bluuebunny/crossref_metadata_2025 huggingface dataset:
Relativistic electron flux growth during storm and non-storm periods as observed by ARASE and GOES satellites
Authors: Belakhovsky Vladimir Borisovich , Pilipenko Vjacheslav , Antonova Elizaveta E. , Miyoshi Yoshizumi , Kasahara Yoshiya , Kasahara Satoshi , Higashio Nana , Shinohara Iku , Hori Tomoaki , Shoya Matsuda , Shoichiro Yokota , Takashima Takeshi , Takefumi Mitani , Keika Kunihiro , Nakamura Satoko
Published: April 2023

Variations of relativistic electron fluxes and wave activity in the Earth magnetosphere are studied in order to determine the contribution of different acceleration mechanisms of the outer radiation belt electrons: ULF mechanism, VLF mechanism, and adiabatic acceleration. The electron fluxes were measured by Arase satellite and geostationary GOES satellites. The ULF power index is used to characterize the wave activity of the magnetosphere in the Pc5 range. To characterize VLF wave activity in the magnetosphere, we use data from Arase satellite (PWE instrument). We consider strongest magnetic storms during the Arase satellite era: May 27-29, 2017; September 7-10, 2017; and August 25-28, 2018. Also, non-storm intervals with a high solar wind speed before and after these storms are considered as well. The magnitudes of relativistic electron fluxes during these magnetic storms (with an average solar wind speed) are found to be greater than that during non-storm intervals with a high solar wind streams. The substorm activity, as characterized AE index, is found to be a necessary condition for the increase of relativistic electron fluxes, whereas a high solar wind speed alone is not always necessary for the relativistic electron growth. The enhancement of relativistic electron fluxes by 1.5-2 orders of magnitude is observed 1-3 days after the ULF index growth and growth of the VLF radiation power. The analysis shows that the growth of VLF and ULF wave activity occurs approximately at the same time and coincides with the growth of substorm activity. Therefore, it is not easy to separate the contribution of these acceleration mechanisms over time. These mechanisms can act on a first phase of electron acceleration. During magnetic storms, the flux intensity maximum shifts to lower L-shells compared to intervals without magnetic storms. The acceleration mechanism associated with the injection of electrons into the region of the magnetic field weakened by the ring current and their subsequent betatron acceleration during the restoration of the magnetic field can work effectively at the second phase of electron acceleration.
The first direct measurements of ventilatory flow and oxygen utilization after exhaustive exercise and natural feeding in a teleost fish, Oncorhynchus mykiss
Authors: Eom Junho , Wood Chris M.
Published: April 2023

A new “less invasive” device incorporating an ultrasonic flow probe and a divided chamber, but no stitching of membranes to the fish, was employed to make the first direct measurements of ventilatory flow rate (V̇w) and % O2 utilization (%U) in juvenile rainbow trout (37 g, 8ºC) after exhaustive exercise (10-min chasing) and natural voluntary feeding (2.72% body mass ration). Under resting conditions, the allometrically scaled V̇w (300 ml kg−1 min−1 for a 37-g trout = 147 ml kg−1 min−1 for a 236-g trout exhibiting the same mass-specific O2 consumption rate, ṀO2) and the convection requirement for O2 (CR = 4.13 L mmol−1) were considerably lower, and the %U (67%) was considerably higher than in previous studies using surgically attached masks or the Fick principle. After exhaustive exercise, V̇w and ṀO2 approximately doubled whereas frequency (fr) and %U barely changed, so increased ventilatory stroke volume (Vsv) was the most important contributor to increased ṀO2. CR declined slightly. Values gradually returned to control conditions after 2–3 h. After voluntary feeding, short-term increases in V̇w, Vsv and ṀO2 were comparable to those after exercise, and fr again did not change. However, %U increased so CR declined even more. The initial peaks in V̇w, Vsv and ṀO2, similar to those after exercise, were likely influenced by the excitement and exercise component of natural feeding. However, in contrast to post-exercise fish, post-prandial fish exhibited second peaks in these same parameters at 1–3 h after feeding, and %U increased further, surpassing 85%, reflecting the true “specific dynamic action” response. We conclude that respiration in trout is much more efficient than previously believed.
Umbilical cord mesenchymal stem cell alleviates asthma via Nrf2/HO-1/NF-κB signaling pathway
Authors: Lin Yiping , Lin Xinxiao , Wu Xiangjie , Ying Xiaoqian , Yu Qian , Chen Li , Pan Huiying , Wu Xiaoyu
Published: April 2023

Background Numerous previous studies have proved the immunomodulatory properties of mesenchymal stem cells (MSCs) especially for human umbilical cord mesenchymal stem cells (UC.MSCs) in the progression of asthma, but the action mechanism remains unclear.Methods In the present work, a rat asthma model induced by ovalbumin (OVA) was established to ascertain the effects of UC.MSCs treatment on inflammation, oxidative stress and airway remodeling. Additionally, both in rat asthma model and TGF-β-induced airway smooth muscle cells (ASMCs), the interaction of UC.MSCs with Nrf2/HO-1/NF-κB pathway was evaluated.Results We demonstrated that OVA-induced inflammation infiltration and the increase of cell counts of eosinophils, lymphocytes, and macrophages were dramatically reduced after UC.MSCs treatment. The downregulated expression of anti-oxidant genes (NQO1 and HO-1), and the reduced GSH levels caused by OVA challenge were restored following the treatment of UC.MSCs. Meanwhile, UC.MSCs also prohibited collagen deposition, suppressed goblet cell hyperplasia and decreased the levels of airway remodeling markers (α-SMA, TGF-β1, MMP9 and TIMP1) in asthma rat model. In in vitro experiments, TGF-β could facilitate the viability of ASMCs and restrain G1 cell cycle arrest, while UC.MSCs revised these changes. Additionally, treatment with UC.MSCs could significantly activate the expression of HO-1 and NRF2, but inhibit NF-κB levels in vivo and in vitro.Conclusions In a word, these findings indicated that UC.MSCs can alleviate asthma via Nrf2/HO-1/NF-κB signaling pathway, which provided a theoretical basis for asthma therapy in clinic.
Dispersion complexity-entropy curves: an effective method to detect the structures of complex systems
Authors: Jiang Runze , Shang Pengjian , Zhang Boyi
Published: April 2023

Complexity-entropy curves(CEC) is a useful tool to detect the structure of time series. It’s widely applied in many research areas since it can distinguish the chaotic system and the stochastic process well. However, the original permutation complexity-entropy curves(PCEC) based on permutation entropy(PE) has a defect for it can not take means and amplitudes of time series into consideration, which may lead to some errors when distinguishing the systems. In this paper, we propose dispersion complexity-entropy curves(DCEC) to overcome the defects of PCEC. In addition, we expand the curves from two-dimension to threedimension. We first compare DCEC with PCEC by simulated data. The result shows that DCEC are not only more distinguishable but also more robust with the change of parameters when detecting periodic series. Then, we apply our method to real-world data to illustrate its practicability. We propose a creative feature extraction method based on DCEC and combine it with MSVM to diagnose the different types of bearing fault, which obtains perfect results for the accuracy achieves 100%. We also apply DCEC to stock indices in different countries and different periods to analyze the complexity degree of financial markets. The results successfully detect American financial crisis in 2008 and the rapid development of the economy in China during 2014-2018. These demonstrate that DCEC can serve as an effective method to analyze complex systems.
Low ratio of IL-10 to IFN-γ and Low IL-10 level indicate good prognosis in Salmonella enterica serovar Typhimurium triggered secondary hemophagocytic lymphohistiocytosis: a case report and literature review
Authors: Chen Yuanyuan , Liang Lingfang , Xu Xiangzhi , Lin Shupeng , Xu Xiaojun
Published: April 2023

Background: Secondary hemophagocytic lymphohistiocytosis triggered by Salmonella enterica serovar Typhimurium is rare in pediatric patients. There is a specific cytokine pattern to differentiate HLH subtypes, including IFN-γ, IL-10, and IL-6, and the ratio of IL-10 to IFN-γ, which can guide HLH treatments choice.
Case presentation: We present a pediatric 9-year old patient who presented with fever and pancytopenia for three days into our hospital, who showed positive results of Salmonella enterica serovar Typhimurium, Human Rhino Virus and Mycoplasma Pneumoniae infections. At the time of admission to our institution, the patient’s Th1/Th2 cytokine results showed that IL-6 was 326 pg/ml, IL-10 was 9.1 pg/ml, and IFN-γ was 246.7 pg/ml, with a ratio of IL-10 to IFN-γ was 0.04. In this study, this patient received meropenem, linezolid, and cefoperazone/sulbactam for anti-infection therapy, combined with high dose methylprednisolone therapy and anti-shock supportive treatments for twice. After careful evaluation, this patient did not receive HLH chemotherapy during the whole disease course, and he recovered well.
Conclusions: Early antimicrobial and supportive treatment would be enough for Salmonellatriggered sHLH with a ratio of IL-10 to IFN-γ ≤ 1.33, and IL-10 ≤ 10.0 pg/ml, and/or IFN-γ ≤ 225 pg/ml on admission, and HLH-94/2004 protocol was not necessary in such condition.
Quantification and Source Identification of Atmospheric Trace Gases over Dhaka, Bangladesh
Authors: Kamal A. T.M. Mustafa , Islam Md Safiqul , Ahmed Tanvir , Hoque Serajul , Salam Abdus
Published: April 2023

The authors have requested that this preprint be removed from Research Square.
Comparative study on clinicopathological features and prognosis of IgA vasculitis nephritis and IgA nephropathy in children
Authors: Lv Yan , Fu Rui , Peng Xiao-Jie , Wang Ying , Yin Ting-Ting , Deng Yan-Qing
Published: April 2023

Background Although IgA vasculitis nephritis (IgAVN) and IgA nephropathy (IgAN) have many clinical and pathological parallels, they also have some differences, and their relationship has not yet been determined. This paper examines the differences in clinicopathology and prognosis between kids with IgAVN and IgAN. Methods We retrospectively analyzed the data of 809 children with IgAVN and 236 children with IgAN between January 2006 and December 2021 to compare the similarities and differences between IgAVN and IgAN in clinicopathology and prognosis. Results IgAN was more prevalent in the summer, whereas IgAVN was more common in the fall (P < 0.0001). IgAN tubular interstitial injury is more severe, chronicity index and total biopsy score were higher than IgAVN (P < 0.0001). The deposition intensity of C3, and the deposition rate of IgA pure in the mesangium, were higher in IgAVN than in IgAN (P < 0.0001), and the intensity of IgA deposition was also higher in IgAVN (P = 0.003). IgAVN had a better prognosis and a higher kidney remission rate (P < 0.0001). Cox regression revealed interstitial fibrosis as an independent risk factor for poor prognosis of IgAVN (HR = 1.449, 95%CI:1.011–2.076, P = 0.043) and IgAN (HR = 2.384, 95%CI:1.313–5.024, P = 0.022). Furthermore, IgA++ (HR = 2.25, 95%CI:1.212–4.175, P = 0.01) and IgA+++ (HR = 12.043, 95%CI:1.498–96.854, P = 0.019) could be risk factors for bad prognosis of IgAVN. Conclusions IgAN was more severe than IgAVN regarding kidney impairment, interstitial damage, and prognosis. There were different levels and locations of immune complex deposition in the kidneys, supporting the notion that they are two distinct diseases. The intensity of IgA deposition may be a risk factor for poor IgAVN prognosis.
Health management service models for the elderly with visual impairment ： a scoping review
Authors: Dong Yu , Wang Aiping
Published: April 2023

Background The incidence of visual impairment(VI ) in older people is gradually increasing. This review aimed to summarise the evidence on existing health management models and strategies for older adults with VI to improve health-related and vision-related quality of life (QoL) in older people.Methods Based on the framework of the scoping review methodology of Arksey and O'Malley (2005), a comprehensive literature search of relevant literature published between January 2010 and June 2022 in PubMed, CINAHL, EMBASE, Web of Science, Cochrane Library, CNKI, VIP, Wanfang database, Sinomed and the grey literature.Results Finally, 31 articles were included. The health management model had a multidisciplinary team low vision rehabilitation model, medical consortium two-way management model, low vision community comprehensive rehabilitation model, medical consortium-family contract service model, screening-referral-follow-up model, and three-level low vision care model. The health management strategy covers nine aspects, the combination of multi-element strategies is feasible, and network information technology has also shown positive results.Conclusions In the future, under the Internet and hierarchical management model, we should provide demand-based personalized support to rationalize and scientifically achieve hierarchical management and improve resource utilization efficiency and eye health outcomes.
Serum Krebs von den Lungen-6 level as a prognostic biomarker in patients with interstitial lung abnormalities
Authors: Kang Hyung Koo , Kang Jiyeon , Seo Woo Jung , Kang Jieun , Park So-Hee , Koo Hyeon-Kyoung , Park Hye Kyeong , Lee Sung-Soon , Shin Jong Wook
Published: April 2023

Data associating progression of interstitial lung abnormalities (ILA) and serum biomarkers, including white blood cell differential counts and Krebs von den Lungen-6 (KL-6) are sparse. This study aimed to evaluate the relationship between disease progression and serum biomarkers in patients with ILA. This retrospective cohort study collected data, such as clinical characteristics, pulmonary function test, chest computed tomography (CT), complete blood cell counts, and KL-6 levels from 159 patients (63 with ILA and 74 with interstitial lung diseases [ILDs]) from October 2021 to September 2022. In 42 patients who had previously undergone chest CT, the risk factors for radiologic progression was evaluated using the receiver operating characteristic curve analysis and multivariate logistic regression. Among the 42 patients with ILA, 12 showed radiological progression. Serum KL-6 showed moderate performance with area under the curves ranging from 0.60–0.93 (p = 0.008) for radiological progression. In multivariate analysis, fibrotic ILA (odds ratio [OR] 6.99; 95% confidence interval [CI], 1.12–43.5) and KL-6 > 400 U/mL (OR, 6.52; 95% CI, 1.14–37.2) were associated with radiological progression. Serum KL-6 level is a reliable indicator of progression of ILA in asymptomatic patients. Patients with serum KL-6 > 400 U/mL require careful observation for radiological progression.
Prevalence, trends and individual patterns of long-term antidepressants medication use in the adult Swiss general population, 2013 - 2021
Authors: Amrein Melanie A. , Hengartner Michael P. , Näpflin Markus , Farcher Renato , Huber Carola A.
Published: April 2023

Purpose: Antidepressant use has increased in many European countries, mostly driven by longer treatment duration. The aim of this study was to provide prevalence rates of long-term users of antidepressants for the Swiss population over the last decade and to investigate associated factors for longer use.
Methods: We examined the prevalence rates of individuals with at least one prescription for antidepressants using longitudinal health claims data. To compare different lengths of prescription duration, we defined short-term (<6 months), medium-term (6-12 months) and long-term users (>12 months). We applied a binary logistic regression model to investigate the effects of population characteristics and treatment patterns on long-term compared to short- and medium-term users.
Results: In 2021, 9% of the Swiss population (n=770 698) received at least one antidepressant prescription. This one-year-prevalence remained stable since 2013. In 2020, the proportion of long-term users was 69.4%, with steady increase from 2014 to 2020. The numbers of medium- and short-term users have decreased during this period. Older age, being a woman, living in an urban area, living in the Italian speaking part of Switzerland, living in a nursing home, being enrolled in a standard care plan, and receiving psychiatric or psychotherapeutic care were factors associated with long-term users.
Conclusion: The proportion of long-term users in Switzerland is steadily increasing. Taking antidepressants longer than recommended may indicate possible overprescribing. Given the ongoing debate about the confounding effects of relapse and withdrawal, more research is needed to investigate antidepressants overprescribing, particularly for older people.
Entanglement propagation and dynamics in non-additive quantum systems
Authors: Giachetti Guido , Defenu Nicolo
Published: April 2023

The prominent collective character of long-range interacting quantum systems makes them promising candidates for quantum technological applications. Yet, lack of additivity overthrows the traditional picture for entanglement scaling and transport, due to the breakdown of the common mechanism based on excitations propagation and confinement. Here, we describe the dynamics of the entanglement entropy in many-body quantum systems with a diverging contribution of the long-range two body potential to the internal energy. While in the strict thermodynamic limit entanglement dynamics is shown to be suppressed, a rich mosaic of novel scaling regimes is observed at intermediate system sizes, due to the possibility to trigger multiple resonant modes in the global dynamics. Quantitative predictions on the shape and timescales of entanglement propagation are made, paving the way to the observation of these phases in current quantum simulators. This picture is connected and contrasted with the case of local many body systems subject to Floquet driving.
Simplified models of aerosol collision and deposition for disease transmission
Authors: Jung Sunghwan
Published: April 2023

Fluid-mechanics research has focused primarily on droplets/aerosols being expelled from infected individuals and transmission of well-mixed aerosols indoors. However, aerosol collisions with susceptible hosts earlier in the spread, as well as aerosol deposition in the nasal cavity, have been relatively overlooked. In this paper, two simple fluid models are presented to gain a better understanding of the collision and deposition between a human and an aerosol. The first model is based on the impact of turbulent diffusion coefficients and air flow in a room on the collisions between aerosols and humans. Infection rates can be determined based on factors such as air circulation and geometry as an infection zone expands from an infected host. The second model clarifies how aerosols of different sizes adhere to different parts of the respiratory tract. Based on the inhalation rate and the nasal cavity shape, the critical particle size and the deposition location can be determined. Our study offers simple fluid models to understand the effects of geometric factors and air flows on the aerosol transmission and deposition.
Efflux pump genes variants in MDR TB strains with discrepant phenotype-genotype correlations may further guide drug resistance interpretation
Authors: Hasan Zahra , Razzak Safina Abdul , Kanji Akbar , Shakoor Sadia , Hasan Rumina
Published: April 2023

Introduction: Whole genome analysis of Mycobacterium tuberculosis (MTB) is an increasingly important method of identification of multi-drug resistance (MDR) in clinical isolates. It is based on the identification of single nucleotide variants (SNVs) in genes associated with resistance. However, there remain gaps in our understanding of phenotype – genotype correlation between strains. Efflux pumps contribute to drug resistance and here we studied SNVs in key efflux pump genes (EP) to investigate their association with resistance.
Methods: Whole genome data of 2221 MTB isolates comprising 1432 susceptible and 789 drug resistant strains were downloaded from ReSeqTB database. MTB lineage and resistance genotyping analysis was performed using an in-house bioinformatics pipeline, MTB-VCF. SNVs in 47 EP genes were categorized according to their SIFT/Polyphen scores.
Results: We identified variants unique to EP in DR isolates. SIFT/Polyphen effect analysis determined 38 high impact SNVs across twenty EP genes (EP) to be present in these 789 genomes. SNVs were not associated with MTB lineages. The EPs with SNVs in DR isolates were Rv1819, Rv0194, Rv0507, Rv2333c, Rv3728, Rv3823, Rv1250, Rv1273, Rv1458, Rv1634, Rv1217, Rv1218, Rv0450, Rv0676c, Rv0191, Rv3008, Rv3756, Rv2688, Rv1704 and Rv1877. Examination of 52 isolates with discrepant phenotype-genotypes resistance comprising, MDR, pre-XDR and XDR strains revealed SNVs in EP associated with RIF and INH (Rv0194, Rv1217_1218, Rv1819, Rv0450, Rv1458, Rv0507), and those associated with fluoroquinolone (Rv1634 and Rv2688) resistance.
Conclusions: We identified SNVs in efflux pumps which could contribute to resistance in MTB strains. It may be important to consider these as part of MTB genome-based resistance interpretation. Functional studies combined with GWAS and RNA profiling would further confirm these findings.
Challenges of considering both extremities of the weight status spectrum to better understand obesity: Insights from the NUTRILEAN Project in Constitutionally Thin Individuals.
Authors: BAILLY Mélina , BOSCARO Audrey , Verney Julien , Tremblay Angelo , King James , Pereira Bruno , COSTES Frédéric , JULIAN Valérie , Duclos Martine , Boirie Yves , Thivel David , BAILLY Mélina
Published: April 2023

While the physiology of obesity has been so extensively investigated to date, only an extremely small number of studies (less than 50) have focused on the other extremity of the weight spectrum: constitutional thinness. Yet, this important state of underweight in the absence of any eating disorders provides a mirror model of obesity that might be particularly insightful in understanding obesity. Nevertheless, important methodological and recruitment-related issues appear when it comes to this complex constitutionally thin phenotype, as experienced by our research group with the realization of the ongoing NUTRILEAN clinical trial. To face this challenge, the present paper aims at identifying, analysing, and discussing the quality of such recruitment processes in publications about constitutional thinness. In this order, a group of experts collectively created a new grading system to assess the level of rigor and quality achieved by each study based on different criteria. The main results were that (i) metabolic-related biasing criteria were poorly observed despite being crucial, (ii) recruitment processes were not detailed enough and with sufficient explicitness, and (iii) recruiting among already identified patients would be associated with both higher sample sizes and better scores of quality. The present work encourages investigators to adopt a high level of rigor despite the complexity and duration of recruitment processes for this specific population, and readers to pay close attention to the quality of recruitment when interpreting the data. To better understand obesity and its physiological adaptations, it seems essential not only to compare it to normal-weight conditions, but also to the other extremity of the weight status spectrum represented by constitutional thinness.
Foxg1 modulation of the Prkcd gene in the lateral habenula mediates trigeminal neuralgia-associated anxiety-like behaviors in mice
Authors: Abudula Aji , Zhang Chen , Chen Teng , Liu Wen-Bo , Mi Wen-Li , Mao-Ying Qi-Liang , Wang Yan-Qing , Chu Yu-Xia
Published: April 2023

Trigeminal neuralgia (TN) is a debilitating condition and often leads to mood disorders such as depression and anxiety. The present study aimed to determine the molecular mechanisms involved in the pathogenesis of TN and its associated anxiety. We found that partial transection of the infraorbital nerve (pT-ION) in mice induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors. Gene microarray analysis found that Foxg1 expression was significantly upregulated after pT-ION, and knocking down Foxg1 by microinjection of adeno-associated virus carrying Foxg1 shRNA into the bilateral lateral habenula (LHb) effectively alleviated pain-related and anxiety-like behaviors. RNA sequencing showed that Prkcd may be the downstream gene modulated by Foxg1. Pharmacological inhibition of protein kinase C delta, the Prkcd-encoded protein, in the LHb effectively reversed pT-ION-induced pain-related and anxiety-like behaviors. Dual luciferase reporter analysis indicated the direct promotion of Prkcd gene expression by Foxg1. In conclusion, trigeminal nerve injury induced the upregulation of Foxg1 in the LHb, which promoted the expression of Prkcd, thus resulting in orofacial pain and anxiety-like behaviors. This finding provides potential therapeutic targets and a theoretical basis for the clinical treatment of TN and its associated anxiety.
Impact of a Guaranteed Access Program to Imatinib on the Survival of Patients with Chronic Myeloid Leukemia
Authors: Lampon Gilberto Barranco , Vidal Itzel , Gama Dulce , Martínez Carlos , Acosta Brenda , Ramos Christian , Martínez Emmanuel , Zazueta Juan , Olarte Irma , Martínez Adolfo , Cervera Eduardo , Mendoza Iveth , Arcos Diana , Cruz Judith
Published: April 2023

Purpose: This work aimed to evaluate the impact of a guaranteed access program to Imatinib on the survival of patients with Chronic Myeloid Leukemia
Methods: We carried out a retrospective, observational, and analytical study of the database of patients diagnosed with Chronic Myeloid Leukemia of the Instituto Nacional de Cancerología and the Hospital General de México Dr. Eduardo to assess overall survival based on guaranteed access or not to Imatinib.
Results: With an average follow-up of 99 months, the estimated 20-year overall survival for all patients was 72% (95% CI, 76-67). A significant difference was found in the 20-year survival probability in favor of patients with guaranteed access 76% (95% CI, 81-71) vs. 61% (95% CI, 69-52) (p<0.001), in addition to those in which they had better attachment 81.2% (95% CI, 85-76) vs. 44.9% (95% CI, 52-37) (p<0.001).
Conclusion: CML is the most frequent chronic leukemia in Mexico, it mainly affects the economically active population (mean age 40), and the prognosis in our country has improved, emulating developed countries; however, the results depend on access to treatment as well as proper monitoring.
Remote Ischemic Conditioning Alleviates Alzheimer’s Disease Pathology in Female TgF344 Rats
Authors: Ma Yuxuan , Sun Wuxiang , Bai Jing , Gao Fujia , Liu Huiyu , Huang Yuanyuan , Hu Jiewei , Xu Chao , Ma Haoran , Yuan Tao , Zhang Xin , Sun Chenxu , Liu Zixuan , Wang Ruimin
Published: April 2023

Alzheimer's disease (AD) has become a global public health crisis and research is urgently needed to explore strategies to prevent, and slow AD progression and improve cognitive function. Growing evidence suggests that blood vessels play a key role in physiological Aβ clearance, and blood biomarkers might hold promise for future diagnosis of AD. Remote ischemic conditioning (RIC), a noninvasive intervention by performing sub-lethal ischemic-reperfusion cycles on limbs, has been reported to exert beneficial effects after stroke, including increasing cerebral blood flow (CBF), anti-inflammation, and capillary remodeling. However, whether and how chronic RIC can prevent AD pathogenesis is largely unclear. In this study, female wild-type (WT) and TgF344 AD rats aged 3 months (young), 12 months (middle-age), and 19 months ± 3 weeks (old) were used to investigate the physical and pathological alterations of CBF and blood-brain barrier (BBB) in frontal parietal cortex. Furthermore, we selected middle-aged animals for RIC intervention five times each week for 4 weeks. Depression and cognitive function were measured using force swimming and Barnes maze tests. We also assessed the effects of aging and RIC intervention on BBB integrity; vascular-associated inflammatory factors VCAM1; dynamic alteration of astrocytes; production and clearance of Aβ; and changes in synaptic-associated proteins. The results revealed that CBF was initially high in young AD rats, followed by a significant decline in both middle- and old-age AD animals. Correspondingly, astrocytes presented reactive astrogliosis in young AD rats, followed by tightly vascular-wrapped hypertrophy in middle-aged AD rats, and degenerative or atrophic morphology in old-age AD rats. Likewise, BBB integrity was significantly impaired with aging in AD rats, as evidenced by loss of tight junction proteins ZO-1, and occludin. RIC intervention elevated CBF and protected capillary integrity, as evidenced by increased expression of TJ proteins and pericyte marker PDGFR1β, and decreases in VCAM1 protein. RIC also reversed degenerative morphology of astrocytes and upregulated A2 astrocyte phenotype markers PTX3, S100A10, and PAN marker GFAP, vimentin, while downregulating A1 astrocyte phenotype marker C3. Furthermore, RIC intervention significantly increased vascular endothelial glucose transporter (GLUT) 1 level and decreased BACE1 and Aβ1–42 levels. Finally, RIC intervention enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in middle-aged AD rats. These results demonstrated that BBB impairment and abnormal alteration of astrocytes occur at the early stage of AD. Chronic RIC intervention exerts vascular- and neuroprotective roles, suggesting that RIC may be a promising intervention targeting the BBB to prevent, and slow AD progression.
Dietary protein intake and all-cause mortality: results from the Kawasaki Aging and Wellbeing Project
Authors: Kurata Hideaki , Meguro Shu , Abe Yukiko , Sasaki Takashi , Asakura Keiko , Arai Yasumichi , Itoh Hiroshi
Published: April 2023

Background: Increased protein intake has been recommended to prevent sarcopenia/frailty, but there are limited reports on the quantity and quality of protein intake needed and the associated prognosis, especially in much older individuals in Asia. In this study, we aimed to investigate the relationship between protein intake and prognosis in Japanese subjects, aged 85 years and older.
Objectives: The data were obtained from The Kawasaki Aging and Wellbeing Project, which is a prospective cohort study of older adults aged between 85 and 89 with no physical disability at baseline. Of the 1026 adults in the cohort, 833 individuals were included in the analysis, excluding those who had not completed the brief self-administered diet history questionnaire or those who scored less than 24 on the Mini-Mental State Examination. The participants were grouped into quartiles based on protein intake: Q1 (protein < 14.7, %Energy), Q2 (14.7 ≤ protein < 16.7, %Energy), Q3 (16.7 ≤ protein < 19.1, %E), and Q4 (19.1 ≤, %Energy). Multivariate Cox proportional hazards models were utilized to evaluate the association between protein intake and all-cause mortality. Kaplan–Meier survival curves were employed to investigate the relationship between protein intake and mortality.
Results: The mean protein intake of our study population was 17.0% of total energy. Animal protein intake, especially fish intake, increased significantly along with total protein intake. The study had an average observation period of 1,218 days and recorded 89 deaths. After adjusting for age, sex, skeletal muscle mass index, medical history, and education, a lower risk of all-cause mortality was observed in the group with the highest protein intake (Q4) than in the group with the lowest protein intake (Q1) (hazard ratio: 0.45, p-value: 0.017, 95% confidence interval: 0.22–0.93). This association between protein intake and prognosis remained robust even after adjusting for serum albumin and other nutrients, in addition to the aforementioned covariates.
Conclusion: Protein intake is associated with a reduced risk of all-cause mortality in older adults aged ≥85 years who engage in independent activities of daily living. This association may impact prognosis via a mechanism that differs from muscle mass maintenance.
AFM kymographs can provide robust conformational transition detection for pharmaceutically relevant membrane proteins in lipid bilayers
Authors: Schaefer Katherine G. , Roberts Arthur G. , King Gavin M.
Published: April 2023

Membrane proteins play critical roles in disease and in the disposition of many pharmaceuticals. A prime example is P-glycoprotein (Pgp) which moves a diverse range of drugs across membranes and out of the cell before a therapeutic payload can be delivered. Conventional structural biology methods have provided a valuable framework for comprehending the complex conformational changes underlying Pgp function, which also includes ATPase activity, but the lack of real-time information hinders understanding. Atomic force microscopy (AFM) is a single-molecule technique that is well-suited for studying active membrane proteins in bilayers and is poised to advance the field beyond static snapshots. After verifying Pgp activity in surface-support bilayers, we used kymograph analysis in conjunction with AFM imaging and simulations to study structural transitions at the 100 ms timescale. Though kymographs are frequently employed to boost temporal resolution, the limitations of the method have not been well characterized, especially for sparse non-crystalline distributions of pharmaceutically relevant membrane proteins like Pgp. Common experimental challenges are analyzed, including protein orientation, instrument noise, and drift. Surprisingly, a lateral drift of 75% of the protein dimension leads to only a 12% probability of erroneous state transition detection; average dwell time error achieves a maximum value of 6%. Rotational drift of proteins like Pgp, with azimuthally-dependent maximum heights, can lead to artifactual transitions. This pitfall may be alleviated by torsional constraints. Confidence in detected transitions may be increased by using conformation-altering ligands such as non-hydrolysable analogs. Overall, the data indicate that AFM kymographs are a viable method to access conformational dynamics for Pgp, but generalizations of the method should be made with caution.
The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer
Authors: Boll Lilian Marie , Perera-Bel Júlia , Rodriguez-Vida Alejo , Arpi Oriol , Rovira Ana , Juanpere Núria , de Oca Sergio Vázquez Montes , Hernández-Llodrà Silvia , Lloreta Josep , Albà M. Mar , Bellmunt Joaquim
Published: April 2023

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. Our findings were validated in an additional cohort. Thus, using clonal TMB over total TMB could increase prediction accuracy. They also show that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting a high immune cell infiltration signature could be an added predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different immune signatures should be considered for predictive models.
Alkaline-based aqueous sodium-ion batteries for large-scale energy storage
Authors: Qiao Shizhang , Wu Han , Hao Junnan , Jiang Yunling , Jiao Yiran , Liu Jiahao , Xu Xin , Davey Kenneth , Wang Chunsheng
Published: April 2023

Aqueous sodium-ion batteries (ASIBs) are practically promising for large-scale energy storage, but their energy density and lifespan are hindered by water decomposition. Current strategies to enhance the water stability include using expensive fluorine-containing salts to create a solid electrolyte interface or adding potentially-flammable organic co-solvents in the electrolyte to reduce water activity. However, these methods have significantly increased cost and safety risk. Shifting electrolytes from near neutrality to alkalinity can fundamentally suppress hydrogen evolution, but trigger oxygen evolution and cathode dissolution. Here, we present an alkaline-type ASIB with Mn-based Prussian blue analogue cathode, which exhibits a record lifespan of 13,000 cycles at 10 C together with high energy density of 90 Wh kg−1 at 0.5 C. This is achieved by building a nickel/carbon layer to induce a H3O+-rich local environment near the cathode surface, thereby suppressing oxygen evolution and cathode dissolution. Simultaneously, Ni atoms can be in-situ embedded into the cathode to enable its durability. At an industry-level mass loading > 30 mg cm−1, the pouch cell exhibits excellent stability with a capacity retention of ~ 100% following 200 cycles at 300 mA g−1, outperforming previously reported aqueous batteries.
A Database for Oncological Research and Quality Assurance: Implementation and first Experiences with the University Clinical Cancer Registry Regensburg
Authors: Saibold Anna , Koller Michael , Mueller Karolina , Koelbl Oliver , Vielsmeier Veronika , Pukrop Tobias , Spies Oliver , Eilers Vivian , Brese Cathleen , Amann Denise , Maurer Julia
Published: April 2023

Legal requirements, certification specifications, as well as the demand for real world data on cancer research and treatment led to the decision to establish the University Clinical Cancer Registry Regensburg. The first organizational step in the implementation process of this oncological data registry was the evaluation and acquisition of suitable tumor documentation and database software. For this purpose, an evaluation matrix comprising required database software criteria was designed and consented to by a multidisciplinary group of experts. Next, a yearly report of the Institute for Cancer Center Certification (OnkoZert 2019) was considered to identify database software already in use. The identified systems were rated according to the established criteria matrix and other relevant aspects. Onkostar was the system considered most suited for building up an oncological data repository. In the second step, the central IT department implemented Onkostar on-premise and migrated digitally available data after an adaptation and verification process. In parallel, a uniformed process for handling emerging oncological research questions was established. For research requirements, three documents were introduced into the clinical workflow: a proposal for data extraction, procedural instructions, and statistical training materials. In the final step, the implemented software and the process for handling research requirements in practice were evaluated by using two exemplary use cases with the focus on clinic-wide analyses and currently relevant scientific topics. A two-month test phase conducted by various user groups showed a preference for Onkostar tumor documentation software from IT-Choice, mainly because of its adjustability to support research and treatment. Newly added and migrated data can be used for certification and research purposes. This software also provides support in current tumor documentation by displaying the course of cancer disease for individual patients over time. Such oncological data registries can be a powerful tool for legally required cancer registration, the certification of medical centers, as well as for additional oncological research. Tumor databases can be helpful in projects on cancer treatment and scientific aims. The experiences made at the University Hospital Regensburg may be used as a guidance for implementing clinical databases in similar settings with interdisciplinary responsibilities.
Phase angle and extracellular water/total body water ratio predict postoperative acute nutritional and inflammatory status in cancer patients
Authors: Meng Liping , Cai Bin , Luo Lan , Chen Sue , Shen Qing , Fu Yafei , Zhu Chenping
Published: April 2023

Objectives To identify the difference of body composition between cancer patients and those non-malignant tumor patients and analyze changes in body composition after surgical treatment for cancer, as well as estimate the relationship of preoperative body composition on postoperative systemic nutritional status and inflammation.Methods 92 patients diagnosed with different type of cancer and 91 non-malignant tumor patients were assessment body composition by bioelectrical impedance analysis (BIA) and compared the changes between two groups. Spearman correlation and multiple linear regression were used to analyze the correlation and relationship between preoperative body composition and postoperative length of stay, albumin (Alb), prealbumin (PreAlb) and C-reactive protein (CRP) in cancer patients, respectively.Results Compared to the normal group, patients with gastric cancer have lower PA (P < 0.1), fat mass index (FMI) and higher extracellular water/total body water (ECW/TBW) ratio (P < 0.05). Regarding patients with prostatic cancer, findings similar to lower PA (male comparison patients 5.91° vs. prostatic cancer patients 5.51°, P < 0.1) in gastric cancer patients in the test cohort were observed. And body cell mass (BCM) in prostatic cancer patients also decreased (male comparison patients 33.43kg vs. prostatic cancer patients 33.21kg, P < 0.1). No significant differences were found in body composition between lung, breast and colorectal cancers and patients in comparison group (P > 0.1). A negative association between preoperative ECW/TBW level and postoperative Alb were observed (β=-125.05, P = 0.0403) in fully adjusted model. We found positive associations between preoperative PA level and postoperative Alb (β = 1.52, P = 0.0593) and preoperative BMI and postoperative CRP (β = 2.54, P = 0.0690). And the preoperative FFM, FFMI, FMI, BCM, HGS level were not associated with length of hospital stay, postoperative Alb, PreAlb and CRP for cancer patients in maximally adjusted models (P > 0.10).Conclusions In conclusion, the results of this study demonstrated that preoperative body composition, especially PA and ECW/TBW ratio, were significantly associated with the Alb, PreAlb and CRP of early stage after operation for cancer patients.
Evaluation of Cardiac Fibrosis and Subclinical Cardiac Changes in Sickle Cell Children by Magnetic Resonance Imaging, Echocardiography and Serum Galectin-3
Authors: Wagdy Reham , Fathy Alaa , Elnekidy Abdelaziz , Salaheldin Geylan , Nazir Hanan , Fahmy Rana , Elkafrawy Hagar , Elkafrawy Fatma
Published: April 2023

Cardiovascular complications account for about one third of the premature mortality rate in patients with sickle cell disease (SCD). Underlying this cardiac risk is a progressive cardiomyopathy which is multifactorial. Recently myocardial fibrosis is assumed to be a novel mechanism for cardiac dysfunction. This study aimed to detect cardiac fibrosis and subclinical cardiac changes in sickle cell children by; cardiac magnetic resonance imaging (CMR), Tissue Doppler Echocardiography (TDE) and Galectin-3. Children with SCD were subjected to assessment of cardiac function by TDE and had estimated serum level of Gal-3. Cardiac MRI was used to assess volumes and function by cine sequence, LGE for detection of focal myocardial fibrosis, native T1 mapping and extracellular volume (ECV) for quantification of diffuse myocardial fibrosis as well as CMR T2* for myocardial iron load. Thirty-four childrenwith SCD (mean age 13.32 ± 3.24 years) were enrolled in our study, another thirty-four healthy children served as controls. Although myocardial iron load by T2* was normal, ECV was increased among all cases with mean level 35.41 ± 5.02 %. The mean of ECV was significantly associated with the frequency of VOCs (P= 0.017) and negatively correlated to hemoglobin level (P=0.005). In consistent with ECV, Galectin-3 level was significantly higher among cases when compared to controls (7.75 ± 1.86 ng/ml versus 6.04 ±1.64 ng/ml, p<0.001) with cutoff value over the ROC curve 6.5ng/ml, sensitivity; 82.5 %, specificity; 72.8%. ECV were significantly higher for cases with Tie index > 0.4 by TDI subgroup when compared to ECV of subgroup with Tie index < 0.4 (38.17 ± 4.25 versus 34.43 ± 5.02, P: 0.03*).In conclusion:ECV is a validated CMR parameter to detect and quantify diffuse interstitial myocardial fibrosis in asymptomatic children with SCD. Cardiac fibrosis in SCD children is associated with frequent attacks of ischemic re-perfusion injury and correlated to the severity of anemia rather than myocardial iron load. Tie index by TDE and serum Gal-3 are recommended screening tools.
Fault-Tree Based Seismic Risk Evaluation and Retrofitting Strategy of Structures
Authors: Alinejad Majid , Ghafory-Ashtiany Mohsen
Published: April 2023

This paper provides a new methodology for seismic performance evaluation and retrofitting of structures using the combination of fault tree and incremental dynamic analysis to cover some of the limitation of the existing methods. These limitations include the qualitative consideration of performance objectives, the consideration of uncertainties, and the lack of a systematic method for determining the retrofitting strategy. In this method, first, the fault tree model of the structure's intended performance is drawn, considering possible failure modes. Then, using incremental dynamic analysis, the seismic fragility curves for all failure modes are derived. In the next step, having these fragility curves and using the fault tree analysis of the structure, the fragility curve of the whole structure is determined. By integrating the fragility curve of the structure and the seismic hazard curve of the site, the intended performance risk is calculated. This risk is a quantitative performance goal that can consider uncertainties. By using importance analysis and minimal cut sets of the fault tree, the risk-based retrofitting options are determined. To show the applicability of the proposed methodology, it is applied on a benchmark reinforced concrete structure in Europe that was designed and built without observing the new seismic standards. The collapse fragility curve and annual risk of collapse of this structure are determined. Using minimal cut sets and importance analysis of the structure’s fault tree, two retrofitting options are identified. The first retrofitting option is decreased collapse risk by 43% and the second one decreased it by 60%.