bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new strategy for immunotherapy of microsatellite‐stable (MSS)‐type advanced colorectal cancer: Multi‐pathway combination therapy with PD‐1/PD‐L1 inhibitors
Authors: Cai Lingli , Chen Anqi , Tang Dong 
Published: March 2024

AbstractColorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)‐microsatellite instability‐low (MSI‐L)/microsatellite stable (MSS) CRC known as ‘cold’ tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi‐pathway regimens combined with PD‐1/PD‐L1 inhibitors can enhance the efficacy of anti‐PD‐1/PD‐L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD‐L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD‐1/PD‐L1 inhibitors in combination with cytotoxic T‐lymphocyte–associated antigen 4 (CTLA‐4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR‐MSI‐L/MSS CRC.
The mean–variance (in)efficiency of duration‐based immunization
Authors: François Pascal , Moraux Franck 
Published: March 2024

AbstractEmpirical studies report inconclusive assessment of duration‐based immunization, notably showing that more sophisticated strategies do not outperform immunization relying on Macaulay duration. This article provides a mean–variance framework to explain this puzzle. We characterize the efficient portfolio allocations for a stylized barbell strategy trading off reinvestment risk with discounting risk. We show, in a model‐free setting, that barbell allocations form a convex set in the mean–variance space, and the endpoints of the efficient frontier can switch as time passes, reversing the set of efficient allocations. Consequently, duration‐based immunization, which is not minimum variance, can exhibit temporary inefficiency. This result is numerically illustrated in a one‐factor Gaussian and a two‐factor non‐Gaussian model. Using yield curve scenarios resampled from U.S. data over the 1977–2020 period, we further corroborate our conclusions non‐parametrically, and find that duration‐based immunization is sometimes inefficient.
Out‐of‐pocket expenditure among patients with diabetic foot ulcer in a tertiary care hospital of south India: A cross‐sectional study
Authors: Seshadri Hariharan , Karthikeyan Venkatesh , Rudrakumar Malavika , Seshadri Prashanth , Vasudevan Damodaran , Ranganathan Vasuki , Dave Tirth , Ghosh Victor , Ramsai Vadada , Kamaraj Balakrishnan 
Published: March 2024

AbstractDiabetic foot ulcer is a debilitating complication of long‐standing diabetes mellitus. Patients lose their earning potential, face repeated hospitalizations, and are forced to bear heavy treatment costs. This places an enormous financial burden on the patients and their families. This study seeks to ascertain the out‐of‐pocket expenditure among these patients and correlate it with their risk factor profile. In this hospital‐based cross‐sectional study, a total of 154 patients with diabetic foot ulcers or amputations have been studied with an elaborate patient questionnaire and relevant clinical examinations. The costs incurred and the risk factors of the patients were analyzed for statistical association. The median total annual out‐of‐pocket expenditure for the management of diabetic foot ulcers among the study participants was found to be ₹29 775 (₹9650–₹81 120) ($378.14 [$122.56–$1030.22]). Out of the total expenditure, 58.49% went towards direct medical costs, 5.64% towards direct non‐medical costs, and 35.88% for indirect costs. Medications, ulcer dressing and periodic debridement have accounted for 79.26% of direct medical costs. Transportation (61.37%) and patient's loss of income (89.45%) account for the major costs under the direct non‐medical and indirect cost categories, respectively. A high ulcer grade and area, long ulcer duration, and past history of ulcers have higher expenditure. Patients seeking treatment from private establishments and those engaged in professional/skilled occupations have higher expenses. Adequate dressing of foot ulcers and proper footwear are associated with lower treatment expenditure. 68.8% of the participants have faced catastrophic expenditure due to treatment costs of diabetic foot ulcers. Adequate glycaemic control and proper foot care are necessary. Patients must seek medical care at the earliest in case of foot ulceration. Clinicians must provide proper wound care, institute effective antibiotics, and manage the complications. Government and insurance schemes are required to alleviate the patients' financial burden.
Racial/ethnic disparities in sleep health among adolescents in South Korea: The role of substance use behaviours
Authors: Jeon Bomin , Chung Sophia J. , Lee Young Ji 
Published: March 2024

AbstractAimTo examine the relationship between racial/ethnic disparities and substance use behaviours (alcohol and tobacco use) and their impact on the sleep health of South Korean adolescents.DesignSecondary analysis of cross‐sectional study data from the 2021 Korea Youth Risk Behaviour Web‐based Survey dataset.MethodsGiven that Korean society has historically linked its racial/ethnic identity to a shared bloodline, we categorized 2644 adolescents from the Korea Youth Risk Behaviour Web‐based Survey based on their racial/ethnic status, determined by their parents' birthplaces. Using multiple linear regression, we investigated whether the impact of racial/ethnic disparities on sleep health (sleep duration, debt, and timing) varies depending on substance use behaviours (alcohol and tobacco use) after controlling for age, sex, household economic status, depressed mood, suicidal ideation, perceived excessive stress, and anxiety level.ResultsDespite no statistical differences in sleep health and the prevalence of substance use between racial/ethnic groups, racial/ethnic minority adolescents experienced greater sleep debt than racial/ethnic majority adolescents when consuming alcohol. Moreover, racial/ethnic minority adolescents were more likely to report psychosocial distress and had lower parental education level.ConclusionRacial/ethnic minority adolescents were more vulnerable to the detrimental effects of alcohol use on sleep health compared to racial/ethnic majority adolescents. This heightened vulnerability may be attributed to the more pronounced psychosocial challenges and the lower socioeconomic status of parents in the racial/ethnic minority group.ImpactRacial/ethnic disparities are concerning in South Korea, particularly since the negative effects of substance use on sleep health are intensified among racial/ethnic minority adolescents. Nurses and other healthcare providers should recognize the importance of addressing the social disadvantages linked to racial/ethnic disparities. Beyond just advocating for the cessation of substance use, it is crucial to address these underlying issues to reduce sleep disparities among South Korean adolescents.Patient or Public ContributionNo patient or public contribution.
Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa
Authors: Chen Yin , Huang Jian‐Ping , Wang Yong‐Jiang , Tu Meng‐Ling , Li Junheng , Xu Bingyan , Peng Guoqing , Yang Jing , Huang Sheng‐Xiong 
Published: March 2024

ABSTRACTCamptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity. Given that two C‐10 modified camptothecin derivatives, topotecan and irinotecan, have been approved as potent anticancer agents, there is a critical need for methods to access other aromatic ring‐functionalized congeners (e.g., C‐9, C‐10, etc.). However, contemporary methods for chemical oxidation are generally harsh and low‐yielding when applied to the camptothecin scaffold, thereby limiting the development of modified derivatives. Reported herein, we have identified four tailoring enzymes responsible for C‐9 modifications of camptothecin from Nothapodytes tomentosa, via metabolomic and transcriptomic analysis. These consist of a cytochrome P450 (NtCPT9H) which catalyzes the regioselective oxidation of camptothecin to 9‐hydroxycamptothecin, as well as two methyltransferases (NtOMT1/2, converting 9‐hydroxycamptothecin to 9‐methoxycamptothecin), and a uridine diphosphate‐glycosyltransferase (NtUGT5, decorating 9‐hydroxycamptothecin to 9‐β‐D‐glucosyloxycamptothecin). Importantly, the critical residues that contribute to the specific catalytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis experiments. This work provides a genetic basis for producing camptothecin derivatives through metabolic engineering. This will hasten the discovery of novel C‐9 modified camptothecin derivatives, with profound implications for pharmaceutical manufacture.
Market Freezes
Authors: GU CHAO , MENZIO GUIDO , WRIGHT RANDALL , ZHU YU 
Published: March 2024

AbstractMarket freezes are an interesting and theoretically challenging phenomenon —they are observed empirically, but cannot occur in standard models. This paper develops a formal theory of recurrent freezes emphasizing liquidity and self‐fulfilling prophecies. While it is well understood how to get hot and cold spells, where prices and quantities fluctuate, we get asset market freezes and thaws where trade completely stops and starts. The simplest specification gets this using negative asset returns. Other specifications use information frictions or fixed costs. We also consider credit freezes, analyze the extent to which the decentralized nature of trade matters, and discuss policy implications.
Nursing experiences and knowledge of paediatric delirium: Analysing knowledge‐practice gaps
Authors: Shon Soonyoung , Kang Minkyung 
Published: March 2024

AbstractBackgroundDelirium commonly occurs in paediatric patients with acute critical illness and negatively affects clinical outcomes. Variations in delirium knowledge levels and its management have been noted among nurses.AimsThis study investigated nurses' experiences and knowledge levels regarding paediatric delirium. Additionally, we aimed to assess the gap between knowledge levels and practical experiences with paediatric delirium.Study DesignThis cross‐sectional descriptive study conveniently sampled paediatric nurses from a university hospital in South Korea between September 2022 and March 2023. Nursing experiences with paediatric delirium and delirium knowledge levels were measured using structured survey questionnaires. Delirium knowledge was scored 0 to 47, and higher scores indicated higher levels of delirium‐related knowledge. Data were analysed using descriptive statistics and presented as mean, standard deviation, frequency and percentage.ResultsA total of 127 paediatric nurses participated in this study; 40.2% had experience with 1–5 delirium cases in the previous year, and 86.6% (n = 110) had never used assessment tools for paediatric delirium assessment. The mean total delirium knowledge score was 34.45 ± 5.4; the mean scores of knowledge regarding aetiology, signs and symptoms and nursing management of delirium were 8.93 ± 1.31, 13.24 ± 2.81 and 12.3 ± 2.7, respectively. Interventions associated with a lower level of delirium‐related knowledge and a lower performance rate included avoiding restraint use and maintaining hydration and electrolyte levels. Interventions associated with a higher level of delirium‐related knowledge but a lower rate of performance comprised providing orientation, offering emotional support, allowing participants to stay with family members and administering medications to manage delirium.ConclusionsAlthough nurses working in paediatric units exhibited high rate of delirium nursing care, there was the gap between their delirium‐related knowledge and practice. Nurses need to be aware of the insufficient part of delirium care, and paediatric delirium education should be reinforced.Relevance to Clinical PracticePreventing, assessing and systematically managing paediatric delirium is crucial, and considering the study results, delirium education among nurses is needed.
Phenotyping xylem connections in grafted plants using X‐ray micro‐computed tomography
Authors: Camboué Marilou , Janoueix Anne , Tandonnet Jean‐Pascal , Spilmont Anne‐Sophie , Moisy Cédric , Mathieu Guillaume , Cordelières Fabrice , Teillon Jérémie , Santesteban Luis Gonzaga , Ollat Nathalie , Cookson Sarah Jane 
Published: March 2024

AbstractPlants are able to naturally graft or inosculate their trunks, branches and roots together, this mechanism is used by humans to graft together different genotypes for a range of purposes. Grafts are considered successful if functional vascular connections between the two genotypes occur. Various techniques can evaluate xylem connections across the graft interface. However, these methods are generally unable to assess the heterogeneity and three‐dimensional (3D) structure of xylem vessel connections. Here we present the use of X‐ray micro‐computed tomography to characterize the 3D morphology of grafts of grapevine. We show that xylem vessels form between the two plants of natural root and human‐made stem grafts. The main novelty of this methodology is that we were able to visualize the 3D network of functional xylem vessels connecting the scion and rootstock in human‐made stem grafts thanks to the addition of a contrast agent to the roots and improved image analysis pipelines. In addition, we reveal the presence of extensive diagonal xylem connections between the main axial xylem vessels in 2‐year old grapevine stems. In conclusion, we present a method that has the potential to provide new insights into the structure and function of xylem vessels in large tissue samples.
The development of pleiotropic phenotypes in powdery mildew‐resistant barley and Arabidopsis thaliana mlo mutants is linked to nitrogen availability
Authors: Freh Matthias , Reinstädler Anja , Neumann Kira D. , Neumann Ulla , Panstruga Ralph 
Published: March 2024

AbstractPowdery mildew‐resistant barley (Hordeum vulgare) and Arabidopsis thaliana mlo mutant plants exhibit pleiotropic phenotypes such as the spontaneous formation of callose‐rich cell wall appositions and early leaf chlorosis and necrosis, indicative of premature leaf senescence. The exogenous factors governing the occurrence of these undesired side effects remain poorly understood. Here, we characterised the formation of these symptoms in detail. Ultrastructural analysis revealed that the callose‐rich cell wall depositions spontaneously formed in A. thaliana mlo mutants are indistinguishable from those induced by the bacterial pattern epitope, flagellin 22 (flg22). We further found that increased plant densities during culturing enhance the extent of the leaf senescence syndrome in A. thaliana mlo mutants. Application of a liquid fertiliser rescued the occurrence of leaf chlorosis and necrosis in both A. thaliana and barley mlo mutant plants. Controlled fertilisation experiments uncovered nitrogen as the macronutrient whose deficiency promotes the extent of pleiotropic phenotypes in A. thaliana mlo mutants. Light intensity and temperature had a modulatory impact on the incidence of leaf necrosis in the case of barley mlo mutant plants. Collectively, our data indicate that the development of pleiotropic phenotypes associated with mlo mutants is governed by various exogenous factors.
CERK1 compromises Fusarium solani resistance by reducing jasmonate level and undergoes a negative feedback regulation via the MMK2‐WRKY71 module in apple
Authors: Pei Tingting , Zhan Minghui , Niu Dongshan , Liu Yuerong , Deng Jie , Jing Yuanyuan , Li Pengmin , Liu Changhai , Ma Fengwang 
Published: March 2024

AbstractFusarium spp., a necrotrophic soil‐borne pathogen, causes root rot disease on many crops. CERK1, as a typical pattern recognition receptor, has been widely studied. However, the function of CERK1 during plant–Fusarium interaction has not been well described. We determined that MdCERK1 is a susceptibility gene in the apple‐Fusarium solani (Fs) interaction, and jasmonic acid (JA) plays a crucial role in this process. MdCERK1 directly targets and phosphorylates the lipoxygenase MdLOX2.1, an enzyme initiating the JA biosynthesis, at positions Ser326 and Thr327. These phosphorylations inhibit its translocation from the cytosol to the chloroplasts, leading to a compromised JA biosynthesis. Fs upregulates MdCERK1 expression during infection. In turn, when the JA level is low, the apple MdWRKY71, a transcriptional repressor of MdCERK1, is markedly upregulated and phosphorylated at Thr99 and Thr102 residues by the MAP kinase MdMMK2. The phosphorylation of MdWRKY71 enhances its transcription inhibition on MdCERK1. Taken together, MdCERK1 plays a novel role in limiting JA biosynthesis. There seems to be an arms race between apple and Fs, in which Fs activates MdCERK1 expression to reduce the JA level, while apple senses the low JA level and activates the MdMMK2‐MdWRKY71 module to elevate JA level by inhibiting MdCERK1 expression.
Charles Waller and Edward Doubleday—Colleagues of James Blundell and early supporters of blood transfusion
Authors: Learoyd Phil 
Published: March 2024

AbstractThe obstetrician James Blundell performed the first human‐to‐human blood transfusion in England during the early part of the 19th century arguing that it could be used as a treatment for post‐partum haemorrhage. During this period, Blundell personally acknowledged two of his medical colleagues Charles Waller and Edward Doubleday as being strong supporters of the use of blood transfusion. This paper outlines the roles that these two men played in the early history of blood transfusion.
A root‐knot nematode effector targets the Arabidopsis cysteine protease RD21A for degradation to suppress plant defense and promote parasitism
Authors: Yu Jiarong , Yuan Qing , Chen Chen , Xu Tianyu , Jiang Yuwen , Hu Wenjun , Liao Aolin , Zhang Jiayi , Le Xiuhu , Li Hongmei , Wang Xuan 
Published: March 2024

SUMMARYMeloidogyne incognita is one of the most widely distributed plant‐parasitic nematodes and causes severe economic losses annually. The parasite produces effector proteins that play essential roles in successful parasitism. Here, we identified one such effector named MiCE108, which is exclusively expressed within the nematode subventral esophageal gland cells and is upregulated in the early parasitic stage of M. incognita. A yeast signal sequence trap assay showed that MiCE108 contains a functional signal peptide for secretion. Virus‐induced gene silencing of MiCE108 impaired the parasitism of M. incognita in Nicotiana benthamiana. The ectopic expression of MiCE108 in Arabidopsis suppressed the deposition of callose, the generation of reactive oxygen species, and the expression of marker genes for bacterial flagellin epitope flg22‐triggered immunity, resulting in increased susceptibility to M. incognita, Botrytis cinerea, and Pseudomonas syringae pv. tomato (Pst) DC3000. The MiCE108 protein physically associates with the plant defense protease RD21A and promotes its degradation via the endosomal‐dependent pathway, or 26S proteasome. Consistent with this, knockout of RD21A compromises the innate immunity of Arabidopsis and increases its susceptibility to a broad range of pathogens, including M. incognita, strongly indicating a role in defense against this nematode. Together, our data suggest that M. incognita deploys the effector MiCE108 to target Arabidopsis cysteine protease RD21A and affect its stability, thereby suppressing plant innate immunity and facilitating parasitism.
Multispectral brain connectivity during visual attention distinguishes controlled from uncontrolled hypertension
Authors: Son Jake J. , Arif Yasra , Oludipe Davina , Weyrich Lucas , Killanin Abraham D. , Wiesman Alex I. , Okelberry Hannah J. , Willett Madelyn P. , Johnson Hallie J. , Wilson Tony W. 
Published: March 2024

AbstractHypertension‐related changes in brain function place individuals at higher risk for cognitive impairment and Alzheimer's disease. The existing functional neuroimaging literature has identified important neural and behavioural differences between normotensive and hypertensive individuals. However, previously‐used methods (i.e. magnetic resonance imaging, functional near‐infrared spectroscopy) rely on neurovascular coupling, which is a useful but indirect measure of neuronal activity. Furthermore, most studies fail to distinguish between controlled and uncontrolled hypertensive individuals, who exhibit significant behavioural and clinical differences. To partially remedy this gap in the literature, we used magnetoencephalography (MEG) to directly examine neuronal activity that is invariant to neurovascular coupling changes induced by hypertension. Our study included 52 participants (19 healthy controls, 15 controlled hypertensives, 18 uncontrolled hypertensives) who completed a modified flanker attention task during MEG. We identified significant oscillatory neural responses in two frequencies (alpha: 8–14 Hz, gamma: 48–60 Hz) for imaging and used grand‐averaged images to determine seeds for whole‐brain connectivity analysis. We then conducted Fisher‐z tests for each pair of groups, using the relationship between the neural connectivity and behavioural attention effects. This highlighted a distributed network of regions associated with cognitive control and selective attention, including frontal‐occipital and interhemispheric occipital connections. Importantly, the inferior frontal cortex exhibited a unique neurobehavioural relationship that distinguished the uncontrolled hypertensive group from the controlled hypertensive and normotensive groups. This is the first investigation of hypertension using MEG and identifies critical whole‐brain connectivity differences based on hypertension profiles.
imageKey points
Structural and functional changes in brain circuitry scale with hypertension severity and increase the risk of cognitive impairment and Alzheimer's disease.
We harness the excellent spatiotemporal precision of magnetoencephalography (MEG) to directly quantify dynamic functional connectivity in healthy control, controlled hypertensive and uncontrolled hypertensive groups during a flanker task.
In the first MEG study of hypertension, we show that there are neurobehavioural relationships that distinguish the uncontrolled hypertensive group from healthy and controlled hypertensive group in the prefrontal cortex.
These results provide novel insights into the differential impact of hypertension on brain dynamics underlying selective attention.
Exploration of High-Frequency Actuation on Gust Response Using Large Eddy Simulation
Authors: Barnes Caleb J. 
Published: March 2024

Abstract
Mitigation of gust-induced separation and aerodynamic loads using a high-frequency blowing/suction slot is demonstrated using high-order implicit large eddy simulation (LES). This approach was previously shown to be effective at alleviating dynamic stall on pitching wings. A NACA0012 wing section operating at a transitional chord-based Reynolds number of Rec=500,000, subsonic freestream Mach number of M∞=0.1, and angles of attack of α = 4 deg and 12 deg is subjected to discrete 1-cos transverse gusts. Gust-induced stall is demonstrated and then active flow control (AFC) is applied to cases vulnerable to gust-induced stall. The flow control strategy is shown to be effective at stall suppression during gust encounter, thereby providing partial alleviation of gust induced loads. This approach is most effective at attenuating pitching moment increment.