectious diseases such as Zika and Ebola. Furthermore, the rapid rise of non-communicable diseases such as diabetes, heart disease, and cancer has placed tremendous strain on healthcare resources and systems. Unfortunately, advancements in drug development, diagnostics, and therapeutics have struggled to keep pace with the emergence and progression of diseases, necessitating the exploration of new technologies for the discovery and development of biomedicines and biotherapies. Synthetic biology, a revolutionary field in modern science, holds great promise in advancing drug development and disease treatment. This review provides a comprehensive overview of recent developments in the application of synthetic biology to medicine, with a specific focus on its role in drug discovery, drug production, and the diagnosis and treatment of various diseases.
Evaluation of the drug–drug interaction between triazole antifungals and cystic fibrosis transmembrane conductance regulator modulators in a real-life cohort
Authors: Jansen Anouk M E , Eggermont Margot N , Wilms Erik B , Aziz Sami , Reijers Monique , Roukema Jolt , Warris Adilia , Brüggemann Roger J M , van der Meer Renske
Published: March 2024

Limited data on the clinical management of drug–drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.
Rapid variability of Markarian 421 during extreme flaring as seen through the eyes of XMM–Newton
Authors: Gokus A , Wilms J , Kadler M , Dorner D , Nowak M A , Kreikenbohm A , Leiter K , Bretz T , Schleicher B , Markowitz A G , Pottschmidt K , Mannheim K , Kreykenbohm I , Langejahn M , McBride F , Beuchert T , Dauser T , Kreter M , Abhir J , Baack D , Balbo M , Biland A , Brand K , Buss J , Eisenberger L , Elsaesser D , Günther P , Hildebrand D , Linhoff M , Paravac A , Rhode W , Sliusar V , Hasan S , Walter R
Published: March 2024

By studying the variability of blazars across the electromagnetic spectrum, it is possible to resolve the underlying processes responsible for rapid flux increases, so-called flares. We report on an extremely bright X-ray flare in the high-peaked BL Lacertae object Markarian 421 (Mrk 421) that occurred simultaneously with enhanced γ-ray activity detected at very high energies by First G-APD Cherenkov Telescope on 2019 June 9. We triggered an observation with XMM–Newton, which observed the source quasi-continuously for 25 h. We find that the source was in the brightest state ever observed using XMM–Newton, reaching a flux of 2.8 × 10−9  $\mathrm{erg\, cm^{-2}\, s^{-1}}$ over an energy range of 0.3–10 keV. We perform a spectral and timing analysis to reveal the mechanisms of particle acceleration and to search for the shortest source-intrinsic time-scales. Mrk 421 exhibits the typical harder-when-brighter behaviour throughout the observation and shows a clock-wise hysteresis pattern, which indicates that the cooling dominates over the acceleration process. While the X-ray emission in different sub-bands is highly correlated, we can exclude large time lags as the computed z-transformed discrete correlation functions are consistent with a zero lag. We find rapid variability on time-scales of 1 ks for the 0.3–10 keV band and down to 300 s in the hard X-ray band (4–10 keV). Taking these time-scales into account, we discuss different models to explain the observed X-ray flare, and find that a plasmoid-dominated magnetic reconnection process is able to describe our observation best.
The nature of compact radio-loud AGN: a systematic look at the LOFAR AGN population
Authors: Chilufya J , Hardcastle M J , Pierce J C S , Croston J H , Mingo B , Zheng X , Baldi R D , Röttgering H J A
Published: March 2024

We investigate the nature of low-luminosity radio-loud active galactic nuclei (RLAGN) selected from the LOFAR Two-metre Sky Survey (LoTSS) first data release (DR1). Using optical, mid-infrared, and radio data, we have conservatively selected 55 radiative AGN candidates from DR1 within the redshift range 0.03 < z < 0.1. We show using high-frequency Karl G. Jansky Very Large Array (VLA) observations that 10 out of 55 objects show radio emission on scales >1–3 kpc, 42 are compact at the limiting resolution of 0.35 arcsec (taking an upper limit on the projected physical size, this corresponds to less than 1 kpc), and three are undetected. The extended objects display a wide range of radio morphologies: two-jet (5), one-jet (4), and double-lobed (1). We present the radio spectra of all detected radio sources which range from steep to flat/inverted and span the range seen for other compact radio sources such as compact symmetric objects (CSOs), compact steep spectrum (CSS) sources, and gigahertz peaked-spectrum (GPS) sources. Assuming synchrotron self-absorption (SSA) for flat/inverted radio spectrum sources, we predict small physical sizes for compact objects to range between 2 and 53 pc. Alternatively, using free–free absorption (FFA) models, we have estimated the free electron column depth for all compact objects, assuming a homogeneous absorber. We find that these objects do not occupy a special position on the power/linear size (P − D) diagram but some share a region with radio-quiet quasars (RQQs) and the so-called ‘FR0’ sources in terms of radio luminosity and linear size.
The distance to CRL 618 through its radio expansion parallax
Authors: Cerrigone Luciano , Umana Grazia , Trigilio Corrado , Menten Karl M , Bordiu Cristobal , Ingallinera Adriano , Leto Paolo , Buemi Carla S , Bufano Filomena , Cavallaro Francesco , Loru Sara , Riggi Simone
Published: March 2024

CRL 618 is a post-Asymptotic Giant Branch star that has started to ionize its ejecta. Its central H ii region has been observed over the last 40 yr and has steadily increased in flux density at radio wavelengths. In this paper, we present data that we obtained with the Very Large Array in its highest frequency band (43 GHz) in 2011 and compare these with archival data in the same frequency band from 1998. By applying the so-called expansion-parallax method, we are able to estimate an expansion rate of 4.0 ± 0.4 mas yr−1 along the major axis of the nebula and derive a distance of 1.1 ± 0.2 kpc. Within errors, this distance estimation is in good agreement with the value of ∼900 pc derived from the expansion of the optical lobes.
Integrating Patient-Reported Outcomes Into Prognostication in Gastroesophageal Cancer: Results of a Population-Based Retrospective Cohort Analysis
Authors: Baccili Cury Megid Thais , Sharma Divya , Baskurt Zeynep , Xiaolu Ma Lucy , Wang Xin , Barron Carly C , Jang Raymond Woo-Jun , Chen Eric Xueyu , Swallow Carol Jane , Mesci Aruz , Yeung Jonathan , Wong Rebecca K S , Brar Savtaj Singh , Veit-Haibach Patrick , Kim John , Bach Yvonne , Aoyama Hiroko , Elimova Elena
Published: March 2024

Background

Patient-reported outcomes measures (PROM) are self-reflections of an individual’s physical functioning and emotional well-being. The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated PRO tool of 10 common symptoms and a patient-reported functional status (PRFS) measure. The prognostic value of this tool is unknown in patients with gastroesophageal cancer (GEC). In this study, we examined the association between the ESAS score and overall survival (OS) in patients with GEC, the prognostication difference between ESAS and Eastern Cooperative Oncology Group (ECOG), and assessed the correlation between PRFS and the physician-reported ECOG performance status (PS).

Methods

The study was a retrospective cohort study of 211 patients with GEC with localized (stages I-III) and metastatic disease who completed at least one baseline ESAS prior to treatment. Patients were grouped into 3 cohorts based on ESAS score. OS was assessed using the Kaplan-Meier method, and the concordance index (c-index) was calculated for ESAS and physician-reported ECOG. The agreement between PRFS and physician-ECOG was also assessed.

Results

In total, 211 patients were included. The median age was 60.8 years; 90% of patients were ECOG PS 0-1; 38% of patients were stages I-III, while 62% were de novo metastatic patients. Median OS in low, moderate, high symptom burden (SB) patients’ cohorts was 19.17 m, 16.39 mm, and 12.68 m, respectively (P < .04). The ability to predict death was similar between physician-ECOG and ESAS (c-index 0.56 and 0.5753, respectively) and PRFS and physician-ECOG (c-index of 0.5615 and 0.5545, respectively). The PS agreement between patients and physicians was 50% with a weighted Kappa of 0.27 (95% CI: 0.17-0.38).

Conclusion

Patient’s SB seems to carry a prognostic significance. ESAS and physician-reported ECOG exhibit comparable prognostic values. Physicians and patients can frequently have divergent opinions on PS. ESAS takes a patient-centered approach and should be encouraged in practice among patients with GEC as an additional tool for prognostication.
Two Hematological Markers Predicting the Efficacy and Prognosis of Neoadjuvant Chemotherapy Using Lobaplatin Against Triple-Negative Breast Cancer
Authors: Wang Cheng , Shi Qiyun , Zhang Guozhi , Wu Xiujuan , Yan Wenting , Wan Andi , Xiong Siyi , Yuan Long , Tian Hao , Ma Dandan , Jiang Jun , Qi Xiaowei , Zhang Yi
Published: March 2024

Background

Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear.

Methods

Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively.

Results

The tpCR rate in the PLR− group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR− group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR−NLR− (PLR− and NLR−) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR− group (P = .028 for EFS; P = .047 for OS). Patients in the PLR−NLR− group had a longer EFS than those in the PLR+/NLR+ group (P = .002).

Conclusion

PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis.
Pleiotropic Effects of miR5504 Underlying Plant Height, Grain Yield and Quality in Rice
Authors: Wang Huihui , Wang Xin , Li Yangyang , Cui Ying , Yan Xin , Gao Jiadong , Ouyang Jiexiu , Li Shaobo
Published: March 2024

MicroRNAs (miRNAs) are known to play critical roles in regulating rice agronomic traits through mRNA cleavage or translational repression. Our previous study indicated that miR5504 regulates plant height by affecting cell proliferation and expansion. Here, the two independent homozygous mir5504 mutants (CR1 and CR2) and overexpression lines (OE1 and OE2) were further used to investigate the functions of miR5504. The panicle length, 1000-grain weight and grain yield per plant of miR5504-OE lines were identical to those of Nipponbare (NIP), but the 1000-grain weight of mir5504 mutants was reduced by about 10% and 9%, respectively. Meanwhile, the grain width and thickness of mir5504 mutants decreased significantly by approximately 10% and 11%, respectively. Moreover, the cytological results revealed a significant decrease in cell number along grain width direction and cell width in spikelet in mir5504, compared with those in NIP. In addition, several major storage substances of the rice seeds were measured. Compared to NIP, the amylose content of the mir5504 seeds was noticeably decreased, leading to an increase of nearly 10 mm in gel consistency (GC) in mir5504 lines. Further investigation confirmed that LOC_Os08g16914 was the genuine target of miR5504: LOC_Os08g16914 over-expression plants phenocopied the mir5504 mutants. This study provides insights into the role of miR5504 in rice seed development.
Light signaling in plants—a selective history
Authors: Huq Enamul , Lin Chentao , Quail Peter H
Published: March 2024

In addition to providing the radiant energy that drives photosynthesis, sunlight carries signals that enable plants to grow, develop and adapt optimally to the prevailing environment. Here we trace the path of research that has led to our current understanding of the cellular and molecular mechanisms underlying the plant's capacity to perceive and transduce these signals into appropriate growth and developmental responses. Because a fully comprehensive review was not possible, we have restricted our coverage to the phytochrome and cryptochrome classes of photosensory receptors, while recognizing that the phototropin and UV classes also contribute importantly to the full scope of light-signal monitoring by the plant.
Natural polymorphisms in ZMET2 encoding a DNA methyltransferase modulate the number of husk layers in maize
Authors: Wang Zi , Xia Aiai , Wang Qi , Cui Zhenhai , Lu Ming , Ye Yusheng , Wang Yanbo , He Yan
Published: March 2024

DNA methylation affects agronomic traits and the environmental adaptability of crops, but the natural polymorphisms in DNA methylation–related genes and their contributions to phenotypic variation in maize (Zea mays) remain elusive. Here, we show that a polymorphic 10-bp insertion/deletion variant in the 3′UTR of Zea methyltransferase2 (ZMET2) alters its transcript level and accounts for variation in the number of maize husk layers. ZMET2 encodes a chromomethylase and is required for maintaining genome-wide DNA methylation in the CHG sequence context. Disruption of ZMET2 increased the number of husk layers and resulted in thousands of differentially methylated regions, a proportion of which were also distinguishable in natural ZMET2 alleles. Population genetic analyses indicated that ZMET2 was a target of selection and might play a role in the spread of maize from tropical to temperate regions. Our results provide important insights into the natural variation of ZMET2 that confers both global and locus-specific effects on DNA methylation, which contribute to phenotypic diversity in maize.
Maize requires arogenate dehydratase 2 for resistance to Ustilago maydis and plant development
Authors: Ren Ru Chang , Kong Ling Guang , Zheng Guang Ming , Zhao Ya Jie , Jiang Xin , Wu Jia Wen , Liu Cuimei , Chu Jinfang , Ding Xin Hua , Zhang Xian Sheng , Wang Guan Feng , Zhao Xiang Yu
Published: March 2024

Maize (Zea mays) smut is a common biotrophic fungal disease caused by Ustilago maydis and leads to low maize yield. Maize resistance to U. maydis is a quantitative trait. However, the molecular mechanism underlying the resistance of maize to U. maydis is poorly understood. Here, we reported that a maize mutant caused by a single gene mutation exhibited defects in both fungal resistance and plant development. maize mutant highly susceptible to U. maydis (mmsu) with a dwarf phenotype forms tumors in the ear. A map-based cloning and allelism test demonstrated that 1 gene encoding a putative arogenate dehydratase/prephenate dehydratase (ADT/PDT) is responsible for the phenotypes of the mmsu and was designated as ZmADT2. Combined transcriptomic and metabolomic analyses revealed that mmsu had substantial differences in multiple metabolic pathways in response to U. maydis infection compared with the wild type. Disruption of ZmADT2 caused damage to the chloroplast ultrastructure and function, metabolic flux redirection, and reduced the amounts of salicylic acid (SA) and lignin, leading to susceptibility to U. maydis and dwarf phenotype. These results suggested that ZmADT2 is required for maintaining metabolic flux, as well as resistance to U. maydis and plant development in maize. Meanwhile, our findings provided insights into the maize response mechanism to U. maydis infection.
Triacylglycerol stability limits futile cycles and inhibition of carbon capture in oil-accumulating leaves
Authors: Johnson Brandon S , Allen Doug K , Bates Philip D
Published: March 2024

Engineering plant vegetative tissue to accumulate triacylglycerols (TAG, e.g. oil) can increase the amount of oil harvested per acre to levels that exceed current oilseed crops. Engineered tobacco (Nicotiana tabacum) lines that accumulate 15% to 30% oil of leaf dry weight resulted in starkly different metabolic phenotypes. In-depth analysis of the leaf lipid accumulation and 14CO2 tracking describe metabolic adaptations to the leaf oil engineering. An oil-for-membrane lipid tradeoff in the 15% oil line (referred to as HO) was surprisingly not further exacerbated when lipid production was enhanced to 30% (LEAFY COTYLEDON 2 (LEC2) line). The HO line exhibited a futile cycle that limited TAG yield through exchange with starch, altered carbon flux into various metabolite pools and end products, and suggested interference of the glyoxylate cycle with photorespiration that limited CO2 assimilation by 50%. In contrast, inclusion of the LEC2 transcription factor in tobacco improved TAG stability, alleviated the TAG-to-starch futile cycle, and recovered CO2 assimilation and plant growth comparable to wild type but with much higher lipid levels in leaves. Thus, the unstable production of storage reserves and futile cycling limit vegetative oil engineering approaches. The capacity to overcome futile cycles and maintain enhanced stable TAG levels in LEC2 demonstrated the importance of considering unanticipated metabolic adaptations while engineering vegetative oil crops.
Cocaine diminishes functional network robustness and destabilizes the energy landscape of neuronal activity in the medial prefrontal cortex
Authors: Borzou Ahmad , Miller Sierra N , Hommel Jonathan D , Schwarz J M
Published: March 2024

We present analysis of neuronal activity recordings from a subset of neurons in the medial prefrontal cortex of rats before and after the administration of cocaine. Using an underlying modern Hopfield model as a description for the neuronal network, combined with a machine learning approach, we compute the underlying functional connectivity of the neuronal network. We find that the functional connectivity changes after the administration of cocaine with both functional-excitatory and functional-inhibitory neurons being affected. Using conventional network analysis, we find that the diameter of the graph, or the shortest length between the two most distant nodes, increases with cocaine, suggesting that the neuronal network is less robust. We also find that the betweenness centrality scores for several of the functional-excitatory and functional-inhibitory neurons decrease significantly, while other scores remain essentially unchanged, to also suggest that the neuronal network is less robust. Finally, we study the distribution of neuronal activity and relate it to energy to find that cocaine drives the neuronal network towards destabilization in the energy landscape of neuronal activation. While this destabilization is presumably temporary given one administration of cocaine, perhaps this initial destabilization indicates a transition towards a new stable state with repeated cocaine administration. However, such analyses are useful more generally to understand how neuronal networks respond to perturbations.
Into the Unknown: Conceptualizing the Experience of Uncertainty in Citizen–State Interactions
Authors: Cecchini Mathilde
Published: March 2024

It is often argued that uncertainty is an inherent characteristic of citizen–state interactions. It is therefore hardly surprising that many scholars of street-level bureaucracy have studied how frontline workers cope with and make discretionary decisions under uncertain conditions. However, citizens’ experiences of uncertainty have received limited attention in the street-level bureaucracy literature. This article argues that understanding citizens’ experiences of uncertainty is highly relevant because experiences of uncertainty are likely to affect mental well-being of individuals negatively. The article seeks to address this gap by building a conceptual framework for understanding and analyzing citizens’ experiences with uncertainty in state–citizen interactions based on theoretical insights from the existing literature and in-depth qualitative analysis of 20 narrative interviews with former coronavirus disease 2019 (COVID-19) patients and their relatives concerning their encounter with health authorities. The article proposes a conceptual framework that distinguishes between epistemic uncertainty and moral uncertainty. Epistemic uncertainty concerns uncertainty about empirical facts or knowledge. Moral uncertainty concerns uncertainty about values due to conflicting or competing norms and values. The article illustrates how these forms of uncertainty may arise before, during, and after citizens’ interaction with frontline workers.
The Rhetorical Post-presidency: Former Presidents as Elite Cue Givers
Authors: Winger Gregory H , Oliver Alex
Published: March 2024

Former presidents are not resigned to quiet anonymity but instead can remain prominent political actors long after exiting the White House. From Jimmy Carter's personal diplomacy to Donald Trump's caustic social media posts, ex-presidents continue to exercise considerable political power despite lacking any official role or governing authority. We argue that this continued post-presidential influence is an outgrowth of the informal powers of the presidency. A president's rhetorical prowess and ability to command national attention do not dissipate upon exiting office but instead form the basis for post-presidential influence. To test this theory, we conducted two survey experiments of former presidents as elite cue givers. We found that although effects are not uniform, statements attributed to former presidents can substantively alter the policy preferences of recipients. However, these effects appear to be highly individualistic and largely tied to copartisan recipients.
Most dynorphin neurons in the zona incerta-perifornical area are active in waking relative to non-rapid-eye movement and rapid-eye movement sleep
Authors: Shiromani Priyattam J , Vidal-Ortiz Aurelio
Published: March 2024

Dynorphin is an endogenous opiate localized in many brain regions and spinal cord, but the activity of dynorphin neurons during sleep is unknown. Dynorphin is an inhibitory neuropeptide that is coreleased with orexin, an excitatory neuropeptide. We used microendoscopy to test the hypothesis that, like orexin, the dynorphin neurons are wake-active. Dynorphin-cre mice (n = 3) were administered rAAV8-Ef1a-Con/Foff 2.0-GCaMP6M into the zona incerta-perifornical area, implanted with a GRIN lens (gradient reflective index), and electrodes to the skull that recorded sleep. One month later, a miniscope imaged calcium fluorescence in dynorphin neurons during multiple bouts of wake, non-rapid-eye movement (NREM), and rapid-eye movement (REM) sleep. Unbiased data analysis identified changes in calcium fluorescence in 64 dynorphin neurons. Most of the dynorphin neurons (72%) had the highest fluorescence during bouts of active and quiet waking compared to NREM or REM sleep; a subset (20%) were REM-max. Our results are consistent with the emerging evidence that the activity of orexin neurons can be classified as wake-max or REM-max. Since the two neuropeptides are coexpressed and coreleased, we suggest that dynorphin-cre-driven calcium sensors could increase understanding of the role of this endogenous opiate in pain and sleep.
Longitudinal study of childhood sleep trajectories and adolescent mental health problems
Authors: Touchette Evelyne , Fréchette-Boilard Gabrielle , Petit Dominique , Geoffroy Marie-Claude , Pennestri Marie-Hélène , Côté Sylvana , Tremblay Richard E , Petitclerc Amélie , Boivin Michel , Montplaisir Jacques
Published: March 2024

Study Objective

To investigate whether childhood sleep trajectories are associated with mental health symptoms such as social phobia, generalized anxiety, depression, attention deficit hyperactivity disorder (ADHD), conduct problems, and opposition at age 15.

Methods

A total of 2120 children took part in the Quebec Longitudinal Study of Child Development. Childhood sleep trajectories were computed from maternal reports at 2.5, 3.5, 4, 6, 8, 10, and/or 12 years. At age 15, 1446 adolescents filled out mental health and sleep questions. A path analysis model was assessed in the full sample.

Results

Four childhood nocturnal sleep duration trajectories were identified: (1) a short pattern (7.5%), (2) a short-increasing pattern (5.8%), (3) a 10 hours pattern (50.7%), and (4) an 11 hours pattern (36.0%). Three childhood sleep latency trajectories were found: (1) a short pattern (31.7%), (2) an intermediate pattern (59.9%), and (3) a long pattern (8.4%). Finally, two childhood wakefulness after sleep-onset trajectories were found: (1) a normative pattern (73.0%) and (2) a long pattern (27.0%). The path analysis model indicated that children following a long childhood sleep latency trajectory were more likely to experience symptoms of depression (β = 0.06, 95% CI: 0.01 to 0.12), ADHD (β = 0.07, 95% CI: 0.02 to 0.13), conduct problems (β = 0.05, 95% CI: 0.00 to 0.10) and opposition (β = 0.08, 95% CI: 0.02 to 0.13) at age 15.

Conclusions

This longitudinal study revealed that children presenting a long sleep latency throughout childhood are at greater risk of symptoms of depression, ADHD, conduct problems, and opposition in adolescence.
Becoming Humanist: Worldview Formation and the Emergence of Atheist Britain
Authors: Strhan Anna , Lee Lois , Shillitoe Rachael
Published: March 2024

It is widely accepted that the growth of “non-religious” identification and “non-belief” in God(s) in many societies is linked to changing religious socialization. However, existing research mapping these intergenerational changes has largely focused on religious decline or the loss of belief—“push” factors—rather than exploring the distinctive non-religious forms of life into which children are growing up, which may operate as “pull” factors. Drawing on a qualitative study conducted with children, their parents, and teachers in England, we demonstrate how children come to inhabit a “humanist condition” through socialization processes in which “pull” factors toward humanism play a significant role and even shape the nature of “push” factors. The significance of new worldviews also helps explain how participants combine humanism with diverse religious and non-religious beliefs and practices. We argue that socialization processes at home and at school are interwoven and can be hard to distinguish in practice.
Distinct taxonomic practices impact patterns of bird endemism in the South American Cerrado savannas
Authors: Lopes Leonardo E , Gonzaga Luiz P , Rodrigues Marcos , da Silva José Maria C
Published: March 2024

Identifying endemic species and the areas of endemism delimited by them is central to biogeography. However, the impact of distinct taxonomic approaches on these patterns is often neglected. We investigated how three different taxonomic approaches impact the patterns of bird endemism in the Cerrado. The first two approaches (at species and subspecies levels) were based on traditional taxonomy based on the biological species concept. The third approach was based on a revised alternative taxonomy that sought to identify evolutionarily significant units (ESUs). In this third approach, after identifying the endemic taxa using traditional taxonomy, we revised their validity, removing biologically meaningless entities. We then detected the areas of endemism delimited by these endemic taxa under the three taxonomic approaches. We found that traditional taxonomy at the species level underestimated bird endemism by ignoring some ESUs that were considered subspecies. In contrast, traditional taxonomy at the subspecies level overestimated bird endemism, leading to the recognition of spurious areas of endemism because several of the purported endemic subspecies were taxonomic artefacts. The revised taxonomy provided a more refined picture of patterns of avian endemism in the Cerrado, suggesting that the use of ESUs improves the results of biogeographical analysis.
Microsomal triglyceride transfer protein is necessary to maintain lipid homeostasis and retinal function
Authors: Grubaugh Catharina R. , Dhingra Anuradha , Prakash Binu , Montenegro Diego , Sparrow Janet R. , Daniele Lauren L. , Curcio Christine A. , Bell Brent A. , Hussain M. Mahmood , Boesze‐Battaglia Kathleen
Published: March 2024

Lipid processing by the retinal pigment epithelium (RPE) is necessary to maintain retinal health and function. Dysregulation of retinal lipid homeostasis due to normal aging or age‐related disease triggers lipid accumulation within the RPE, on Bruch's membrane (BrM), and in the subretinal space. In its role as a hub for lipid trafficking into and out of the neural retina, the RPE packages a significant amount of lipid into lipid droplets for storage and into apolipoprotein B (APOB)‐containing lipoproteins (Blps) for export. Microsomal triglyceride transfer protein (MTP), encoded by the MTTP gene, is essential for Blp assembly. Herein we test the hypothesis that MTP expression in the RPE is essential to maintain lipid balance and retinal function using the newly generated RPEΔMttp mouse model. Using non‐invasive ocular imaging, electroretinography, and histochemical and biochemical analyses we show that genetic depletion of Mttp from the RPE results in intracellular lipid accumulation, increased photoreceptor‐associated cholesterol deposits, and photoreceptor cell death, and loss of rod but not cone function. RPE‐specific reduction in Mttp had no significant effect on plasma lipids and lipoproteins. While APOB was decreased in the RPE, most ocular retinoids remained unchanged, with the exception of the storage form of retinoid, retinyl ester. Thus suggesting that RPE MTP is critical for Blp synthesis and assembly but is not directly involved in plasma lipoprotein metabolism. These studies demonstrate that RPE‐specific MTP expression is necessary to establish and maintain retinal lipid homeostasis and visual function.
A novel intracoronary hypothermia device reduces myocardial reperfusion injury in pigs
Authors: Pei Zhiqiang , Qiu Jin , Zhao Yongchao , Song Shuai , Wang Rui , Luo Wei , Cai Xingxing , Liu Bin , Chen Han , Yin Jiasheng , Weng Xinyu , Wu Yizhe , Li Chenguang , Shen Li , Ge Junbo
Published: March 2024

Background:

Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury.

Methods:

This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes (n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group (n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls (n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed.

Results:

The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH.

Conclusions:

The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.
Associations of demographics, aggravating factors, comorbidities, and treatments with atopic dermatitis severity in China: A national cross-sectional study
Authors: Zhao Jiahui , Zhang Zhixin , Chen Hongguang , Dou Xia , Zhao Zuotao , Liu Lingling , Wang Yang , Li Hang
Published: March 2024

Background:

Atopic dermatitis (AD) is a chronic inflammatory skin disorder impacting populations worldwide, although its clinical characteristics and patient demographics remain uncharacterized in China. The aim of this study was to investigate the demographics, comorbidities, aggravating factors, and treatments in AD patients across different age groups in China.

Methods:

This cross-sectional study included Chinese AD patients from 205 hospitals spanning 30 provinces. Patients completed dermatologist-led surveys of general medical history, comorbidities, AD-related aggravating factors, and medications. Two-level mixed-ordered logistic regression was used to evaluate aggravating factors.

Results:

Overall, 16,838 respondents were included in the final analysis (age 30.9 ± 24.1 years). The proportion of severe AD was the highest in patients with AD onset at ≥60 years (26.73%). Allergic rhinitis and hypertension were the most common atopic and metabolism-related non-atopic comorbidities, respectively. AD severity was significantly associated with chronic urticaria, food allergies, and diabetes. Aggravating factors including foods, seasonal changes, and psychological factors were also linked to AD severity. The cross-sectional survey implied that severe AD may be related to the undertreatment of effective systemic or topical interventions.

Conclusion:

To enhance the management of AD, it is crucial to consider both aggravating factors and the increased utilization of systemic immunotherapy.

Registration:

ClinicalTrials.gov Identifier: NCT05316805, CORNERSTONE
Incidence, prevalence, and causes of spinal injuries in China, 1990–2019: Findings from the Global Burden of Disease Study 2019
Authors: Liu Chenjun , Xu Tingling , Xia Weiwei , Xu Shuai , Zhu Zhenqi , Zhou Maigeng , Liu Haiying
Published: March 2024

Background:

Spinal injuries are an urgent public health priority; nevertheless, no China-wide studies of these injuries exist. This study measured the incidence, prevalence, causes, regional distribution, and annual trends of spinal injuries in China from 1990 to 2019.

Methods:

We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 to estimate the incidence and prevalence of spinal injuries in China. The data of 33 provincial-level administrative regions (excluding Taiwan, China) provided by the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention (CDC) were use to systematically analyze the provincial etiology, geographical distribution, and annual trends of spinal injuries. The Bayesian meta-regression tool DisMod-MR 2.1 was used to ensure the consistency among incidence, prevalence, and mortality rates in each case.

Results:

From 1990 to 2019, the number of living patients with spinal injuries in China increased by 138.32%, from 2.14 million to 5.10 million, while the corresponding age-standardized prevalence increased from 0.20% (95% uncertainty interval [UI]: 0.18–0.21%) to 0.27% (95% UI: 0.26–0.29%). The incidence of spinal injuries in China increased by 89.91% (95% UI: 72.39–107.66%), and the prevalence increased by 98.20% (95% UI: 89.56–106.82%), both the most significant increases among the G20 countries; 71.00% of the increase could be explained by age-specific prevalence. In 2019, the incidence was 16.47 (95% UI: 12.08–22.00, per 100,000 population), and the prevalence was 358.30 (95% UI: 333.96–386.62, per 100,000 population). Based on the data of 33 provincial-level administrative regions provided by CDC, age-standardized incidence and prevalence were both highest in developed provinces in Eastern China. The primary causes were falls and road injuries; however, the prevalence and specific causes differed across provinces.

Conclusions:

In China, the overall disease burden of spinal injuries increased significantly during the past three decades but varied considerably according to geographical location. The primary causes were falls and road injuries; however, the prevalence and specific causes differed across provinces.
The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)
Authors: Ng Kwet Shing Richard H. , Clayton Lucy B. , Smith Samuel L. , Watson Marc J. , McKenzie Litza M. , Chalmers David P. , Whitaker Gareth , Bilmen Jonathan G.
Published: March 2024

BACKGROUND

Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.

OBJECTIVES

Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.

DESIGN

Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.

SETTING

Single clinical centre in the UK, April to July 2021.

PARTICIPANTS

Twenty-one healthy male and female individuals.

INTERVENTIONS

Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.

MAIN OUTCOME MEASURES

Overall drug exposure to last measurable concentration (AUC0 to last) and extrapolated to infinity (AUC0 to ∞) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.

RESULTS

Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC0 to last and AUC0 to ∞, respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.

CONCLUSION

NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.

TRIAL REGISTRATION

EudraCT Number: 2020-005719-35, MHRA approval.