bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conditional deletion of LRRC8A in the brain protects against stroke damage independently of effect on swelling-activated glutamate release
Authors: Balkaya Mustafa , Dohare Preeti , Chen Sophie , Schober Alexandra L. , Fidaleo Antonio M. , Nalwalk Julia W. , Sah Rajan , Mongin Alexander A. 
Published: December 2022

ABSTRACTThe ubiquitous volume-regulated anion channels (VRACs), which are composed of LRRC8 proteins, facilitate cell volume homeostasis, and contribute to many other physiological processes. Prior studies demonstrated that treatment with non-specific VRAC blockers, or brain-specific deletion of the essential VRAC subunit LRRC8A, are highly protective in rodent stroke. In this work, we tested the widely accepted idea that harmful effects of VRACs in the brain are mediated by pathological release of the excitatory transmitter glutamate. We used two molecular genetic strategies to ablate LRRC8A expression in either brain astrocytes only (inducible deletion ofLrrc8aflox/floxwithAldh1l1CreERT2) or the majority of brain cells (neurons, astrocytes, and oligodendrocytes withNestinCre). To produce stroke, genetically modified mice were subjected to a 40-minute occlusion of the middle cerebral artery. The inducible deletion of astrocytic LRRC8A yielded no histological or behavioral protection. In contrast, the brain-wide LRRC8A knockout reduced ischemic infarction by ~50% in both heterozygotes (Het) and the fullLrrc8aknockout (KO) as compared to the controlLrrc8aflox/+genotype. However, despite identical brain damage, Het and KO mice dramatically differed in their VRAC activities. Het mice had full swelling-activated glutamate release, while KO animals showed its virtual absence. These new findings refute the notion that VRAC-mediated glutamate release plays significant role in ischemic brain injury.
Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism
Authors: Solé-Navais Pol , Juodakis Julius , Ytterberg Karin , Wu Xiaoping , Vaudel Marc , Helgeland Øyvind , Flatley Christopher , Geller Frank , Finel Moshe , Zhao Mengqi , Lazarus Philip , Magnus Per , Andreassen Ole A. , Njolstad Pål R. , Feenstra Bjarke , Muglia Louis J. , Johansson Stefan , Zhang Ge , Jacobsson Bo 
Published: December 2022

AbstractJaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2,000), with the most compelling locus located in theUGT1A*genes region. The alternate allele of a common missense variant affecting the sequence ofUGT1A4(with low affinity for bilirubin) reduces the susceptibility to jaundice five-fold (rs6755571, A allele OR = 0.2, p-value = 2.7 × 10−55, frequency = 6.4%). eQTL colocalization analyses indicate that the association may be driven by regulation ofUGT1A1(the primary bilirubin conjugation enzyme) in the intestines, but not in the liver. Analysis of the parental transmitted and non-transmitted alleles in 23,000 parent-offspring trios captures known effects of maternal-fetal ABO blood group incompatibility on neonatal jaundice. Our results reveal marked differences in the pathways involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting a distinct biological basis.
MERLIN-DEFICIENT iPSCs AS ANIN VITROMODEL SYSTEM FOR STUDIYNGNF2PATHOGENESIS
Authors: Catasús Núria , Torres-Martin Miguel , Rosas Inma , Kuebler Bernd , Casals-Sendra Gemma , Mazuelas Helena , Negro Alex , Roca-Ribas Francesc , Amilibia Emilio , Aran Begoña , Veiga Anna , Raya Ángel , Gel Bernat , Blanco Ignacio , Serra Eduard , Carrió Meritxell , Castellanos Elisabeth 
Published: December 2022

ABSTRACTNF2-related schwannomatosis is an autosomal dominant syndrome that predisposes to the development of benign tumors of the nervous system. Schwannomas, particularly bilateral vestibular schwannomas (VS), are the most characteristic features of the disease. These tumors are caused by the bi-allelic inactivation of theNF2gene in a cell of the Schwann cell lineage. Our current understanding of the molecular pathogenesis of theNF2gene, as well as the development of new effective therapies is hampered by the absence of human non-perishable cell-based bearing distinctNF2pathogenic variants. With this aim, we generated and characterized three isogenic paired induced pluripotent stem cell (iPSC) lines with single or bi-allelic inactivation ofNF2by combining the direct reprogramming of VS cells with the use of CRISPR/Cas9 editing. Our results show a critical function ofNF2for the maintenance of a stable pluripotent state. However, we were able to nudge them towards the Neural Crest-Schwann Cell (NC-SC) axis by applying a 3D Schwann cell differentiation protocol.NF2(+/−) andNF2(−/−) spheroids homogeneously expressed classical markers of the NC-SC lineage. In addition,NF2(−/−) SC-like spheroids showed dysregulation of multiple signaling pathways already described for merlin-deficient SC, and altered in human schwannomas. Therefore,NF2(+/−) andNF2(−/−) SC-like spheroids can represent a bona fide humanin vitrocellular model to study the role ofNF2pathogenesis.
Earnings management and underperformance after seasoned equity offerings: a cross-country study
Authors: Opare Solomon , Houqe Muhammad , van Zijl Tony 
Published: December 2022

PurposeThis purpose of this study is to examine the association between earnings management (accruals earnings management (AEM) and/or real activities manipulation (RAM)) and firm underperformance following seasoned equity offerings (SEOs) using cross-country data.Design/methodology/approachThe study applies ordinary least squares regression analyses to a sample of 11,764 observations on firms from 22 countries over the period from 2005 to 2017. The methods include weighted least squares regression, sub-sampling approach and alternative measures of firm performance, earnings management and legal regime for robustness tests as well as a two-stage least squares instrumental variable (IV) approach to address endogeneity concerns.FindingsThe results suggest that RAM has a greater negative impact on post-SEO performance than AEM. The result is economically significant for RAM only. The results also reveal that the negative impact of earnings management, in particular RAM, on post-SEO performance is greater in countries with a strong legal regime than in other countries.Practical implicationsEarnings management around SEOs has important implications for investors, regulators and policymakers. The study suggests that policymakers should improve the current legal conditions to promote fairness in the equity market.Originality/valueThe results from the cross-country data support earlier results from single-country studies on the impact of earnings management on post-SEO performance. The study also provides new evidence on the variation in the impact of earnings management according to the strength of the legal regime operating in a country.
Adult autism spectrum disorder: knowledge, attitude and practice of health system professionals
Authors: Alaghband-rad Javad , Ardeshir Maryam , Hakki Kazazi Elham , Motamed Mahtab 
Published: December 2022

Purpose
The prevalence of children with autism spectrum disorder (ASD) is rising. As children with ASD become adults, the need for appropriate physical and mental health care becomes more evident. Lack of knowledge and inadequate training about adult ASD can lead to discomfort in management and service delivery to this population. This study aims to assess knowledge, attitude and practice of health-care providers for patients with adult ASD and to determine the needs of health-care staff to provide convenient care to adult patients with ASD.

Design/methodology/approach
This cross-sectional study was conducted in 2019–2020 among health-care professionals in Iran using an online questionnaire.

Findings
In this study, 182 health-care professionals (67.6% mental health professionals) participated. A minority of participants mentioned having excellent or very good knowledge about autism (10%) or acceptable access to clinical tools and guidelines (27%). Around 67% of professionals believed that patients with ASD are not cooperative. The most preferred training was training on effective communication strategies with ASD patients (64.8%).

Practical implications
The authors found a gap in knowledge and training of adult ASD diagnosis and management among health-care providers.

Originality/value
This study highlights the significance of empowering professionals with better training to manage adult autism.
Equine blood flow restriction training: Safety validation
Authors: Johnson Sherry A. , Frisbie David D. , Griffenhagen Gregg M. , King Melissa R. 
Published: December 2022

AbstractBackgroundBlood flow restriction (BFR) has become a key rehabilitative tool for human orthopaedic conditions. With modernised technology and evolution of clinical application, patient‐specific delivery of occlusion percentages is now considered the standard of care in human patients due to improved therapeutic outcomes and minimised safety risks. Safety validation and limb occlusion pressure (LOP) data for horses, however, are lacking.Objective(1) To determine if BFR exposure resulted in forelimb biomechanical gait dysfunction as safety validation and (2) to investigate inter‐horse and inter‐limb LOP differences.Study designControlled in vivo experiment.MethodsDaily unilateral forelimb BFR was performed in four horses over 56 days. Clinical examinations and objective gait analyses were performed on Days 0, 28 and 56. Daily LOP values were determined by Doppler evaluation to deliver 80% vascular occlusion at a walk. A linear mixed model evaluated for differences in lameness, kinetic and kinematic gait parameters.ResultsThere were no significant differences in forelimb lameness (range of Grades 0–2 across all forelimbs), kinematic or kinetic gait parameters over time or between BFR‐exposed and control (contralateral) limbs (p > 0.05). Clinically apparent complications related to BFR such as thrombosis or dermatitis were not appreciated. Significant differences in mean LOP values between various horses (p < 0.001) and measured left (204.48 mmHg) and right (173.78 mmHg) forelimbs (p < 0.001) were observed. Mean LOP and standard deviation across all readings was 189.1 ± 22.2 mmHg.Main limitationsOptimal BFR occlusion percentages and protocols with documented clinical efficacy are unknown. Small study population.ConclusionsExposure to BFR did not result in forelimb biomechanical dysfunction in four horses. Applied pressures of 75–151 mmHg would likely simulate a range of 50%–80% vascular occlusion in horses, but inherent physiological variation between horses and forelimbs warrants incorporation of individual pressures.
Mechanistic forecasts of species responses to climate change: The promise of biophysical ecology
Authors: Briscoe Natalie J. , Morris Shane D. , Mathewson Paul D. , Buckley Lauren B. , Jusup Marko , Levy Ofir , Maclean Ilya M. D. , Pincebourde Sylvain , Riddell Eric A. , Roberts Jessica A. , Schouten Rafael , Sears Michael W. , Kearney Michael Ray 
Published: December 2022

AbstractA core challenge in global change biology is to predict how species will respond to future environmental change and to manage these responses. To make such predictions and management actions robust to novel futures, we need to accurately characterize how organisms experience their environments and the biological mechanisms by which they respond. All organisms are thermodynamically connected to their environments through the exchange of heat and water at fine spatial and temporal scales and this exchange can be captured with biophysical models. Although mechanistic models based on biophysical ecology have a long history of development and application, their use in global change biology remains limited despite their enormous promise and increasingly accessible software. We contend that greater understanding and training in the theory and methods of biophysical ecology is vital to expand their application. Our review shows how biophysical models can be implemented to understand and predict climate change impacts on species' behavior, phenology, survival, distribution, and abundance. It also illustrates the types of outputs that can be generated, and the data inputs required for different implementations. Examples range from simple calculations of body temperature at a particular site and time, to more complex analyses of species' distribution limits based on projected energy and water balances, accounting for behavior and phenology. We outline challenges that currently limit the widespread application of biophysical models relating to data availability, training, and the lack of common software ecosystems. We also discuss progress and future developments that could allow these models to be applied to many species across large spatial extents and timeframes. Finally, we highlight how biophysical models are uniquely suited to solve global change biology problems that involve predicting and interpreting responses to environmental variability and extremes, multiple or shifting constraints, and novel abiotic or biotic environments.
Sorafenib plus hepatic arterial infusion chemotherapy versus sorafenib alone for advanced hepatocellular carcinoma: A systematic review and meta‐analysis
Authors: Long Yin , Song Xingdong , Guan Yan , Lan Ran , Huang Ziqi , Li Senlin , Zhang Lei 
Published: December 2022

AbstractBackgroundThe combination of sorafenib and hepatic arterial infusion chemotherapy (HAIC) is expected to exert a synergistic anticancer effect. We conducted this systematic review to examine the efficacy and safety of sorafenib plus HAIC vs sorafenib alone for advanced hepatocellular carcinoma (HCC).MethodsWe systematically searched the PubMed, Embase, and Cochrane Library with the following search terms: “sorafenib,” “hepatic arterial infusion chemotherapy,” “HAIC,” “advanced,” “hepatocellular carcinoma,” and “HCC.” Pooled hazard ratios (HRs) and 95% CIs were calculated for overall survival (OS) and progression‐free survival (PFS), and we calculated the pooled risk ratios (RRs) and 95% CIs for objective response rate (ORR) and adverse events (AEs).ResultsWe found that sorafenib plus HAIC was associated with significantly better OS (HR, 0.56; 95% CI, 0.37–0.83; P < 0.01), PFS (HR, 0.44; 95% CI, 0.27–0.72; P < 0.01), and ORR (RR, 3.77; 95% CI, 1.87–7.58; P < 0.01) than sorafenib alone in advanced HCC. Grade 3/4 AEs were more frequent in the sorafenib plus HAIC group, including leukopenia (RR, 4.54; 95% CI, 1.77–11.64; P < 0.01), neutropenia (RR, 7.81; 95% CI, 3.36–18.16; P < 0.01), thrombocytopenia (RR, 2.97; 95% CI, 1.98–4.46; P < 0.01), anemia (RR, 2.24; 95% CI, 1.22–4.09; P < 0.01), anorexia (RR, 2.37; 95% CI, 1.07–5.27; P = 0.03), nausea (RR, 2.98; 95% CI, 1.19–7.42; P = 0.02), and vomiting (RR, 3.99; 95% CI, 1.14–14.01; P = 0.03).ConclusionSorafenib plus HAIC improved OS, PFS, and ORR compared with sorafenib alone in advanced HCC, with acceptable safety profile.
Unraveling urban advantages—A meta‐analysis of agglomeration economies
Authors: Donovan Stuart , de Graaff Thomas , de Groot Henri L. F. , Koopmans Carl C. 
Published: December 2022

AbstractA large body of empirical literature considers the productive advantages of cities, or “agglomeration economies.” We present a meta‐analysis of this literature that draws on 6684 agglomeration elasticities from 294 studies spanning 54 countries and six decades. We find that elasticities are likely to lie in the range 0.015–0.039 and, like earlier reviews, that the controls enabled by detailed data are associated with smaller estimates. We make five main contributions: First, we find evidence that publication selection imparts a positive bias to the literature; second, we adopt novel methods that tend to yield more precise parameter estimates than conventional approaches; third, unlike earlier reviews, we do not find large differences between most countries nor an association with national income; fourth, we report new associations, for example between elasticities and the spatial scope of agglomeration, which may reflect underlying microeconomic channels; and fifth, we find evidence that elasticities for manufacturing sectors have fallen in recent decades, possibly due to lower freight costs and stricter environmental regulations.
A phenomenology of direct observation in residency: Is Miller's ‘does’ level observable?
Authors: Rietmeijer Chris B. T. , van Esch Suzanne C. M. , Blankenstein Annette H. , van der Horst Henriëtte E. , Veen Mario , Scheele Fedde , Teunissen Pim W. 
Published: December 2022

AbstractIntroductionGuidelines on direct observation (DO) present DO as an assessment of Miller's ‘does’ level, that is, the learner's ability to function independently in clinical situations. The literature, however, indicates that residents may behave ‘inauthentically’ when observed. To minimise this ‘observer effect’, learners are encouraged to ‘do what they would normally do’ so that they can receive feedback on their actual work behaviour. Recent phenomenological research on patients' experiences with DO challenges this approach; patients needed—and caused—some participation of the observing supervisor. Although guidelines advise supervisors to minimise their presence, we are poorly informed on how some deliberate supervisor participation affects residents' experience in DO situations. Therefore, we investigated what residents essentially experienced in DO situations.MethodsWe performed an interpretive phenomenological interview study, including six general practice (GP) residents. We collected and analysed our data, using the four phenomenological lenses of lived body, lived space, lived time and lived relationship. We grouped our open codes by interpreting what they revealed about common structures of residents' pre‐reflective experiences.ResultsResidents experienced the observing supervisor not just as an observer or assessor. They also experienced them as both a senior colleague and as the patient's familiar GP, which led to many additional interactions. When residents tried to act as if the supervisor was not there, they could feel insecure and handicapped because the supervisor was there, changing the situation.DiscussionOur results indicate that the ‘observer effect’ is much more material than was previously understood. Consequently, observing residents' ‘authentic’ behaviour at Miller's ‘does’ level, as if the supervisor was not there, seems impossible and a misleading concept: misleading, because it may frustrate residents and cause supervisors to neglect patients' and residents' needs in DO situations. We suggest that one‐way DO is better replaced by bi‐directional DO in working‐and‐learning‐together sessions.
Periplaneta americana extract promotes osteoblast differentiation of human alveolar bone marrow mesenchymal stem cells
Authors: Xu Jie , Zhao Bin , Lin Weimin , Liu Yuting , Zhang Xiao , Wang Yuan , Zhang Yanjun , Liu Weiqing , Seriwatanachai Dutmanee , Yuan Quan 
Published: December 2022

AbstractObjectivesThis study aims to investigate the effects of Traditional Chinese medicine, Periplaneta americana extract (PAE), on osteoblast differentiation of human alveolar bone marrow‐derived mesenchymal stem cells (hABMMSCs).Materials and MethodsHuman alveolar bone marrow‐derived mesenchymal stem cells were treated with different concentrations of PAE. Cell Counting Kit‐8 (CCK‐8) assay and transwell migration assay were conducted to evaluate cell proliferation and migration, respectively. Alkaline phosphatase (ALP) staining, ALP activity assay, and Alizarin red S staining were performed to detect osteogenesis in hABMMSCs. In addition, real‐time quantitative polymerase chain reaction (RT‐qPCR) and western blot (WB) assay were performed to evaluate expression levels of osteogenic markers. Finally, RNA sequencing analysis and WB were carried out to elucidate the underlying mechanism.ResultsA total of 0.1 mg/ml PAE promoted cell proliferation and migration. PAE also increased ALP activity and mineralized nodule formation of hABMMSCs. In addition, PAE upregulated the expression of osteogenesis‐related genes (RUNX2, COL1A1, and BGLAP). RNA‐sequencing analysis revealed that PAE activated the focal adhesion signaling pathway. Treatment with Defactinib, an inhibitor of FAK, attenuated the effects induced by PAE.ConclusionsPAE could enhance osteoblast differentiation of hABMMSCs through focal adhesion signaling pathway, suggesting a therapeutic potential for the alveolar bone defect.
Macrophage migration inhibitory factor MtMIF3 prevents the premature aging of Medicago truncatula nodules
Authors: Wang Li , Yang Jieyu , Tan Wenjun , Guo Yile , Li Jiaqi , Duan Chuntao , Wei Gehong , Chou Minxia 
Published: December 2022

AbstractMacrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in immune response in animals. However, the role of MIFs in plants such as Medicago truncatula, particularly in symbiotic nitrogen fixation, remains unclear. An investigation of M. truncatula—Sinorhizobium meliloti symbiosis revealed that MtMIF3 was mainly expressed in the nitrogen‐fixing zone of the nodules. Silencing MtMIF3 using RNA interference (Ri) technology resulted in increased nodule numbers but higher levels of bacteroid degradation in the infected cells of the nitrogen‐fixing zone, suggesting that premature aging was induced in MtMIF3‐Ri nodules. In agreement with this conclusion, the activities of nitrogenase, superoxide dismutase and catalase were lower than those in controls, but cysteine proteinase activity was increased in nodulated roots at 28 days postinoculation. In contrast, the overexpression of MtMIF3 inhibited nodule senescence. MtMIF3 is localized in the plasma membrane, nucleus, and cytoplasm, where it interacts with methionine sulfoxide reductase B (MsrB), which is also localized in the chloroplasts of tobacco leaf cells. Taken together, these results suggest that MtMIF3 prevents premature nodule aging and protects against oxidation by interacting with MtMsrB.
Second hepatitis C virus transmission by blood components since introduction of mandatoryNATscreening in Germany
Authors: Himmelsbach Kiyoshi , Mueller Susanne , Kress Julia , Fiedler Sarah A. , Miskey Csaba , Ivics Zoltan , Patek Alexander , Chudy Michael 
Published: December 2022

AbstractBackgroundViral safety of blood products in Germany has improved significantly over the last two decades. We describe the second documented transfusion‐transmitted (TT) episode for the hepatitis C virus (HCV) in Germany since mandatory nucleic acid amplification techniques (NAT) screening was introduced in 1999.Study Design and MethodsWhen a repeat donor who had tested negative for anti‐HCV tested positive for HCV RNA by NAT in a minipool (MP) of eight, a look‐back procedure was initiated. Qualitative, quantitative and genotyping assays were used to investigate the titers of the quarantined fresh frozen plasma (FFP) from the donor and a serum sample from the recipient of the pooled platelet concentrate (PPC). Amplified products of 5'UTR and HVR1 were used for sequence comparison to characterize the HCV genomic identity of donor and recipient samples.ResultsAll NAT tests utilized in this procedure were able to detect a low HCV RNA titer (~15 IU/ml) in the FFP from the donation. Dilution of FFP by factor 8 was performed to mimic an MP, and the detection rate correlated well with the claimed sensitivity of the tests. Analysis of donor and recipient samples revealed genotype 3a viral transmission confirmed by sequence analysis.ConclusionThis TT HCV case could have been prevented by individual donation (ID) NAT. However, a low titer blood donation in the window period (WP) is very rare. Residual risk calculation for TT HCV in the WP revealed that, compared to MP‐NAT testing, ID‐NAT would improve blood safety only marginally.