bluuebunny/crossref_metadata_2025 huggingface dataset:
APE1 shRNA‐loaded cancer stem cell‐derived extracellular vesicles reverse Erlotinib resistance in non‐small cell lung cancer via the IL‐6/STAT3 signalling
Authors: Tang Chun‐Han , Qin Ling , Gao Ying‐Chun , Chen Tai‐Yu , Xu Ke , Liu Tao , Ren Tao
Published: May 2022

Objective

Apurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin‐6 (IL‐6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL‐6 signalling in Erlotinib resistance of non‐small cell lung cancer (NSCLC).

Methods

We selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib‐resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib‐sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC‐EVs) and RCSCs (RCSC‐EVs) and co‐cultured with RCSCs with or without short hairpin RNA (shRNA)‐targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL‐6/STAT3 signalling.

Results

It was found that NSCLC cells could internalize both RCSC‐EVs and PCSC‐EVs. RCSC‐EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL‐6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL‐6/STAT3 signalling. Additionally, shAPE1‐loaded RCSC‐EVs suppressed the Erlotinib resistance of NSCLC via the IL‐6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation.

Conclusions

Collectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL‐6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib‐resistant NSCLC.
CPHEN‐014: Comprehensive phenotyping of mouse regulatory T cells relevant to viral infections
Authors: Chen Qian , Benamar Mehdi , Chan Tsz Man Fion , Wang Muyun , Chatila Talal A.
Published: May 2022

Regulatory T (Treg) cells are a specialized subpopulation of CD4+ T cells that enforce peripheral immune tolerance. Treg cells act to suppress exuberant immune responses, limit inflammation, and promote tissue repair, thereby maintaining homeostasis and tolerance to self‐antigens and those of the commensal microbial flora. Treg cells are characterized by the expression of the master regulator Foxp3, which plays a major role in Treg cells development and function. Under inflammatory conditions, Foxp3+ Treg cells may acquire effector T cell programs that modify their phenotype and function, reflecting their plasticity. During microbial infections, Treg cells act to limit the immunopathology triggered by the host immune response to pathogens albeit at the potential risk of pathogen persistence. In this review, we will discuss the influence of Treg cells on the outcome of viral infection and will give an overview of the Treg phenotype at steady‐state and in inflammatory conditions.
Observed shyness leads to more automatic imitation in early childhood
Authors: MacGowan Taigan L. , Mirabelli James , Obhi Sukhvinder S. , Schmidt Louis A.
Published: May 2022

The authors investigated children's automatic imitation in the context of observed shyness by adapting the widely used automatic imitation task (AIT). AIT performance in 6‐year‐old children (N = 38; 22 female; 71% White) and young adults (17–22 years; N = 122; 99 female; 32% White) was first examined as a proof of concept and to assess age‐related differences in responses to the task (Experiment 1). Although error rate measures of automatic imitation were comparable between children and adults, children displayed less reaction time interference than adults. Children's shyness coded from direct behavioral observations was then examined in relation to AIT scores (Experiment 2). Observed shyness at 5 years old predicted higher automatic imitation one year later. We discuss the latter findings in the context of an adaptive strategy. We argue that shy children may possess a heightened sensitivity to others’ motor cues and therefore are more likely to implicitly imitate social partners’ actions. This tendency may serve as a strategy to signal appeasement and affiliation, allowing for shy children to blend in and feel less inhibited in a social environment.
Regiodivergent Synthesis of Benzothiazole‐Based Isosorbide Imidates by Oxidative N‐Heterocyclic Carbene Catalysis
Authors: Ragno Daniele , De Risi Carmela , Massi Alessandro , Di Carmine Graziano , Toldo Sofia , Leonardi Costanza , Bortolini Olga
Published: May 2022

A novel N‐heterocyclic carbene (NHC)‐promoted regiodivergent protocol for exo (2‐OH) and endo (5‐OH) isosorbide (IS) imidates synthesis is described. The disclosed strategy allows the straightforward synthesis of monoimidate‐isosorbides (MIIs) endowed with the biologically relevant benzothiazole (BTA) moiety under mild oxidative conditions, starting from easy‐accessible aldimines. Process optimization encompassed the use of stoichiometric diquinone as well as atmospheric oxygen as oxidant species, focusing on reaction dichotomy between oxidative and oxygenative pathways. The reaction scope was investigated on a representative selection of BTA‐containing aldimines and further extended to congeners bearing different biologically pivotal N‐heterocyclic rings (benzoxazole, thiazole and isoxazole), observing good levels of yield (up to 87 %) and regioselectivity (exo/endo up to 10.0; endo/exo up to 7.0). Furthermore, the employment of an immobilized‐NHC under heterogeneous conditions was assessed, showing satisfactory selectivity towards exo‐MIIs (exo/endo=3.8). Overall, the methodology presented provided an unprecedented collection of high value‐added products with potential applications in different fields.
Investigating the potential of lead‐free double perovskite Cs2AgBiBr6 material for solar cell applications: A theoretical study
Authors: Raj Abhishek , Kumar Manish , Kumar Arvind , Laref Amel , Anshul Avneesh
Published: May 2022

Recently, Silver‐Bismuth based lead‐free double perovskite solar cells (PSCs) have established their significance as a possible substitute for lead‐based absorber in the PSCs due to its higher stability and nontoxic properties. In the present work, lead‐free double perovskite Cs2AgBiBr6 compound has been used as an absorber in the layered structure of PSC. This compound has been studied in details for its physical properties (electronic and optical) using the first principle calculation. Additionally, a lead‐free PSC is designed in SACPS‐1D simulation software with cell configuration of FTO/TiO2/Cs2AgBiBr6/Spiro‐OMeTAD/Au and studied for its various parameters useful for its applications in PSCs. Initially, the device is optimized under experimental counterpart to validate the simulation study and further various other material parameters such as band‐gap, defect density, thickness of absorber, series resistance and operating temperature are optimized to deliver improved performance. The final optimized lead‐free double PSCs exhibited power conversion efficiency (PCE) of 6.68%, open‐circuit voltage (VOC) of 0.90 V, current density (JSC) of 11.09 mA/cm2 and fill factor (FF) of 66.61%. Further, different ETLs such as TiO2, SnO2, ZnO, IGZO and PCBM are simulated with proposed device configuration and found TiO2 and SnO2 as suitable ETL candidate for Cs2AgBiBr6 based lead‐free PSCs.
Green synthesis of Size‐Controlled copper oxide nanoparticles as catalysts for H2 production from industrial waste aluminum
Authors: Amrani Mokhtar Ali , Alrafai H. A. , Al‐nami Samar Y. , Obeidat Firas , Alwahbani Fawaz , Alhammadi Mohammed A. , Qasem Ammar
Published: May 2022

Extensive research and development in the processes of production and generation of hydrogen are needed to make renewable hydrogen cost‐competitive with fossil hydrogen. As a result, developing hydrogen energy from low‐cost components and synthesizing it from renewable resources is an important issue that can be considered a global challenge. The current research provided a continuous H2 energy production from waste aluminum in a water medium using copper oxide nanoparticles (CuO NPs) as catalysts in the reaction. CuO NPs have been prepared by a green, easy, inexpensive, and systematic method using Catha edulis L. (Khat) extract as reducing and capping agents. Separately, CuO NPs prepared in an alkaline media using the conventional hydrothermal process have been described and reported for comparison. Multidisciplinary tools were used to characterize the powders for structural, morphological, and surface aspects. CuO NPs were homogeneous, well‐dispersed, and have fine diameters with an average of 6 nm, owing to the abundant biomolecules in the plant extract. The synthesized samples were utilized as catalysts for H2 production from industrial waste aluminum with a 1/0.02 ration of Al/CuO by weight. The primary results revealed a higher H2 production yield and rapid rate in alkaline than acidic mediums. Under all conditions, the CuO NPs prepared from the extract had better catalytic activity than those prepared by a conventional method. The results proved that the reaction temperature prompts the reaction kinetics more than other parameters. The optimum H2 yield could be optimized at a temperature of 70°C, 1/50 ratio of CuO/waste Al, and near‐neutral solutions. The above conditions are ideal for designing a continuous production reactor. The hydrogen generated using industrial waste aluminum in the present system is a cost‐effective and sustainable approach.
Health degradation assessment of proton exchange membrane fuel cell based on multi‐model probability fusion
Authors: Yang Yang , Zhu Wenchao , Xie Changjun , Du Banghua , Zhao Bo , Deng Zhanfeng , Li Yang , Shi Ying , Li Weibo , Zhang Leiqi , Song Jie
Published: May 2022

The existing impedance estimation methods for proton exchange membrane fuel cell (PEMFC) based on single equivalent circuit model (ECM) cannot accurately measure electrochemical impedance spectroscopy (EIS) at all times in the future or in the whole frequency range, which affects the accuracy of state‐of‐health (SOH) estimation with EIS as aging index. Therefore, a novel health assessment approach based on multi‐model probability fusion is proposed for improving the accuracy and reliability of SOH estimation. Five typical ECMs are selected to describe PEMFC, and chaotic particle swarm optimization algorithm with dynamic inertia weight (DIW‐CPSO) is used for identifying the model parameters. The parameters related to aging are extracted for predicting the SOH, and Bayesian theorem‐based multi‐model probability approach is adopted to calculate the optimal weights of synthesizing the SOHs estimated by the five ECMs. This approach is applied to real EIS data sets of Stack FC at current 20A, 45A and 70A. The results show that the EIS estimation results of the proposed approach have better performance in the sense of root mean square error and Euclidean error. The accuracies of SOH evaluation are 46.38%, 28.69% and 10.94% higher than the single ECM respectively, and have higher accuracy compared with previous studies.
Improving the performance of recovered lead oxide powder from waste lead paste as active material for lead‐acid battery
Authors: Li Jiangmin , Cao Jing , Chen Zhengyang , Yu Jiajia , Zhang Junfeng , Chen Biao , Wu Lei , Zhou Shengquan , Rao Yanzhao
Published: May 2022

It is a very green process to recover lead resources from waste lead‐acid batteries for remanufacturing lead‐acid batteries but recovered lead oxide from waste lead‐acid battery as active electrode material often exhibits poor performance. In this paper, HRPSoC (high rate charged) cycle life can be greatly improved by adding two kinds of nanometer lead sulfate carbon composite material into the anode material prepared from recovered lead oxide powder. PbSO4/Pb@CB (PPC) and PbSO4/Pb@MC (PMC) composite material have a multistage porous/mesoporous structure to provide a reaction site of Pb deposition and to increase the electrochemical active area of lead‐carbon electrode, which improves the circulation reversibility. The resulting HRPSoC of lead‐acid battery of PPC and PMC battery is 45 957 and 6767 cycles, which are 15.5 and 2.8 times that of a blank battery (2960), respectively. The proposed research provides a promising strategy for directly using active substances of recycled lead powder for lead‐acid batteries which greatly benefit to lead resource recycling.
Stochastic configuration network based on improved whale optimization algorithm for nonstationary time series prediction
Authors: Chen Zi‐yu , Xiao Fei , Wang Xiao‐kang , Deng Min‐hui , Wang Jian‐qiang , Li Jun‐Bo
Published: May 2022

The stochastic configuration network (SCN), a type of randomized learning algorithm, can solve the infeasible problem in random vector functional link (RVFL) by establishing a supervisory mechanism. The advantages of fast learning, convergence and not easily falling into local optima make SCN popular. However, the prediction effect of SCN is affected by the parameter settings and the nonstationarity of input data. In this paper, a hybrid model based on variational mode decomposition (VMD), improved whale optimization algorithm (IWOA), and SCN is proposed. The SCN will predict relatively stable data after decomposition by VMD, and parameters of SCN are optimized by IWOA. The IWOA diversifies the initial population by employing logistic chaotic map based on bit reversal and improves the search ability by using Lévy flight. The exploration and exploitation of IWOA are superior to those of other optimization algorithms in multiple benchmark functions and CEC2020. Moreover, the proposed model is applied to the prediction of the nonstationary wind speeds in four seasons. We evaluate the performance of the proposed model using four evaluation indicators. The results show that the R2 of the proposed model under four seasons are more than 0.999, and the root mean square error, mean absolute error, and symmetric mean absolute percentage error are less than 0.3, 0.17, and 13%, respectively, which are almost 1/10, 1/10, and 1/4 those of SCN, respectively.
Are internally consistent forecasts rational?
Authors: Tian Jing , Doko Tchatoka Firmin , Goodwin Thomas
Published: May 2022

Economic forecasts, such as the Survey of Professional Forecasters (SPF), are revised multiple times before realization of the target. This paper studies the sources of forecast revisions. By decomposing the fixed‐event forecast error into a rational component due to unanticipated future shocks and an irrational component due to measurement error in acquired information or forecasters' reactions, we derive the conditions under which fixed‐event forecasts that contain an irrational forecast error can still possess the second moment properties of rational forecasts. We show that internal consistency of fixed‐event forecasts depends on the magnitude of the rational and irrational components in the revisions. As such, fixed‐event forecasts subject to irrational error may still be internally consistent, although they are not rational, as evidence in many empirical studies. We illustrate our methodology with the SPF inflation forecasts data. Our results show evidence of a sizeable and heterogeneous irrational forecast error component across forecast horizons and a high irrational‐to‐news ratio for most forecasters. This finding also provides insight into why forecast revision effort is not always fully compensated by revision reward.
Long‐term priming of hypothalamic microglia is associated with energy balance disturbances under diet‐induced obesity
Authors: Fernández‐Arjona María del Mar , León‐Rodríguez Ana , Grondona Jesús M. , López‐Ávalos María D.
Published: May 2022

Exposure of microglia to an inflammatory environment may lead to their priming and exacerbated response to future inflammatory stimuli. Here we aimed to explore hypothalamic microglia priming and its consequences on energy balance regulation. A model of intracerebroventricular administration of neuraminidase (NA, which is present in various pathogens such as influenza virus) was used to induce acute neuroinflammation. Evidences of primed microglia were observed 3 months after NA injection, namely (1) a heightened response of microglia located in the hypothalamic arcuate nucleus after an in vivo inflammatory challenge (high fat diet [HFD] feeding for 10 days), and (2) an enhanced response of microglia isolated from NA‐treated mice and challenged in vitro to LPS. On the other hand, the consequences of a previous NA‐induced neuroinflammation were further evaluated in an alternative inflammatory and hypercaloric scenario, such as the obesity generated by continued HDF feeding. Compared with sham‐injected mice, NA‐treated mice showed increased food intake and, surprisingly, reduced body weight. Besides, NA‐treated mice had enhanced microgliosis (evidenced by increased number and reactive morphology of microglia) and a reduced population of POMC neurons in the basal hypothalamus. Thus, a single acute neuroinflammatory event may elicit a sustained state of priming in microglial cells, and in particular those located in the hypothalamus, with consequences in hypothalamic cytoarchitecture and its regulatory function upon nutritional challenges.
Perioperative intravenous iron to treat patients with fractured hip surgery: A systematic review and meta‐analysis
Authors: Sinclair Rhona C. F. , Bowman Miranda J. A. , Moppett Iain K. , Gillies Michael A.
Published: May 2022

Background

Treatment of preoperative anemia with intravenous iron is common within elective surgical care pathways. It is plausible that this treatment may improve care for people with hip fractures many of whom are anemic because of pre‐existing conditions, fractures, and surgery.

Objective

To review the evidence for intravenous iron administration on outcomes after hip fracture.

Design

We followed a predefined protocol and conducted a systematic review and meta‐analysis of the use of intravenous iron to treat anemia before and after emergency hip fracture surgery. The planned primary outcome was a difference in length of stay between those treated with intravenous iron and the control group. Other outcomes analyzed were 30‐day mortality, requirement for blood transfusion, changes in quality of life, and hemoglobin concentration on discharge from the hospital.

Data Sources

EMBASE, MEDLINE, The Cochrane Library (CENTRAL, DARE) databases, Clinicaltrials.gov, and ISRCTN trial registries. Date of final search March 2022.

Eligibility Criteria

Adult patients undergoing urgent surgery for hip fracture. Studies considered patients who received intravenous iron and were compared with a control group.

Results

Four randomized controlled trials (RCT, 732 patients) and nine cohort studies (2986 patients) were included. The RCTs were at low risk of bias, and the nonrandomized studies were at moderate risk of bias. After metanalysis of the RCTs there was no significant difference in the primary outcome, length of hospital stay, between the control group and patients receiving intravenous iron (mean difference: −0.59, 95% confidence interval [CI]; −1.20 to 0.03; I2 = 30%, p = 0.23). Intravenous iron was not associated with a difference in 30‐day mortality (n = 732, OR: 1.14, 95% CI: 0.62−2.1; I2 = 0%, p = 0.50), nor with the requirement for transfusion (n = 732, OR: 0.85, 95% CI: 0.63−1.14; I2 = 0%, p < 0.01) in the analyzed RCTs. Functional outcomes and quality of life were variably reported in three studies.

Conclusion

The evidence on the use of intravenous iron in patients with hip fracture is low quality and shows no difference in length of acute hospital stay and transfusion requirements in this population. Improved large, multicentre, high‐quality studies with patient‐centered outcomes will be required to evaluate the clinical and cost‐effectiveness of this treatment.
Different human papillomavirus types share early natural history transitions in immunocompetent women
Authors: Adebamowo Sally N. , Befano Brian , Cheung Li C. , Rodriguez Ana Cecilia , Demarco Maria , Rydzak Greg , Chen Xiaojian , Porras Carolina , Herrero Rolando , Kim Jane J. , Castle Philip E. , Wentzensen Nicolas , Kreimer Aimée R. , Schiffman Mark , Campos Nicole G.
Published: May 2022

Necessary stages of cervical carcinogenesis include acquisition of a carcinogenic human papillomavirus (HPV) type, persistence associated with the development of precancerous lesions, and invasion. Using prospective data from immunocompetent women in the Guanacaste HPV Natural History Study (NHS), the ASCUS‐LSIL Triage Study (ALTS) and the Costa Rica HPV Vaccine Trial (CVT), we compared the early natural history of HPV types to inform transition probabilities for health decision models. We excluded women with evidence of high‐grade cervical abnormalities at any point during follow‐up and restricted the analysis to incident infections in all women and prevalent infections in young women (aged <30 years). We used survival approaches accounting for interval‐censoring to estimate the time to clearance distribution for 20 529 HPV infections (64% were incident and 51% were carcinogenic). Time to clearance was similar across HPV types and risk classes (HPV16, HPV18/45, HPV31/33/35/52/58, HPV 39/51/56/59 and noncarcinogenic HPV types); and by age group (18‐29, 30‐44 and 45‐54 years), among carcinogenic and noncarcinogenic infections. Similar time to clearance across HPV types suggests that relative prevalence can predict relative incidence. We confirmed that there was a uniform linear association between incident and prevalent infections for all HPV types within each study cohort. In the absence of progression to precancer, we observed similar time to clearance for incident infections across HPV types and risk classes. A singular clearance function for incident HPV infections has important implications for the refinement of microsimulation models used to evaluate the cost‐effectiveness of novel prevention technologies.
Survival, cost and added therapeutic benefit of drugs granted early access through the French temporary authorization for use program in solid tumors from 2009 to 2019
Authors: Pham Fiona Y.‐V. , Jacquet Emmanuelle , Taleb Amina , Monard Adrien , Kerouani‐Lafaye Ghania , Turcry Florence , Brunel Liora , Grudé Françoise , Yoldjian Isabelle , Sainte‐Marie Isabelle , Boudali Lotfi , Blay Jean‐Yves , Albin Nicolas
Published: May 2022

Decisions on market authorization (MA) and reimbursement have different durations across countries because of health technology assessment (HTA) procedures and negotiations between manufacturers and national authorities. To overcome this delay, France has implemented a Temporary Authorization for Use (ATU) program that allows early access to drugs before MA, in order to treat patients with unmet medical needs. The objectives of our study were to establish the added therapeutic benefit (ATB) of ATUs for solid tumors and to investigate the correlations between three tools evaluating ATB and survival outcomes and drug costs. Data on ATUs granted from January 2009 to December 2019 to treat solid tumors were analyzed. An assessment of their ATB was conducted using the American Society of Clinical Oncology‐Value Framework (ASCO‐VF), the European Society for Medical Oncology‐Magnitude Clinical Benefit Scale (ESMO‐MCBS) and the French HTA criterion, clinical added value (CAV). The latter score determines reimbursement and national market access. Thirty‐five drugs in 39 indications were granted ATUs. All of them obtained MA and derived a clinical benefit to be reimbursed by the Social Security. Twenty‐eight (71.8%) had CAV compared to preexisting therapies. 24/38 (63.2%) had a 4‐5 ESMO‐MCBS score and 19/33 (57.6%) had an ASCO‐VF score over 45. No correlations were found between cost, PFS, OS, CAV and ASCO‐VF score, while high ESMO‐MCBS scores were correlated to OS. In conclusion, many patients were treated with innovations before MA thanks to ATU, although there are discrepancies between ATB scales, hence the importance of international collaboration in the evaluation of innovative therapies.
Electrical signals regulate the release of insulin from electrodeposited chitosan composite hydrogel: An in vitro and in vivo study
Authors: Tong Jun , Liu Hongyu , Qi Luhe , Deng Hongbing , Du Yumin , Shi Xiaowen
Published: May 2022

Electrical signal controlled drug release from polymeric drug delivery system provides an efficient way for accurate and demandable drug release. In this work, insulin was loaded on inorganic nanoplates (layered double hydroxides, LDHs) and coated on a copper wire by co‐electrodeposition with chitosan. The formed structure in chitosan composite hydrogel entrapped insulin efficiently, which were proved by various techniques. In addition, the drug loaded chitosan composite hydrogel demonstrated good biocompatibility as suggested by cell attachment. In vitro drug release experiment showed fast responsive pulsed release of insulin by biasing electrical signals. The in vivo experiment in diabetic rats revealed controllable insulin release in plasma and stable decrease of blood glucose can be achieved by using appropriate electrical signal. In addition, HE staining suggested negligible effect to the tissue by electrical signals. This work suggests that the electrical signal controlled insulin release from chitosan composited hydrogel may be a promising administration route for insulin.
The impact of loan covenants on audit delays and audit fees
Authors: Parkash Mohinder , Singhal Rajeev , Zhu Yun (Ellen)
Published: May 2022

We provide evidence on the impact of loan covenants on audit delays and audit fees. We find that for most covenants, firms with a particular covenant have longer audit delays than firms without that covenant. On average, we observe that adding one more loan covenant will delay the audit report by at least 1 day. We also found that adding one more loan covenant increases audit fees by 1.2%.
Contagion of credit risk: Comparative analysis before and after the pandemic of COVID‐19
Authors: Ito Takayasu
Published: May 2022

The spreads of credit default swaps (CDS) in Germany, Japan, United Kingdom, and United States move together before the COVID‐19 pandemic with few mutual causalities. However, they do not move together after the pandemic and have more mutual causalities. The credit risk of four major countries—Germany, Japan, United Kingdom, and United States are connected due to their relative stability before the pandemic. However, they are not connected in terms of the differences in public spending between the countries during COVID‐19. This makes the CDS market more sensitive to credit risk in each nation, resulting in the independent move of credit risk among the four countries.
A promoter variant in theOTCgene associated with late and variable age of onset hyperammonemia
Authors: Han Sangwoo T. , Anderson Katherine J. , Bjornsson Hans T. , Longo Nicola , Valle David
Published: May 2022

Ornithine transcarbamylase deficiency (OTCD) is an X‐linked inborn error caused by loss of function variants in theOTCgene typically associated with severe neonatal hyperammonemia. Rare examples of late‐onset OTCD have also been described. Here, we describe anOTCpromoter variant, c.‐106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the sameOTCvariant segregating in a large family with late‐onset OTCD with variable expressivity (Family 2). We show that thisOTCpromoter variant reduces expression >5‐fold in a dual‐luciferase assay that tests promoter function. Addition of an upstreamOTCenhancer increases expression of both the wild type and the c.‐106C>A variant promoter constructs >5‐fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lowerOTCexpression. Under normal demand on urea cycle function,OTCexpression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequateOTCexpression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.
Sophoridine inhibits endotoxin-induced acute lung injury by enhancing autophagy of macrophage and reducing inflammation
Authors: Liang Jinping , Liu Juntong , Tang Yezhen , Peng Qian , Zhang Ling , Ma Xiaoxia , Xu Nan , Wei Jun , Han Huaiqin
Published: May 2022

Acute lung injury (ALI) is characterized by uncontrolled inflammation, which can lead to respiratory distress syndrome and cause patient death. In this study, we sought to determine the role of sophoridine, a compound purified from sophora, in ALI. A mouse model of ALI was established by treating mice with LPS through nonexposed tracheal instillation. After LPS-induced mice were treated with sophoridine, LPS-induced alveolar wall thickening, alveolar interstitial inflammatory exudation and thickening, and the degree of pulmonary edema were found to be inhibited. Macrophages play an important role in inflammation, and in vitro experiments have demonstrated that sophoridine reduces the LPS-induced expression of inflammatory factors by macrophages, suggesting that sophoridine may inhibit lung inflammation in LPS-treated mice through reduces the secretion of inflammatory factors. Further, treatment with sophoridine up-regulated autophagy in macrophage cells in vitro and mouse lung tissues in vivo. LPS can bind to TLRs and activate the MyD88/NF-κB pathways, leading to increased inflammation in the pathogenesis of ALI. Our findings revealed that sophoridine down-regulated the expression of TLR4/MyD88/NF-κB and mTOR mRNA and protein in mouse pulmonary tissue. Collectively, these findings indicate that sophoridine may inhibit LPS-induced ALI by enhancing autophagy of macrophages and reducing inflammation.
Changes in the peripheral and central auditory performance in the elderly—A cross‐sectional study
Authors: Pürner Dominik , Schirkonyer Volker , Janssen Thomas
Published: May 2022

Age‐related hearing loss (ARHL, formerly presbycusis) is due to a variety of lifetime damages to the auditory system and is characterized by bilateral sensorineural hearing loss, impaired speech understanding in noise and central sound processing deficits. Despite its commonness, the pathogenesis has not been completely clarified yet; especially the existence of an independent central ARHL component still remains controversial. We present the results of a cross‐sectional topodiagnostic test battery study which aimed at separating aging‐ and hearing loss‐related effects on all parts of the auditory system by current test procedures. Three groups of 30 participants each underwent extensive topodiagnostic test procedures (otoscopy, tympanometry, questionnaires, pure‐tone audiometry, DPOAE threshold measurements, auditory brainstem response, central auditory discrimination tests, and speech‐in‐noise test). By comparing the results of the normally hearing young (18–26 years) and healthy control group, the normally hearing elderly group (60–80 years) and the hearing‐impaired elderly group (60–80 years), we deduced aging and hearing loss‐related effects on auditory performance. All measurements indicated a significant deterioration of auditory performance in the elderly, partly associated with aging and partly with age‐related hearing loss. Our study thereby contributes to a multifocal concept of ARHL. All parts of the auditory system are impaired by aging, age‐related hearing loss, or a combination of both. Further evidence for an independent central ARHL component, not attributable to peripheral hearing loss, is provided by the results of the central auditory discrimination test.
New improved Brazilian daily weather gridded data (1961–2020)
Authors: Xavier Alexandre C. , Scanlon Bridget R. , King Carey W. , Alves Aline I.
Published: May 2022

The demand for meteorological gridded datasets has increased within the last few years to inform studies such those in climate, weather, and agriculture. These studies require those data to be readily usable in standard formats with continuous spatial and temporal coverage. Since 2016, Brazil has a daily gridded meteorological data set with spatial resolution of 0.25° × 0.25° from January 1, 1980 to December 31, 2013 which was well received by the community. The main objective of this work is to improve the Brazilian meteorological data set. We do this by increasing the resolution of the minimum and maximum temperature (Tmax and Tmin) gridded interpolations from 0.25° × 0.25° to 0.1° × 0.1° by incorporating data on topographic relief, and increasing the time period covered (January 1, 1961–July 31, 2020). Besides Tmax and Tmin, we also gridded precipitation (pr), solar radiation (Rs), wind speed (u2), and relative humidity (RH) using observed data from 11,473 rain gauges and 1,252 weather stations. By means of ranked cross‐validation statistics, we selected the best interpolation among inverse distance weighting and angular distance weighting methods. We determined that interpolations for Tmax and Tmin are improved by using the elevation of a query point, that accounts for topographic relief, and a temperature lapse rate. Even though this new version has ≈25 years more data relative to the previous one, statistics from cross‐validation were similar. To allow researchers to assess the performance of the interpolation relative to station data in the area, we provide two types of gridded controls.
Modelling of hydrological and environmental flow dynamics over a central Himalayan river basin through satellite altimetry and recent climate projections
Authors: Kumar Nirmal , Dubey Amit Kumar , Goswami Uttam Puri , Singh Sudhir Kumar
Published: May 2022

The Himalayan region is vulnerable to climate change, which is triggering extreme hydrological events. To understand the impact of climate emission scenarios on different hydrological flow dynamics of the Himalayan region, a thorough hydrological investigation is needed for improved water resource management. Hence, this research exemplifies the use of remote sensing, modelling techniques, and recent climate projections (CMIP5 and CMIP6) for the assessment of hydrological flow dynamics in the central Himalayan catchment. The SWAT model is calibrated/validated using gauge observation and satellite altimetry‐derived river discharge and used for long‐term hydrological simulations (1979–2100). CMIP6 models predicted that there would be a steady rise in high flows in all the projected scenarios. Flow duration curve for CMIP5 and CMIP6 models depicted that high flow of short duration would be frequent in future. The environmental flow components (EFCs) were calculated using the indicator of hydrologic alteration tool. The SWAT model simulations of hydrological and EFCs under CMIP6 climate projections are found to be significantly more vulnerable to climate warming than CMIP5, which could be due to socioeconomic pathway emission scenarios.
LC–MS/MS‐based metabolomics approach revealed novel phytocompounds from sugarcane rind with promising pharmacological value
Authors: Rao Muhammad Junaid , Duan Mingzheng , Wei Xiaoshuang , Zuo Hou , Ma Li , Tahir ul Qamar Muhammad , Li Min , Han Shijian , Hu Lihua , Wang Lingqiang
Published: May 2022

BACKGROUND

Sugarcane provides many secondary metabolites for the pharmacological and cosmetic industries. Secondary metabolites, such as phenolic compounds, flavonoids, and anthocyanins, have been studied, but few reports focus on the identification of alkaloid and non‐alkaloid phytocompounds in sugarcane.

RESULTS

In this study, we identified 40 compounds in total from the rinds of cultivated sugarcane varieties (including eight alkaloids, 24 non‐alkaloids, and eight others) by using the liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach. Among these compounds, 31 were novel and are reported for the first time in sugarcane. Some alkaloids such as 3‐indoleacrylic acid,N,N‐dimethyl‐5‐methoxytryptamine, tryptamine, 6‐hydroxynicotinic acid, and 6‐deoxyfagomine are identified the first time in sugarcane rind. Four alkaloids such as trigonelline, piperidine, 3‐indoleacrylic acid, and 6‐deoxyfagomine are found abundantly in sugarcane rind and these compounds have promising pharmaceutical value. Some phytocompounds such as choline and acetylcholine (non‐alkaloid compounds) were most common in the rind of ROC22 and Yuetang93/159 (YT93/159). Hierarchical cluster analysis and principal component analysis revealed that the ROC22, Taitang172 (F172), and Yuetang71/210 (YT71/210) varieties were quite similar in alkaloid composition when compared with other sugarcane varieties. We have also characterized the biosynthesis pathway of sugarcane alkaloids. The rind of F172, ROC22, and YT71/210 showed the highest total alkaloid content, whereas the rind of ROC16 revealed a minimum level. Interestingly, the rind extract from YT71/210 and F172 showed maximum antioxidant activity, followed by ROC22.

CONCLUSION

Our results showed the diversity of alkaloid and non‐alkaloid compounds in the rind of six cultivated sugarcanes and highlighted the promising phytocompounds that can be extracted, isolated, and utilized by the pharmacological industry. © 2022 Society of Chemical Industry.
Osteogenic activities of four calcium‐chelating microalgae peptides
Authors: Yu Huilin , Chen Yixuan , Zhu Jiajin
Published: May 2022

BACKGROUND

Adequate calcium intake is necessary to prevent osteoporosis, which poses significant public health challenges. The natural bioactive peptide calcium chelates have been regarded as superior calcium supplements. Microalgae peptides are regarded as potential candidates for protection from bone loss in osteoporosis. This study aimed to prepare microalgae calcium‐chelating peptides from four microalgae proteins and assess their osteogenic activities in osteoporosis‐like zebrafish.

RESULTS

After in vitro gastrointestinal digestion, 4.42% Chlorella pyrenoidosa protein, 2.74% Nannochloropsis oceanica protein, 6.07% Arthospira platensis protein and 10.47% Dunaliella salina protein were retained. The calcium‐chelating capacities of four microalgae protein hydrolysates (MPHs) ranged from 14.10 ± 7.16% to 34.11 ± 9.34%. CaCl2 addition increased the maximum absorption peaks, absorption intensities and particle sizes of MPHs. Calcium‐chelating MPHs showed stronger osteogenic activities than MPHs in the osteoporosis‐like zebrafish model, with significantly increased mineralized tissue area and integrated optical density.

CONCLUSION

Microalgae proteins have favorable digestibilities. Among the four MPHs, Nannochloropsis oceanica protein hydrolysates showed the highest calcium‐chelating capacity, which might be due to its high degree of hydrolysis after in vitro digestion and high content of Ser, Tyr, Thr, Asp and Glu. The absorption intensities and particle sizes of MPHs both increased after calcium addition. MPH treatment could reverse dexamethasone‐induced osteoporosis of zebrafish, and MPHs‐Ca chelates showed higher osteogenic activities in osteoporosis‐like phenotype zebrafish. © 2022 Society of Chemical Industry.
Unraveling the Photovoltaic, Mechanical, and Microstructural Properties and Their Correlations in Simple Poly(3‐pentylthiophene) Solar Cells
Authors: Yang Xuantong , Gao Mengyuan , Bi Zhaozhao , Liu Yang , Xian Kaihu , Peng Zhongxiang , Qi Qingchun , Li Saimeng , Song Jinsheng , Ma Wei , Ye Long
Published: May 2022

The power conversion efficiency of polythiophene organic solar cells is constantly refreshed. Despite the renewed device efficiency, very few efforts have been devoted to understanding how the type of electron acceptor alters the photovoltaic and mechanical properties of these low‐cost solar cells. Herein, the authors conduct a thorough investigation of photovoltaic and mechanical characteristics of a simple yet less‐explored polythiophene, namely poly(3‐pentylthiophene) (P3PT), in three different types of organic solar cells, where ZY‐4Cl, PC71BM, and N2200 are employed as three representative acceptors, respectively. Compared with the reference poly(3‐hexylthiophene) (P3HT)‐based solar cells, P3PT‐based devices, all perform more efficiently. Particularly, the P3PT:ZY‐4Cl blend exhibits the highest efficiency (ca. 10%) among the six combinations and outperforms the prior top‐performance system P3HT:ZY‐4Cl. Furthermore, the blend films based on N2200 exhibit a high crack‐onset strain of ∼38% on average, which is approximately 15‐ and 17‐times higher than those of ZY‐4Cl and PC71BM, respectively. The microstructural origins for the above difference are well elucidated by detailed grazing incidence X‐ray scattering and microscopy analysis. This work not only underlines the potential of P3PT in prolific solar cell research but also demonstrates the superior tensile properties of polythiophene‐based all‐polymer blends for the preparation of stretchable solar cells.
Input layer regularization for magnetic resonance relaxometry biexponential parameter estimation
Authors: Rozowski Michael , Palumbo Jonathan , Bisen Jay , Bi Chuan , Bouhrara Mustapha , Czaja Wojciech , Spencer Richard G.
Published: May 2022

Many methods have been developed for estimating the parameters of biexponential decay signals, which arise throughout magnetic resonance relaxometry (MRR) and the physical sciences. This is an intrinsically ill‐posed problem so that estimates can depend strongly on noise and underlying parameter values. Regularization has proven to be a remarkably efficient procedure for providing more reliable solutions to ill‐posed problems, while, more recently, neural networks have been used for parameter estimation. We re‐address the problem of parameter estimation in biexponential models by introducing a novel form of neural network regularization which we call input layer regularization (ILR). Here, inputs to the neural network are composed of a biexponential decay signal augmented by signals constructed from parameters obtained from a regularized nonlinear least‐squares estimate of the two decay time constants. We find that ILR results in a reduction in the error of time constant estimates on the order of 15%–50% or more, depending on the metric used and signal‐to‐noise level, with greater improvement seen for the time constant of the more rapidly decaying component. ILR is compatible with existing regularization techniques and should be applicable to a wide range of parameter estimation problems.
Diet of the Chanyu and his people: Stable isotope analysis of the human remains from Xiongnu burials in western and northern Mongolia
Authors: Zhou Ligang , Mijiddorj Enkhbayar , Erdenebaatar Diimaajav , Lan Wanli , Liu Bin , Iderkhangai Tumur‐Ochir , Ulziibayar Sodnom , Galbadrakh Baatar
Published: May 2022

This study was designed to study the effect of social stratification on human diet in the Xiongnu society. Human remains unearthed from three different sites in western and northern Mongolia were analyzed for stable carbon and nitrogen isotope values. The results demonstrate that a certain amount of C4 component was consumed by people of different social levels. The three noble individuals from terrace tombs at the Gol Mod 2 site ate a similar diet to most of the burial followers buried in satellite tombs, indicating similar lifestyle or a close relationship between them. Commoners from the Ereen Hailaas were very close to the nobles in isotopic features; this might indicate dietary similarity or could be related to the environment factors. The Salkhitiin Am commoners were lower in both carbon and nitrogen isotope values compared with other Xiongnu people analyzed before; it is likely that they had a quite different diet featuring less C4 plant and animal protein. If such dietary variation was not related to social stratification, possible differences in subsistence strategies or dietary traditions should be considered. These results provide an important window into the social structure and subsistence strategies of the Xiongnu people and will facilitate future study on cultural communication and material exchange across the Eurasian continent.
Factors influencing outcomes of older children with medulloblastoma over 15 years in Peru, a resource‐limited setting
Authors: Diaz‐Coronado Rosdali Y. , Reinecke James Brandon , Stanek Joseph R. , Finlay Jonathan L. , Hernández Broncano Eddy , Chávez Paredes Sharon , Tunque Yesenia Miranda , Heredia Zelaya Adela , Casavilca Zambrano Sandro , García‐Corrochano Medina Pamela , Ojeda Medina Luis , Orrego Puelles Enrique , Torres Malca Ebert , Sernaque Quintana Raymundo , Quispe Valverde William , García León Juan L. , Osorio Diana S.
Published: May 2022

Background

Medulloblastoma is the most common malignant brain tumor in children. While survival has improved in high‐income countries (HIC), the outcomes for patients in low‐to‐middle‐income countries (LMIC) are unclear. Therefore, we sought to determine the survival of children with medulloblastoma at the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 1997 and 2013 in Peru.

Methods

Between 1997 and 2013, data from 103 children older than 3 years with medulloblastoma were analyzed. Fourteen patients were excluded. The patients were split into two distinct cohorts, 1997–2008 and 2009–2013, corresponding with chemotherapy regimen changes. Event‐free (EFS) and overall survival (OS) were calculated using the Kaplan–Meier method, whereas prognostic factors were determined by univariate analysis (log‐rank test).

Results

Eighty‐nine patients were included; median age was 8.1 years (range: 3–13.9 years). The 5‐year OS was 62% (95% CI: 53%–74%), while EFS was 57% (95% CI: 48%–69%). The variables adversely affecting survival were anaplastic histology (compared to desmoplastic; OS: HR = 3.4, p = .03), metastasis (OS: HR = 3.5, p = .01; EFS: HR = 4.3, p = .004), delay in radiation therapy of 31–60 days (compared to ≤30 days; EFS: HR = 2.1, p = .04), and treatment 2009–2013 cohort (OS: HR = 2.2, p = .02; EFS: HR = 2.0, p = .03).

Conclusions

Outcomes for medulloblastoma at INEN were low compared with HIC. Anaplastic subtype, metastasis at diagnosis, delay in radiation therapy, and treatment in the period 2009–2013 negatively affected the outcomes in our study. Multidisciplinary teamwork, timely delivery of treatment, and partnerships with loco‐regional groups and colleagues in HIC is likely beneficial.