bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review and meta-analysis for the impact of rod materials and sizes in the surgical treatment of adult spine deformity
Authors: Bowden Dawn , Michielli Annalisa , Merrill Michelle , Will Steven
Published: July 2022

Purpose

To assess clinical and safety outcomes associated with different rod materials and diameters in adult spinal deformity (ASD) surgery.

Methods

A systematic literature review and meta-analysis evaluated ASD surgery using pedicle screw fixation systems with rods of different materials and sizes. Postoperative outcomes (i.e., Cobb, sagittal vertical axis, and pelvic tilt angle) and complications (i.e., pseudarthrosis and rod breakage) were assessed. Random effects models (REMs) pooled data for outcomes reported in ≥ 2 studies.

Results

Among 50 studies evaluating ASD surgery using pedicle screw fixation systems, 17 described rod material/diameter. Postoperative outcomes did not statistically differ between cobalt–chromium (CoCr) vs. titanium (Ti) rods (n = 2 studies; mean [95% confidence interval (CI)] sagittal vertical axis angle: CoCr 37.00° [18.58°–55.42°] and Ti 32.58° [24.62°–40.54°]; mean [95% CI] pelvic tilt angle: CoCr 26.20° [22.87°–29.53°] and Ti 20.15° [18.0°–22.31°]). The pooled proportion (95% CI) of pseudarthrosis was 15% (7–22%) for CoCr and 12% (− 8–32%) for stainless steel (SS) (n = 2 studies each; Chi2 = 0.07, p = 0.79). The pooled proportion (95% CI) of broken rods was 12% (1–22%) for Ti (n = 3 studies) and 10% (2–19) for CoCr (n = 1 study). Among 6.0–6.35 mm rods, the pooled (95% CI) postoperative Cobb angle (n = 2) was 12.01° (9.75°–14.28°), sagittal vertical axis angle (n = 4) was 35.32° (30.02°–40.62°), and pelvic tilt angle was 21.11° (18.35°–23.86°).

Conclusions

For ASD patients undergoing posterior fixation and fusion, there are no statistically significant differences in postoperative outcomes or complications among rods of varying materials and diameters. Benchmark postsurgical outcomes and complication rates by rod material and diameter are provided.

Level of Evidence

III
An anatomy of the academic ranking of world universities (Shanghai ranking)
Authors: Docampo D. , Egret D. , Cram L.
Published: July 2022

International academic rankings of research universities are widely applied and heavily criticised. Amongst the many international rankings, the Shanghai ranking has been particularly influential. Although this ranking’s primary data are generally accessible and its methods are published in outline format, it does not follow that its outputs are predictable or straightforward. In practice, the annual and time series Shanghai rankings rely on data and rules that are complex, variable, and not fully revealed. Patterns and changes in the ranking may be misinterpreted as intrinsic properties of institutions or systems when they are actually beyond the influence of any university or nation. This article dissects the rules that connect raw institutional data to the published ranking, using the 2020 edition as a reference. Analysing an ARWU review of ranking changes over 2004–2016, we show how exogenous or methodological changes have often driven changes in ranking. Stakeholders can be misled if they believe that changes are intrinsic to institutions’ performance. We hope to inform and warn the media, governments, and institutions about the merits and risks of using the Shanghai ranking to evaluate relative institutional performance and its evolution.
Accumulation of carotenoids in Brassica rapa ssp. chinensis by a high proportion of blue in the light spectrum
Authors: Frede Katja , Baldermann Susanne
Published: July 2022

Carotenoids have the potential to improve the human health which leads to an increasing consumer demand for carotenoid-rich vegetables. The implementation of new, less energy-consuming vegetable production systems using artificial light such as light-emitting diodes (LEDs) is essential. In the present study, pak choi (Brassica rapa ssp. chinensis ‘Black Behi’) sprouts were grown under a combination of blue and white LEDs, red and white LEDs or only white LEDs for 7 days. Total carotenoid levels of ~ 700 ng/mg DM were measured under white LEDs. The combination of blue and white LEDs increased the carotenoid levels by ~ 15% in comparison to only white LEDs, while red and white LEDs reduced them. The transcript levels of important carotenoid metabolism-related genes were enhanced under blue and white LEDs. Phytoene measurement after Norflurazon-treatment, a phytoene desaturase inhibitor, revealed that phytoene increased by 38% (37.5 µM Norflurazon) and by 56% (50.0 µM Norflurazon) after growth under blue and white LEDs in comparison to only white LEDs suggesting an up-regulation of the upper carotenoid biosynthetic pathway. Thus, the transcript levels and the enhanced phytoene levels correlated well with the higher accumulation of carotenoids under blue and white LEDs. Furthermore, a comparison to sprouts grown under blue LEDs without additional white LEDs showed that blue light alone does not increase the phytoene levels after Norflurazon-treatment. Overall, this study demonstrated a beneficial effect of a higher blue light percentage in growing carotenoid-rich pak choi sprouts, and implies that an increased biosynthesis within the upper carotenoid biosynthetic pathway is responsible for the enhanced carotenoid accumulation.

Graphical abstract
Lignin derived carbon materials: current status and future trends
Authors: Zhang Wenli , Qiu Xueqing , Wang Caiwei , Zhong Lei , Fu Fangbao , Zhu Jiahao , Zhang Zejie , Qin Yanlin , Yang Dongjie , Xu Chunbao Charles
Published: July 2022

Developing novel techniques to convert lignin into sustainable chemicals and functional materials is a critical route toward the high-value utilization of lignocellulosic biomass. Lignin-derived carbon materials hold great promise for applications in energy and chemical engineering, catalysis and environmental remediation. In this review, the state-of-art sciences and technologies for controllable synthesis of lignin-derived carbon materials are summarized, pore structure engineering, crystalline engineering, and morphology controlling methodologies are thoroughly outlined and critically discussed. Green chemical engineering with cost-effectiveness and precise carbonization tuning microstructure are future research trends of lignin-derived carbon materials. Future research directions that could be employed to advance lignin-derived carbon materials toward commercial applications are then proposed.
The Association Between Erectile Dysfunction and Sleep Parameters: Data from a Prospective, Controlled Cohort
Authors: Wu Xu , Zhang Yuyang , Zhang Wei , Liu Guodong , Jiang Hui , Huang Houbao , Zhang Xiansheng
Published: July 2022

Background

Many studies have reported a possible strong relationship between poor sleep quality, sleep disruption, sleep disorders, and erectile dysfunction (ED).

Aim

This study aimed to investigate the relationship between sleep quality and ED.

Methods

Patients diagnosed with ED by the International Index of Erectile Function-5 (IIEF-5) questionnaire and 72 healthy adult men were included. Participants completed the questionnaire, underwent a detailed physical examination, and provided blood samples. All enrolled subjects then wore the Fitbit Charge 2 that monitored sleep throughout the night.

Outcomes

Primary outcome measures included scores on the IIEF-5, General Anxiety Disorder-7 (GAD-7) scale, Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and sleep monitoring parameters obtained from Fitbit Charge 2.

Results

Finally, a total of 107 ED patients and 72 healthy adult men were enrolled in this study. Univariate analysis indicated that the GAD-7 (P < .001), PHQ-9 (P < .001), and PSQI scores (P < .001) significantly differed according to the presence/absence of ED. Further multiple logistic regression analysis showed that the PHQ-9 (odds ratio [OR]: 1.227, 95% confidence interval [CI]: 1.070-1.407; P = .003) and PSQI scores (OR: 1.220, 95%CI: 1.116-1.334; P < .001) were independent risk factors for ED. Analysis of objective sleep monitoring parameters showed that total sleep time (TST) (P = .001), sleep onset latency (SOL) (P = .026), deep sleep (N3) duration (P = .011) and rapid eye movement (REM) sleep duration (P < .001) were significantly differed between the 2 groups, with durations in the ED group significantly lower than those in the non-ED group. In addition, receiver operating characteristic (ROC) curve analysis indicated that the REM sleep duration had the highest area under the curve (AUC: 0.728) of all sleep parameters, with a P value < .001, a sensitivity of 72.2% and a specificity of 73.8%.

Clinical Implications

Urologists and andrologists should be aware of impacted sleep quality and depression in ED patients.

Strengths & Limitations

The strength of this study is that the relationship between sleep quality and ED was assessed with both a subjective scale and an objective sleep monitoring tool. However, our study only described an association between sleep quality and ED and did not establish a causal relationship.

Conclusion

Sleep parameters are strongly associated with ED, indicating that poor sleep quality may increase the likelihood of ED.
Pre-Exposure Prophylaxis for HIV Infection as a Public Health Tool
Authors: Beyrer Chris , McCormack Sheena , Grulich Andrew
Published: July 2022

The efficacy of pre-exposure prophylaxis, PrEP, with antiviral agents for prevention of HIV infection has been demonstrated in multiple randomized controlled trials and demonstration projects. These trials have studied prevention at the individual level. The effectiveness of PrEP as a public health intervention to reduce HIV incidence at community and population levels is being actively evaluated but is less well described. In reviewing the available data on PrEP as a public health intervention, three significant examples have demonstrated success, and all have been among communities of gay, bisexual and other men who have sex with men (MSM).
From Private Influence to Public Amendment? The Senate's Amendment Rate in the 41st, 42nd and 43rd Canadian Parliaments
Authors: McCallion Elizabeth
Published: July 2022

Recent reforms to the Canadian Senate removed senators from the Liberal Party caucus and changed the appointment process to be more nonpartisan. This article asks: to what extent did the reforms affect legislative oversight in the Senate? By studying the Senate's legislative amendments, I find that the reformed Senate is more willing to amend bills than it was previously. The reforms led to sharp increases in the Senate's amendment rate, the number of amendments moved and the percentage of successful motions in amendment. In interviews, senators revealed that they see oversight differently following the reforms. Senators no longer have opportunities to advise the government in caucus, so they have begun using amendments to exercise oversight. This article concludes that the reforms shifted senators’ understanding of their function of oversight, leading to a higher amendment rate and increased visible scrutiny of government by the Senate.
The Bride of the Holy Trinity: The Role of Mary in Mechthild of Magdeburg's Mystical Theology
Authors: Zoutendam Erin Risch
Published: July 2022

This article adds to our understanding of late medieval women's religious writing by examining the role of the Virgin Mary in Mechthild of Magdeburg's thirteenth-century mystical text The Flowing Light of the Godhead (Das fließende Licht der Gottheit). The Virgin Mary was ubiquitous in late medieval religious writing, but she played different roles and modeled different ways of life, reflecting the particular aims of individual authors. In Mechthild's text, Mary is depicted as a spiritual teacher who actively draws the narrator into higher forms of the mystical life. Mechthild also portrays the Virgin in several traditional roles, adapting each of these roles to support her particular vision of the mystical life. Mary thus functions as a model for religious experience in The Flowing Light, while also authorizing and sanctioning Mechthild's contemplative ideals.
An Enslaver's Guide to Slavery Reform: William Dunlop's 1690 Proposals to Christianize Slaves in the British Atlantic
Authors: Moore Peter N.
Published: July 2022

When it was first brought to light in 2010, an anonymously authored, unpublished document from 1690, Proposals for the propagating of the Christian Religion, and Converting of Slaves whether Negroes or Indians in the English plantations, appeared to support claims for an emerging humanitarian sensibility among Christian antislavery reformers in seventeenth-century England. This article argues that Scottish Covenanter, colonizer, and enslaver William Dunlop was the author of these proposals. Dunlop's authorship casts them in a new light, showing the complex ways Christianity and slavery were entangled in this period and the challenges Reformed Protestants faced in their attempts to disentangle them. Dunlop's Reformed background and experience in the Presbyterian resistance movement during the “killing times” of the early 1680s led him to view slavery as anti-Christian tyranny and liberty as the will of God. But during his time in Carolina he was deeply implicated in enslaving illegally seized Christian Indian captives, African chattel slaves, white indentured servants seeking freedom in Spanish Catholic Florida, and even fellow Covenanters banished to the plantations for their resistance to episcopacy. Dunlop's proposals emerged from these dual contexts. They tried and failed to imagine a form of Christian slavery that gave enough freedom to enslaved people to lead authentic Christian lives, showing instead that Christianity and slavery were incompatible and offering reformers only a stark choice: not Christian slavery, but Christianity or slavery.
Factors influencing the diversity and distribution of epiphytic lichens and bryophytes on the relict tree Zelkova abelicea (Lam.) Boiss. (Ulmaceae)
Authors: Fazan Laurence , Gwiazdowicz Dariusz J. , Fragnière Yann , Fałtynowicz Wiesław , Ghosn Dany , Remoundou Ilektra , Rusińska Anna , Urbański Paweł , Pasta Salvatore , Garfì Giuseppe , Kozlowski Gregor
Published: July 2022

Trees have a crucial importance in the functioning of ecosystems on Earth. They are among the largest and longest-living taxa and provide habitat and shelter to numerous species belonging to diverse groups of organisms. Relict trees are of particular interest through their history of survival and adaptation, and because they potentially shelter rare or threatened organisms today. We investigated for the first time the diversity and distribution of epiphytic lichens and bryophytes found on the Cretan (Greek) endemic and relict phorophyte Zelkova abelicea (Ulmaceae). Our results showed that Z. abelicea hosts a high number of epiphytes. The Levka Ori mountain range in western Crete seems to be a hot spot for epiphytic lichens on Z. abelicea. Bryophytes had the highest diversity on Mt Kedros in central Crete but were absent from several other sites. Moreover, 17% of the studied lichens were recorded for the first time for Crete and 5% have never been recorded for Greece. Geographical position and browsing intensity seem to be important factors influencing the epiphytic community encountered. Tree morphology (dwarfed or arborescent) was also significant in influencing community composition although it was not possible to dissociate this factor from the effect of topography. Dwarfed individuals were found to have as much epiphytic diversity as arborescent trees. Ecological indicator values showed that high epiphytic diversity was found in some sites despite signs of eutrophication and disturbance due to pastoral activities and suggest the co-occurrence of both disturbance tolerant and sensitive species. Our results show how little is known about the biodiversity of Cretan phorophytes and highlights the need for further research on the topic.
The hidden borderline patient: patients with borderline personality disorder who do not engage in recurrent suicidal or self-injurious behavior
Authors: Zimmerman Mark , Becker Lena
Published: July 2022

Background

Despite the significant psychosocial morbidity associated with borderline personality disorder (BPD), its underrecognition is a significant clinical problem. BPD is likely underdiagnosed, in part, because patients with BPD usually present with chief complaints associated with mood, anxiety, and substance use disorders. When patients with BPD do not exhibit self-harm behavior, we suspect that BPD is less likely to recognized. An important question is whether the absence of this criterion, which might attenuate the likelihood of recognizing and diagnosing the disorder, identifies a subgroup of patients with BPD who are ‘less borderline’ than patients with BPD who do not manifest this criterion.

Methods

Psychiatric outpatients were evaluated with a semi-structured diagnostic interview for DSM-IV BPD, 390 of whom were diagnosed with BPD. We compared the demographic and clinical characteristics of patients with BPD who do and do not engage in repeated suicidal and self-harm behavior.

Results

Approximately half of the patients with BPD did not meet the suicidality/self-injury diagnostic criterion for the disorder. There were no differences between the patients who did and did not meet this criterion in occupational impairment, likelihood of receiving disability payments, impairment in social functioning, level of educational achievement, comorbid psychiatric disorders, history of childhood trauma, or severity of depression, anxiety, or anger upon presentation for treatment.

Conclusions

Repeated self-injurious and suicidal behavior is not synonymous with BPD. It is critical for clinicians to be aware that the absence of repeated self-injury and suicide threats/gestures or attempts does not rule out the diagnosis of BPD.
Why Do Poor People Not Take up Benefits? Evidence from the Barcelona’s B-MINCOME Experiment
Authors: LAÍN BRU , JULIÀ ALBERT
Published: July 2022

Non-take-up, i.e. individuals not applying for a benefit they are eligible for, is a widespread problem limiting the reach of welfare and protection systems. This paper seeks to understand it by means of a theoretical framework comprising two levels of analysis: the claimants’ individual characteristics in relation to the information barriers they face, and the administrative logic and functioning regarding the communications strategy used by public institutions. To test the hypotheses of these two levels of analysis, the paper analyses the B-MINCOME pilot scheme, a cash transfer programme implemented in the city of Barcelona between 2017 and 2019. Findings indicate that, although claimants’ characteristics may play a significant role, the administrative functioning and the communications strategy are fundamental in determining take-up rates. The conclusions briefly address some of the technical and moral concerns raised by non-take-up.
‘In my end is my beginning’: Peter Grimes and Death in Venice
Authors: Lambert Sterling
Published: July 2022

Benjamin Britten, gravely ill at the time of its composition, was surely aware that Death in Venice would be his last opera, and it is not surprising that the work should make reference to his first opera, Peter Grimes, as if to bookend his entire operatic career, and survey the enormous distance he had travelled, as a hallmark of what might be considered the composer's late style. Even so, the dramatic and musical relationships between the two works are unusually extensive. Both operas concern an outsider at odds with the society around him, in a strange reflection of the composer's particular situation as he wrote each work. Each is set in a place particularly special to the composer, where land borders sea in a metaphor for the boundary between life and death. Finally, the protagonist's interactions with a mysterious silent boy in each case hints at a part of Britten's character that dared not speak its name. These dramatic correspondences are paralleled in important musical connections between the operas, despite their ostensibly very different musical languages. Britten's final opera could therefore be understood to exemplify the famous words borrowed by T.S. Eliot from Mary, Queen of Scots: ‘In my end is my beginning’, an appropriate concept given the degree to which Britten was occupied with Eliot's verse at this time.
Balancing Equity and Efficiency in Kidney Allocation: An Overview
Authors: Elalouf Amir , Pliskin Joseph S.
Published: July 2022

Organs for transplantation are a scarce resource. Markedly, the transplant community’s primary challenge is the stark disparity between the number of patients awaiting deceased donor organ transplants and the rate at which organs become available. However, the allocation of a limited number of organs poses another constant challenge: maintaining an equilibrium between renal transplant utility and equity, that is, striking a balance between the utilitarian argument of medical efficiency and the principle of equity. In this comprehensive overview, the authors delve into the challenge of maintaining an acceptable balance between equity and efficiency and elaborate on some of the factors that might inform a decisionmaker’s evaluation of the extent to which a given allocation scheme is efficient or equitable.
Case Vignettes in Transplant Psychiatry Ethics
Authors: Chin H. Paul
Published: July 2022

The demand for liver transplants continues to far exceed the number of available viable donor organs; hence, it is of utmost importance to determine those individuals who are best able to care for these valuable, limited resources as potential recipients. At the same time, psychiatric comorbidity is common in the course of end-stage liver disease and can be mutually complicating. This article focuses on liver transplant candidacy from a psychiatric perspective, using illustrative cases to underscore the foundational facets of medical ethics that serve as the guide to these complex medical and ethical decisions.
Notes from an Organ Recipient: Once is Enough
Authors: Condon Annie Klebahn
Published: July 2022

In this paper, the author describes her personal experiences with liver disease and the challenges both before and after receiving an organ transplant. She describes how organs are currently allocated and offers her perspective on what fairness entails in situations where organs fail and patients need multiple organs.
A Philosophy for Choosing Doctors
Authors: Appel Jacob M.
Published: July 2022

This essay advocates for the wholesale reevaluation of the process used by American medical schools for selecting physicians, examining fundamental questions such as the purpose of physicians and the nature of meritocracy. It raises questions about the size of medical school classes, the specific academic requirements, and the inadequacy of current efforts to increase diversity. Ultimately, the essay argues for consideration of a range of reforms that will focus on the community-empowering aspects of medical admissions decisions.
When left is right: The role of typological similarity in multilinguals’ inhibitory control performance
Authors: Von Grebmer Zu Wolfsthurn Sarah , Gupta Anna , Pablos Leticia , Schiller Niels O.
Published: July 2022

Both inhibitory control and typological similarity between two languages feature frequently in current research on multilingual cognitive processing mechanisms. Yet, the modulatory effect of speaking two typologically highly similar languages on inhibitory control performance remains largely unexplored. However, this is a critical issue because it speaks directly to the organisation of the multilingual's cognitive architecture. In this study, we examined the influence of typological similarity on inhibitory control performance via a spatial Stroop paradigm in native Italian and native Dutch late learners of Spanish. Contrary to our hypothesis, we did not find evidence for a differential Stroop effect size for the typologically similar group (Italian–Spanish) compared to the typologically dissimilar group (Dutch–Spanish). Our results therefore suggest a limited influence of typological similarity on inhibitory control performance. The study has critical implications for characterising inhibitory control processes in multilinguals.
Caregiving subsidies and spousal early retirement intentions
Authors: Costa-Font Joan , Vilaplana-Prieto Cristina
Published: July 2022

Balancing caregiving duties and employment can be both financially and emotionally burdensome, especially when care is provided to a spouse at home. Caregiving subsidies can play a role in helping caregivers to cope with such duties. This paper demonstrates how providing financial respite for caregivers can influence individuals' decisions to retire early. We investigate the impact of a reform that extended long-term care (LTC) benefits (in the form of subsidies and supports) on the intention of a caregiving spouse to retire early in Spain. We subsequently examine the effect of austerity spending cuts reducing such publicly funded benefits, and we compare the estimates to the effects of an early retirement reform among private sector workers around the same time. Our preferred estimates suggest evidence of a 10pp reduction in early retirement intentions after the extension of LTC benefits even though the effect is heterogeneous by type of benefit. Consistently, austerity spending cuts in benefits are found to weaken retirement intentions. Even more importantly, our estimates suggest that cuts in caregiving subsidies exert a much stronger effect on early retirement intentions than actual early retirement reforms.
Automatic classification and neurotransmitter prediction of synapses in electron microscopy
Authors: Zhang Angela , Shailja S. , Borba Cezar , Miao Yishen , Goebel Michael , Ruschel Raphael , Ryan Kerrianne , Smith William , Manjunath B. S.
Published: July 2022

This paper presents a deep-learning-based workflow to detect synapses and predict their neurotransmitter type in the primitive chordate Ciona intestinalis (Ciona) electron microscopic (EM) images. Identifying synapses from EM images to build a full map of connections between neurons is a labor-intensive process and requires significant domain expertise. Automation of synapse classification would hasten the generation and analysis of connectomes. Furthermore, inferences concerning neuron type and function from synapse features are in many cases difficult to make. Finding the connection between synapse structure and function is an important step in fully understanding a connectome. Class Activation Maps derived from the convolutional neural network provide insights on important features of synapses based on cell type and function. The main contribution of this work is in the differentiation of synapses by neurotransmitter type through the structural information in their EM images. This enables the prediction of neurotransmitter types for neurons in Ciona, which were previously unknown. The prediction model with code is available on GitHub.
Roles of lncRNA LVBU in regulating urea cycle/polyamine synthesis axis to promote colorectal carcinoma progression
Authors: Meng Xiangqi , Peng Jingxuan , Xie Xiaoshan , Yu Fenghai , Wang Wencong , Pan Qihao , Jin Huilin , Huang Xiaoling , Yu Hongyan , Li Shengrong , Feng Dianying , Liu Qingxin , Fang Lekun , Lee Mong-Hong
Published: July 2022

Altered expression of Urea Cycle (UC) enzymes occurs in many tumors, resulting a metabolic hallmark termed as UC dysregulation. Polyamines are synthesized from ornithine, and polyamine synthetic genes are elevated in various tumors. However, the underlying deregulations of UC/ polyamine synthesis in cancer remain elusive. Here, we characterized a hypoxia-induced lncRNA LVBU (lncRNA regulation via BCL6/urea cycle) that is highly expressed in colorectal cancer (CRC) and correlates with poor cancer prognosis. Increased LVBU expression promoted CRC cells proliferation, foci formation and tumorigenesis. Further, LVBU regulates urea cycle and polyamine synthesis through BCL6, a negative regulator of p53. Mechanistically, overexpression of LVBU competitively bound miR-10a/miR-34c to protect BCL6 from miR-10a/34c-mediated degradation, which in turn allows BCL6 to block p53-mediated suppression of genes (arginase1 ARG1, ornithine transcarbamylase OTC, ornithine decarboxylase 1 ODC1) involved in UC/polyamine synthesis. Significantly, ODC1 inhibitor attenuated the growth of patient derived xenografts (PDX) that sustain high LVBU levels. Taken together, elevated LVBU can regulate BCL6-p53 signaling axis for systemic UC/polyamine synthesis reprogramming and confers a predilection toward CRC development. Our data demonstrates that further drug development and clinical evaluation of inhibiting UC/polyamine synthesis are warranted for CRC patients with high expression of LVBU.
Decreased expression of hypoxia-inducible factor 1α (HIF-1α) in cord blood monocytes under anoxia
Authors: Schlegel Christiane , Liu Kai , Spring Bärbel , Dietz Stefanie , Poets Christian F. , Hudalla Hannes , Lajqi Trim , Köstlin-Gille Natascha , Gille Christian
Published: July 2022

Background

Infections are a major cause for morbidity and mortality in neonates; however, the underling mechanisms for increased infection susceptibility are incompletely understood. Hypoxia, which is present in inflamed tissues, has been identified as an important activation signal for innate immune cells in adults and is mainly mediated by hypoxia-inducible factor 1α (HIF-1α). Fetal tissue pO2 physiologically is low but rises immediately after birth.

Methods

In this study, the effect of low oxygen partial pressure (pO2) on HIF-1α expression and its targets phagocytosis, reactive oxygen species (ROS) production and vascular endothelial growth factor (VEGF) secretion was compared in vitro between immune cells from adult peripheral blood and cord blood using anoxia, HIF-1α stabilizer desferroxamin (DFO) and E. coli as stimuli.

Results

We show that anoxia-induced HIF-1α protein accumulation, phagocytosis, ROS-production and VEGF-expression were greatly diminished in cord blood compared to adult cells. E. coli led to HIF-1α gene expression in adult and cord blood immune cells; however, cord blood cells failed to accumulate HIF-1α protein and VEGF upon E. coli stimulation.

Conclusions

Taken together, our results show a diminished activation of cord blood immune cells by low pO2, which might contribute to impaired reactivity in the context of infection.

Impact

Neonatal immune cells do not accumulate HIF-1α under low oxygen partial pressure leading to decreased phagocytosis and decreased ROS production.

We demonstrate a previously unknown mechanism of reduced activation of neonatal immune cells in the context of an inflammatory response.

This could contribute to the increased susceptibility of newborns and preterm infants to infection.
Suicidality in clinically stable bipolar disorder and schizophrenia patients during the COVID-19 pandemic
Authors: Li Yu-Chen , Bai Wei , Cai Hong , Wu Yuxuan , Zhang Ling , Ding Yan-Hong , Yang Juan-Juan , Du Xiangdong , Zeng Zhen-Tao , Lu Chang-Mou , Feng Ke-Xin , Mi Wen-Fang , Zhang Lan , Liu Huan-Zhong , Balbuena Lloyd , Cheung Teris , Su Zhaohui , An Feng-Rong , Xiang Yu-Tao
Published: July 2022

The coronavirus disease 2019 (COVID-19) pandemic has a disproportionate impact on vulnerable subpopulations, including those with severe mental illness (SMI). This study examined the one-year prevalence of suicidal ideation (SI), suicide plans (SP), and suicide attempts (SA) in bipolar disorder (BD) and schizophrenia (SCZ) patients during the pandemic. Prevalence rates were compared between the two disorders and associated factors were examined. A survey was conducted in six tertiary psychiatric hospitals and psychiatric units. People with a diagnosis of BD or SCZ were invited to participate. SI, SP, and SA (suicidality for short) were assessed and associated factors were examined using binary logistical regression. The 1-year prevalence of SI, SP and SA in BD patients were 58.3%, (95% CI: 54.1–62.6%), 38.4% (95% CI: 34.3–42.6%) and 38.6% (95% CI: 34.5–42.8%), respectively, which were higher than the corresponding figures in SCZ patients (SI: 33.2%, 95% CI: 28.6–37.8%; SP: 16.8%, 95% CI: 13.2–20.5%; SA: 19.4%, 95% CI: 15.5–23.3%). Patients with younger age, experience of cyberbullying, a history of SA among family or friends, a higher fatigue and physical pain score, inpatient status, and severe depressive symptoms were more likely to have suicidality. The COVID-19 pandemic was associated with increased risk of suicidality, particularly in BD patients. It is of importance to regularly screen suicidality in BD and SCZ patients during the pandemic even if they are clinically stable.
Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease
Authors: Dong An-qi , Yang Ya-ping , Jiang Shu-min , Yao Xiao-yu , Qi Di , Mao Cheng-jie , Cheng Xiao-yu , Wang Fen , Hu Li-fang , Liu Chun-feng
Published: July 2022

Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated byDrd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specificAtg5 knockdownin vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.
CD95 gene deletion may reduce clonogenic growth and invasiveness of human glioblastoma cells in a CD95 ligand-independent manner
Authors: Quijano-Rubio Clara , Silginer Manuela , Weller Michael
Published: July 2022

CD95 (Fas/APO-1) is a multifunctional cell surface receptor with antithetic roles. First described to mediate cell death, interactions of CD95 with its natural ligand, CD95L, have also been described to induce tumor-promoting signaling leading to proliferation, invasion and stem cell maintenance, mainly in cancer cells that are resistant to CD95-mediated apoptosis. While activation of CD95-mediated apoptosis in cancer cells may not be clinically practicable due to toxicity, inhibition of tumor-promoting CD95 signaling holds therapeutic potential. In the present study, we characterized CD95 and CD95L expression in human glioma-initiating cells (GIC), a glioblastoma cell population with stem cell features, and investigated the consequences of CRISPR-Cas9-mediated CD95 or CD95L gene deletion. In vitro, GIC expressed CD95 but not CD95L and were sensitive to CD95-mediated apoptosis. Upon genetic deletion of CD95, GIC acquired resistance to CD95L-induced apoptosis but exhibited inferior clonogenic growth, sphere-forming capacity, and invasiveness compared with control cells, suggesting the existence of CD95L-independent constitutive CD95 signaling with tumor-promoting properties in GIC. In vivo, GIC expressed CD95 and a non-canonical form of CD95L lacking the CD95-binding region. CD95 genetic deletion did not prolong survival in immunocompromised GIC-bearing mice. Altogether, these data indicate that canonical CD95L may not be expressed in human GIC and suggest the existence of a CD95L-independent CD95-signaling pathway that maintains some malignancy traits of GIC. The lack of altered survival of tumor-bearing mice after genetic deletion of CD95 suggests that CD95 signaling is not essential to maintain the growth of human GIC xenografted into the brains of nude mice. The ligand-independent tumor-promoting role of constitutive CD95 in our GIC models in vitro highlights the complexity and challenges associated with targeting CD95 with therapeutic intent.
Functional characterization of FBXL7 as a novel player in human cancers
Authors: Wang Yue , Shen Xiao , Gong Longyuan , Zhao Yongchao , Xiong Xiufang
Published: July 2022

F-box and leucine-rich repeat protein 7 (FBXL7), an F-box protein responsible for substrate recognition by the SKP1-Cullin-1-F-box (SCF) ubiquitin ligases, plays an emerging role in the regulation of tumorigenesis and tumor progression. FBXL7 promotes polyubiquitylation and degradation of diverse substrates and is involved in many biological processes, including apoptosis, cell proliferation, cell migration and invasion, tumor metastasis, DNA damage, glucose metabolism, planar cell polarity, and drug resistance. In this review, we summarize the downstream substrates and upstream regulators of FBXL7. We then discuss its role in tumorigenesis and tumor progression as either an oncoprotein or a tumor suppressor, and further describe its aberrant expression and association with patient survival in human cancers. Finally, we provide future perspectives on validating FBXL7 as a cancer biomarker for diagnosis and prognosis and/or as a potential therapeutic target for anticancer treatment.
Hetero-bivalent nanobodies provide broad-spectrum protection against SARS-CoV-2 variants of concern including Omicron
Authors: Ma Huan , Zhang Xinghai , Zheng Peiyi , Dube Peter H. , Zeng Weihong , Chen Shaohong , Cheng Qingyu , Yang Yunru , Wu Yan , Zhou Junhui , Hu Xiaowen , Xiang Yan , Zhang Huajun , Chiu Sandra , Jin Tengchuan
Published: July 2022

SARS-CoV-2 variants with adaptive mutations have continued to emerge, causing fresh waves of infection even amongst vaccinated population. The development of broad-spectrum antivirals is thus urgently needed. We previously developed two hetero-bivalent nanobodies (Nbs), aRBD-2-5 and aRBD-2-7, with potent neutralization activity against the wild-type (WT) Wuhan isolated SARS-CoV-2, by fusing aRBD-2 with aRBD-5 and aRBD-7, respectively. Here, we resolved the crystal structures of these Nbs in complex with the receptor-binding domain (RBD) of the spike protein, and found that aRBD-2 contacts with highly-conserved RBD residues and retains binding to the RBD of the Alpha, Beta, Gamma, Delta, Delta plus, Kappa, Lambda, Omicron BA.1, and BA.2 variants. In contrast, aRBD-5 and aRBD-7 bind to less-conserved RBD epitopes non-overlapping with the epitope of aRBD-2, and do not show apparent binding to the RBD of some variants. However, when fused with aRBD-2, they effectively enhance the overall binding affinity. Consistently, aRBD-2-5-Fc and aRBD-2-7-Fc potently neutralized all of the tested authentic or pseudotyped viruses, including WT, Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.1.1 and BA.2. Furthermore, aRBD-2-5-Fc provided prophylactic protection against the WT and mouse-adapted SARS-CoV-2 in mice, and conferred protection against the Omicron BA.1 variant in hamsters prophylactically and therapeutically, indicating that aRBD-2-5-Fc could potentially benefit the prevention and treatment of COVID-19 caused by the emerging variants of concern. Our strategy provides new solutions in the development of broad-spectrum therapeutic antibodies for COVID-19.
A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
Authors: Liu Yang , Zhang Xianwen , Liu Jianying , Xia Hongjie , Zou Jing , Muruato Antonio E. , Periasamy Sivakumar , Kurhade Chaitanya , Plante Jessica A. , Bopp Nathen E. , Kalveram Birte , Bukreyev Alexander , Ren Ping , Wang Tian , Menachery Vineet D. , Plante Kenneth S. , Xie Xuping , Weaver Scott C. , Shi Pei-Yong
Published: July 2022

We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, but restores its replication on interferon-deficient Vero-E6 cells that are approved for vaccine production. The ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the ∆3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the ∆3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter ∆3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that ∆3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.
Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders
Authors: Boonsawat Paranchai , Horn Anselm H. C. , Steindl Katharina , Baumer Alessandra , Joset Pascal , Kraemer Dennis , Bahr Angela , Ivanovski Ivan , Cabello Elena M. , Papik Michael , Zweier Markus , Oneda Beatrice , Sirleto Pietro , Burkhardt Tilo , Sticht Heinrich , Rauch Anita
Published: July 2022

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.
Valence bond glass state in the 4d1 fcc antiferromagnet Ba2LuMoO6
Authors: Mustonen O. H. J. , Mutch H. M. , Walker H. C. , Baker P. J. , Coomer F. C. , Perry R. S. , Pughe C. , Stenning G. B. G. , Liu C. , Dutton S. E. , Cussen E. J.
Published: July 2022

B-site ordered 4d1 and 5d1 double perovskites have a number of potential exotic ground states including multipolar order, quantum spin liquids and valence bond glass states. These arise from the complex interactions of spin-orbital entangled Jeff = 3/2 pseudospins on the geometrically frustrated fcc lattice. The 4d1 Mo5+ perovskite Ba2YMoO6 has been suggested to have a valence bond glass ground state. Here we report on the low temperature properties of powder samples of isostructural Ba2LuMoO6: the only other known cubic 4d1 perovskite with one magnetic cation. Our muon spectroscopy experiments show that magnetism in this material remains dynamic down to 60 mK without any spin freezing or magnetic order. A singlet-triplet excitation with a gap of Δ = 28 meV is observed in inelastic neutron scattering. These results are interpreted as a disordered valence bond glass ground state similar to Ba2YMoO6. Our results highlight the differences of the 4d1 double perovskites in comparison to cubic 5d1 analogues, which have both magnetic and multipolar order.
Ribonucleotide reductase M2B in the myofibers modulates stem cell fate in skeletal muscle
Authors: Chen Wan-Jing , Lin I-Hsuan , Lee Chien-Wei , Yoshioka Kiyoshi , Ono Yusuke , Yan Yu-Ting , Yen Yun , Chen Yi-Fan
Published: July 2022

The balance among quiescence, differentiation, and self-renewal of skeletal muscle stem cells (MuSCs) is tightly regulated by their intrinsic and extrinsic properties from the niche. How the niche controls MuSC fate remains unclear. Ribonucleotide reductase M2B (Rrm2b) modulates MuSC quiescence/differentiation in muscle in response to injury. Rrm2b knockout in myofibers, but not in MuSCs, led to weakness of muscles, such as a loss of muscle mass and strength. After muscle injury, damaged myofibers were more efficiently repaired in the Rrm2b myofiber-specific knockout mice than the control mice, but these myofibers were thinner and showed weak functioning. Rrm2b-deleted myofibers released several myokines, which trigger MuSCs to differentiate but not re-enter the quiescent stage to replenish the stem cell pool. Overall, Rrm2b in the myofibers plays a critical role in modulating the MuSC fate by modifying the microenvironment, and it may lead to a possible strategy to treat muscle disorders.
The University of Pennsylvania glioblastoma (UPenn-GBM) cohort: advanced MRI, clinical, genomics, & radiomics
Authors: Bakas Spyridon , Sako Chiharu , Akbari Hamed , Bilello Michel , Sotiras Aristeidis , Shukla Gaurav , Rudie Jeffrey D. , Santamaría Natali Flores , Kazerooni Anahita Fathi , Pati Sarthak , Rathore Saima , Mamourian Elizabeth , Ha Sung Min , Parker William , Doshi Jimit , Baid Ujjwal , Bergman Mark , Binder Zev A. , Verma Ragini , Lustig Robert A. , Desai Arati S. , Bagley Stephen J. , Mourelatos Zissimos , Morrissette Jennifer , Watt Christopher D. , Brem Steven , Wolf Ronald L. , Melhem Elias R. , Nasrallah MacLean P. , Mohan Suyash , O’Rourke Donald M. , Davatzikos Christos
Published: July 2022

Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the “University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics” (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed withde novoglioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during routine clinical practice, at the University of Pennsylvania Health System, (b) accompanying clinical, demographic, and molecular information, (d) perfusion and diffusion derivative volumes, (e) computationally-derived and manually-revised expert annotations of tumor sub-regions, as well as (f) quantitative imaging (also known as radiomic) features corresponding to each of these regions. This collection describes our contribution towards repeatable, reproducible, and comparative quantitative studies leading to new predictive, prognostic, and diagnostic assessments.