bluuebunny/crossref_metadata_2025_split huggingface dataset:
Balancing Equity and Efficiency in Kidney Allocation: An Overview
Authors: Elalouf Amir , Pliskin Joseph S. 
Published: July 2022

AbstractOrgans 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

AbstractThe 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.
A Philosophy for Choosing Doctors
Authors: Appel Jacob M. 
Published: July 2022

AbstractThis 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

AbstractBoth 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

AbstractBalancing 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

Abstract
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

AbstractAltered 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

Abstract
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

AbstractThe 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

AbstractInflammation 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

AbstractCD95 (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

AbstractF-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

AbstractSARS-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

AbstractWe 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

AbstractThe 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.