bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher Education in Times of Instability and Disruption: Rethinking Notions of Values, Value Creation and Instructional Practices in Vietnam and Beyond
Authors: Felix Jonathan J.
Published: February 2021

The disruptive nature of the COVID-19 pandemic has created a massive shift in instructional practices in higher education across the globe. The impact of this pandemic on education globally has led to a surge in online teaching and the use of various digital technologies and platforms to support instructional practices. However, this world-changing event has foregrounded the limitations of technology in addition to other important indications, particularly as it relates to the notion of value and by extension value creation. Within the context of the Vietnamese higher education ecosystem, what is evident is that a re-evaluation of values is worth considering, in terms of the value of local higher education institutions, in addition to the value creation produced by the same. This article will engage with pertinent implications for the post-COVID realities which offer untold challenges and opportunities in Vietnam and elsewhere. Moreover, the post-COVID realities of late modernity only serve to accentuate the importance of values and value creation in this context as higher education institutions would re-evaluate, rethink, and retool approaches to instructional practices. A focus on questions of value aids in considering the broader conditions and contexts which support some of the fruitful and situated outcomes of higher education which includes human capital development, employment, social mobility and the production of modern social identities.
Circulating microRNA-125b Levels Are Associated With the Risk of Vascular Calcification in Healthy Community-Dwelling Older Adults
Authors: Chao Chia-Ter , Han Der-Sheng , Huang Jenq-Wen
Published: February 2021

Background: Vascular calcification (VC) is a subclinical manifestation of vascular disease burden among older adults, conferring an elevated mortality risk. Biomarkers capable of detecting and risk-stratifying VC associated with advanced age remains unavailable, impeding our effort to provide optimal care to geriatric patients.

Objectives: In this study, we aimed to investigate whether circulating miR-125b served as a potential indicator for VC in relatively healthy older adults.

Methods: Community-dwelling older adults (age ≥65) were prospectively recruited during 2017, followed by clinical features documentation and VC rating based on aortic arch calcification (AAC) and abdominal aortic calcification (AbAC). Multiple logistic regression was done to evaluate the relationship between circulating miR-125b levels, VC presence and severity, followed by selecting the optimal cutoff point for VC diagnosis.

Results: A total of 343 relatively healthy older adults (median age, 73.8 years; 40% male; 59.8% having AAC) were enrolled, with a median circulating miR-125b level of 0.012 (interquartile range, 0.003–0.037). Those with more severe AAC had progressively decreasing miR-125b levels (p<0.001). Multiple regression analyses showed that having higher miR-125b levels based on the median value were associated with a substantially lower risk of AAC [odds ratio (OR) 0.022, 95% confidence interval (CI) 0.011–0.044] compared to those having lower ones. An optimal cutoff of miR-125b for identifying AAC in older adults was 0.008, with a sensitivity and specificity of 0.86 and 0.80, respectively. Similar findings were obtained when using AbAC as the endpoint.

Conclusions: We found that miR-125b serves as an independent indicator for VC in relatively healthy older adults, and may potentially be linked with VC pathophysiology.
Compound Heterozygous KCNQ1 Mutations Causing Recessive Romano–Ward Syndrome: Functional Characterization by Mutant Co-expression
Authors: González-Garrido Antonia , Domínguez-Pérez Mayra , Jacobo-Albavera Leonor , López-Ramírez Omar , Guevara-Chávez José Guadalupe , Zepeda-García Oscar , Iturralde Pedro , Carnevale Alessandra , Villarreal-Molina Teresa
Published: February 2021

Next Generation Sequencing has identified many KCNQ1 genetic variants associated with type 1 long QT or Romano-Ward syndrome, most frequently inherited in an autosomal dominant fashion, although recessive forms have been reported. Particularly in the case of missense variants, functional studies of mutants are of aid to establish variant pathogenicity and to understand the mechanistic basis of disease. Two compound heterozygous KCNQ1 mutations (p.A300T and p.P535T) were previously found in a child who suffered sudden death. To provide further insight into the clinical significance and basis for pathogenicity of these variants, different combinations of wildtype, A300T and P535T alleles were co-expressed with the accessory β-subunit minK in HEK293 cells, to analyze colocalization with the plasma membrane and some biophysical phenotypes of homo and heterotetrameric channels using the patch-clamp technique. A300T homotetrameric channels showed left-shifted activation V1/2 as previously observed in Xenopus oocytes, decreased maximum conductance density, slow rise-time300ms, and a characteristic use-dependent response. A300T slow rise-time300ms and use-dependent response behaved as dominant biophysical traits for all allele combinations. The P535T variant significantly decreased maximum conductance density and Kv7.1-minK-plasma membrane colocalization. P535T/A300T heterotetrameric channels showed decreased colocalization with plasma membrane, slow rise-time300ms and the A300T characteristic use-dependent response. While A300T left shifted activation voltage dependence behaved as a recessive trait when co-expressed with WT alleles, it was dominant when co-expressed with P535T alleles.

Conclusions: The combination of P535T/A300T channel biophysical properties is compatible with recessive Romano Ward syndrome. Further analysis of other biophysical traits may identify other mechanisms involved in the pathophysiology of this disease.
Chenodeoxycholic Acid Modulates Bile Acid Synthesis Independent of Fibroblast Growth Factor 19 in Primary Human Hepatocytes
Authors: Johansson Helene , Søndergaard Jonas Nørskov , Jorns Carl , Kutter Claudia , Ellis Ewa C. S.
Published: February 2021

Bile acids (BAs) are detergents essential for intestinal absorption of lipids. Disruption of BA homeostasis can lead to severe liver damage. BA metabolism is therefore under strict regulation by sophisticated feedback mechanisms. The hormone-like protein Fibroblast growth factor 19 (FGF19) is essential for maintaining BA homeostasis by down regulating BA synthesis. Here, the impact of both FGF19 and chenodeoxycholic acid (CDCA) on primary human hepatocytes was investigated and a possible autocrine/paracrine function of FGF19 in regulation of BA synthesis evaluated. Primary human hepatocytes were treated with CDCA, recombinant FGF19 or conditioned medium containing endogenously produced FGF19. RNA sequencing revealed that treatment with CDCA causes deregulation of transcripts involved in BA metabolism, whereas treatment with FGF19 had minor effects. CDCA increased FGF19 mRNA expression within 1 h. We detected secretion of the resulting FGF19 protein into medium, mimicking in vivo observations. Furthermore, medium enriched with endogenously produced FGF19 reduced BA synthesis by down regulating CYP7A1 gene expression. However, following knockdown of FGF19, CDCA still independently decreased BA synthesis, presumably through the regulatory protein small heterodimer partner (SHP). In summary, we show that in primary human hepatocytes CDCA regulates BA synthesis in an FGF19-independent manner.
Endocrinology of the Aging Prostate: Current Concepts
Authors: Cannarella Rossella , Condorelli Rosita A. , Barbagallo Federica , La Vignera Sandro , Calogero Aldo E.
Published: February 2021

Benign prostate hyperplasia (BPH), one of the most common diseases in older men, adversely affects quality-of-life due to the presence of low urinary tract symptoms (LUTS). Numerous data support the presence of an association between BPH-related LUTS (BPH-LUTS) and metabolic syndrome (MetS). Whether hormonal changes occurring in MetS play a role in the pathogenesis of BPH-LUTS is a debated issue. Therefore, this article aimed to systematically review the impact of hormonal changes that occur during aging on the prostate, including the role of sex hormones, insulin-like growth factor 1, thyroid hormones, and insulin. The possible explanatory mechanisms of the association between BPH-LUTS and MetS are also discussed. In particular, the presence of a male polycystic ovarian syndrome (PCOS)-equivalent may represent a possible hypothesis to support this link. Male PCOS-equivalent has been defined as an endocrine syndrome with a metabolic background, which predisposes to the development of type II diabetes mellitus, cardiovascular diseases, prostate cancer, BPH and prostatitis in old age. Its early identification would help prevent the onset of these long-term complications.
Effects of Melatonin on Neurobehavior and Cognition in a Cerebral Palsy Model of plppr5−/− Mice
Authors: Sun Yuxiao , Ma Liya , Jin Meifang , Zheng Yuqin , Wang Dandan , Ni Hong
Published: February 2021

Cerebral palsy (CP), a group of clinical syndromes caused by non-progressive brain damage in the developing fetus or infant, is one of the most common causes of lifelong physical disability in children in most countries. At present, many researchers believe that perinatal cerebral hypoxic ischemic injury or inflammatory injury are the main causes of cerebral palsy. Previous studies including our works confirmed that melatonin has a protective effect against convulsive brain damage during development and that it affects the expression of various molecules involved in processes such as metabolism, plasticity and signaling in the brain. Integral membrane protein plppr5 is a new member of the plasticity-related protein family, which is specifically expressed in brain and spinal cord, and induces filopodia formation as well as neurite growth. It is highly expressed in the brain, especially in areas of high plasticity, such as the hippocampus. The signals are slightly lower in the cortex, the cerebellum, and in striatum. Noteworthy, during development plppr5 mRNA is expressed in the spinal cord, i.e., in neuron rich regions such as in medial motor nuclei, suggesting that plppr5 plays an important role in the regulation of neurons. However, the existing literature only states that plppr5 is involved in the occurrence and stability of dendritic spines, and research on its possible involvement in neonatal ischemic hypoxic encephalopathy has not been previously reported. We used plppr5 knockout (plppr5−/−) mice and their wild-type littermates to establish a model of hypoxicischemic brain injury (HI) to further explore the effects of melatonin on brain injury and the role of plppr5 in this treatment in an HI model, which mainly focuses on cognition, exercise, learning, and memory. All the tests were performed at 3–4 weeks after HI. As for melatonin treatment, which was performed 5 min after HI injury and followed by every 24h. In these experiments, we found that there was a significant interaction between genotype and treatment in novel object recognition tests, surface righting reflex tests and forelimb suspension reflex tests, which represent learning and memory, motor function and coordination, and the forelimb grip of the mice, respectively. However, a significant main effect of genotype and treatment on performance in all behavioral tests were observed. Specifically, wild-type mice with HI injury performed better than plppr5−/− mice, regardless of treatment with melatonin or vehicle. Moreover, treatment with melatonin could improve behavior in the tests for wild-type mice with HI injury, but not for plppr5−/− mice. This study showed that plppr5 knockout aggravated HI damage and partially weakened the neuroprotection of melatonin in some aspects (such as novel object recognition test and partial nerve reflexes), which deserves further study.
Whole Genome Sequencing Prioritizes CHEK2, EWSR1, and TIAM1 as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer
Authors: Srivastava Aayushi , Giangiobbe Sara , Skopelitou Diamanto , Miao Beiping , Paramasivam Nagarajan , Diquigiovanni Chiara , Bonora Elena , Hemminki Kari , Försti Asta , Bandapalli Obul Reddy
Published: February 2021

Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.
Macrophage M2 Co-expression Factors Correlate With the Immune Microenvironment and Predict Outcome of Renal Clear Cell Carcinoma
Authors: Wang Yutao , Yan Kexin , Lin Jiaxing , Li Jun , Bi Jianbin
Published: February 2021

Purpose: In the tumor microenvironment, the functional differences among various tumor-associated macrophages (TAM) are not completely clear. Tumor-associated macrophages are thought to promote the progression of cancer. This article focuses on exploring M2 macrophage-related factors and behaviors of renal clear cell carcinoma.

Method: We obtained renal clear cell carcinoma data from TCGA-KIRC-FPKM, GSE8050, GSE12606, GSE14762, and GSE3689. We used the “Cibersort” algorithm to calculate type M2 macrophage proportions among 22 types of immune cells. M2 macrophage-related co-expression module genes were selected using weighted gene co-expression network analysis (WGCNA). A renal clear cell carcinoma prognosis risk score was built based on M2 macrophage-related factors. The ROC curve and Kaplan–Meier analysis were performed to evacuate the risk score in various subgroups. The Pearson test was used to calculate correlations among M2 macrophage-related genes, clinical phenotype, immune phenotype, and tumor mutation burden (TMB). We measured differences in co-expression of genes at the protein level in clear renal cell carcinoma tissues.

Results: There were six M2 macrophage co-expressed genes (F13A1, FUCA1, SDCBP, VSIG4, HLA-E, TAP2) related to infiltration of M2 macrophages; these were enriched in neutrophil activation and involved in immune responses, antigen processing, and presentation of exogenous peptide antigen via MHC class I. M2-related factor frequencies were robust biomarkers for predicting the renal clear cell carcinoma patient clinical phenotype and immune microenvironment. The Cox regression model, built based on M2 macrophage-related factors, showed a close prognostic correlation (AUC = 0.78). The M2 macrophage-related prognosis model also performed well in various subgroups. Using western blotting, we found that VSIG4 protein expression levels were higher in clear renal cell carcinoma tissues than in normal tissues.

Conclusion: These co-expressed genes were most related to the M2 macrophage phenotype. They correlated with the immune microenvironment and predicted outcomes of renal clear cell carcinoma. These co-expressed genes and the biological processes associated with them might provide the basis for new strategies to intervene via chemotaxis of M2 macrophages.
Systemic Multi-Omics Analysis Reveals Amplified P4HA1 Gene Associated With Prognostic and Hypoxic Regulation in Breast Cancer
Authors: Murugesan Manikandan , Premkumar Kumpati
Published: February 2021

Breast cancer (BC) is a common malignant tumor in females around the world. While multimodality therapies exist, the mortality rate remains high. The hypoxic condition was one of the potent determinants in BC progression. The molecular mechanisms underpinning hypoxia and their association with BC can contribute to a better understanding of tailored therapies. In this study, two hypoxic induced BC transcriptomic cohorts (GSE27813 and GSE47533) were assessed from the GEO database. The P4HA1 gene was identified as a putative candidate and significantly regulated in hypoxic BC cells compared to normal BC cells at different time intervals (6 h, 9 h, 16 h, 32 h, and 48 h). In patients with Luminal (p < 1E-12), triple-negative subclasses (p = 1.35059E-10), Stage 1 (p = 8.8817E-16), lymph node N1 (p = 1.62436E-12), and in the 40–80 age group (p = 1.62447E-12), the expression of P4HA1 was closely associated with the clinical subtypes of BC. Furthermore, at the 10q22.1 chromosomal band, the P4HA1 gene displayed a high copy number elevation and was associated with a poor clinical regimen with overall survival, relapse-free survival, and distant metastases-free survival in BC patients. In addition, using BioGRID, the protein–protein interaction (PPI) network was built and the cellular metabolic processes, and hedgehog pathways are functionally enriched with GO and KEGG terms. This tentative result provides insight into the molecular function of the P4HA1 gene, which is likely to promote hypoxic-mediated carcinogenesis, which may favor early detection of BC and therapeutic stratification.
Medication Adherence After Acute Coronary Syndrome in Women Compared With Men: A Systematic Review and Meta-Analysis
Authors: Bots Sophie H. , Inia Jose A. , Peters Sanne A. E.
Published: February 2021

Introduction: Pharmacological treatment is an important component of secondary prevention in acute coronary syndrome (ACS) survivors. However, adherence to medication regimens is often suboptimal, reducing the effectiveness of treatment. It has been suggested that sex influences adherence to cardiovascular medication, but results differ across studies, and a systematic overview is lacking.

Methods: We performed a systematic search of PubMed and EMBASE on 16 October 2019. Studies that reported sex-specific adherence for one or more specific medication classes for ACS patients were included. Odds ratios, or equivalent, were extracted per medication class and combined using a random effects model.

Results: In total, we included 28 studies of which some had adherence data for more than one medication group. There were 7 studies for angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) (n = 100,909, 37% women), 8 studies for antiplatelet medication (n = 37,804, 27% women), 11 studies for beta-blockers (n = 191,339, 38% women), and 17 studies for lipid-lowering medication (n = 318,837, 35% women). Women were less adherent to lipid-lowering medication than men (OR = 0.87, 95% CI 0.82–0.92), but this sex difference was not observed for antiplatelet medication (OR = 0.95, 95% CI 0.83–1.09), ACEIs/ARBs (OR = 0.95, 95% CI 0.78–1.17), or beta-blockers (OR = 0.97, 95% CI 0.86–1.11).

Conclusion: Women with ACS have poorer adherence to lipid-lowering medication than men with the same condition. There are no differences in adherence to antiplatelet medication, ACEIs/ARBs, and beta-blockers between women and men with ACS.
Case Report: Early Transplant Rejection of a Methanol-Intoxicated Donor Heart in a Young Female Patient. A Diagnostic Approach With CMR, Cardiac Biopsy, and Genetic Risk Assessment
Authors: Stoiber Lukas , Schoenrath Felix , Knosalla Christoph , Milting Hendrik , Klingel Karin , Tschöpe Carsten , Tanacli Radu , Gebker Rolf , Berger Alexander , Pieske Burkert , Kelle Sebastian
Published: February 2021

This case report describes the contributions of multimodality imaging, cardiac biopsy, and genetic sequencing to the diagnosis and management of heart transplant rejection in a 23-year old patient with dilated cardiomyopathy.
TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation
Authors: Shi Yong , Su Wantong , Zhang Lei , Shi Chengyu , Zhou Jinren , Wang Peng , Wang Hao , Shi Xiaoli , Wei Song , Wang Qi , Auwerx Johan , Schoonjans Kristina , Yu Yue , Pan Rui , Zhou Haoming , Lu Ling
Published: February 2021

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with dysregulation of liver metabolism and inflammation. G-protein coupled bile acid receptor 1 (TGR5) is a cell surface receptor that is involved in multiple metabolic pathways. However, the functions of TGR5 in regulating macrophage innate immune activation in NASH remain unclear. Here, we found that TGR5 expression was decreased in liver tissues from humans and mice with NASH. Compared to wild type (WT) mice, TGR5-knockout (TGR5−/−) mice exhibited exacerbated liver damage, increased levels of proinflammatory factors, and enhanced M1 macrophage polarization. Moreover, TGR5 deficiency facilitated M1 macrophage polarization by promoting NLRP3 inflammasome activation and caspase-1 cleavage. Taken together, our findings revealed that TGR5 signaling attenuated liver steatosis and inflammation and inhibited NLRP3-mediated M1 macrophage polarization in NASH.
Increased Frequency of Dysfunctional Siglec-7−CD57+PD-1+ Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease
Authors: Sakamoto Yuzuru , Yoshio Sachiyo , Doi Hiroyoshi , Mori Taizo , Matsuda Michitaka , Kawai Hironari , Shimagaki Tomonari , Yoshikawa Shiori , Aoki Yoshihiko , Osawa Yosuke , Yoshida Yuji , Arai Taeang , Itokawa Norio , Atsukawa Masanori , Ito Takanori , Honda Takashi , Mise Yoshihiro , Ono Yoshihiro , Takahashi Yu , Saiura Akio , Taketomi Akinobu , Kanto Tatsuya
Published: February 2021

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56+ NK cell and CD56dim NK cell populations compared with HVs, and the CD56dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7+CD56dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7−CD57+PD-1+CD56dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.
Relevance of the Pyroptosis-Related Inflammasome Pathway in the Pathogenesis of Diabetic Kidney Disease
Authors: Liu Pan , Zhang Zhengdong , Li Yao
Published: February 2021

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD) in many developed and developing countries. Pyroptosis is a recently discovered form of programmed cell death (PCD). With progress in research on DKD, researchers have become increasingly interested in elucidating the role of pyroptosis in DKD pathogenesis. This review focuses on the three pathways of pyroptosis generation: the canonical inflammasome, non-canonical inflammasome, and caspase-3-mediated inflammasome pathways. The molecular and pathophysiological mechanisms of the pyroptosis-related inflammasome pathway in the development of DKD are summarized. Activation of the diabetes-mediated pyroptosis-related inflammasomes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Toll-like receptor 4 (TLR4), caspase-1, interleukin (IL)-1β, and the IL-18 axis, plays an essential role in DKD lesions. By inhibiting activation of the TLR4 and NLRP3 inflammasomes, the production of caspase-1, IL-1β, and IL-18 is inhibited, thereby improving the pathological changes associated with DKD. Studies using high-glucose–induced cell models, high-fat diet/streptozotocin-induced DKD animal models, and human biopsies will help determine the spatial and temporal expression of DKD inflammatory components. Recent studies have confirmed the relationship between the pyroptosis-related inflammasome pathway and kidney disease. However, these studies are relatively superficial at present, and the mechanism needs further elucidation. Linking these findings with disease activity and prognosis would provide new ideas for DKD research.
Building the Next Generation of Humanized Hemato-Lymphoid System Mice
Authors: Martinov Tijana , McKenna Kelly M. , Tan Wei Hong , Collins Emily J. , Kehret Allie R. , Linton Jonathan D. , Olsen Tayla M. , Shobaki Nour , Rongvaux Anthony
Published: February 2021

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseasesin vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these “humanized” mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.
Implications of Laboratory Tests in Disease Grading and Death Risk Stratification of COVID-19: A Retrospective Study in Wuhan, China
Authors: Bai Yang , Wang Enxin , Zhao Shoujie , Li Jing , Zhu Yejing , Zhang Yongchao , Cao Liang , Liu Haitao , Dong Yushu , Wang Fang , Liang Guobiao , Liu Lei
Published: February 2021

Background: Although laboratory tests have become an indispensable part in clinical practice, its application in severity classification and death risk stratification of COVID-19 remains unvalidated. This study aims to explore the significance of laboratory tests in the management of COVID-19.

Methods: In 3,342 hospitalized patients with COVID-19, those of mild or moderate subtype were categorized into the non-severe group, while those of severe or critical subtype were categorized into the severe group. Initial laboratory data were analyzed and compared according to disease severity and outcome. Diagnostic models for the severe group were generated on risk factors identified by logistic regression and receiver operating characteristic (ROC) analyses. Cox regression and ROC analyses on risk factors were utilized to construct prognostic models.

Results: In identification of patients in the severe group, while age, neutrophil-to-lymphocyte ratio, and α-hydroxybutyrate dehydrogenase were identified as independent predictors, the value of combination of them appears modest [area under the curve (AUC) = 0.694]. Further ROC analyses indicated that among patients in the severe group, laboratory indices had a favorable value in identifying patients of critical subtype rather than severe subtype. For death outcome, IL-6, co-existing cerebrovascular disease, prothrombin time activity, and urea nitrogen were independent risk factors. An IL-6 single-parameter model was finalized for distinguishing between fatal and recovered individuals (AUC = 0.953). Finally, a modified death risk stratification strategy based on clinical severity and IL-6 levels enables more identification of non-survivors in patients with non-critical disease.

Conclusions: Laboratory screening provides a useful tool for COVID-19 management in identifying patients with critical condition and stratifying risk levels of death.
Altered Regional Cerebral Blood Flow and Brain Function Across the Alzheimer's Disease Spectrum: A Potential Biomarker
Authors: Zhang Qianqian , Wang Qing , He Cancan , Fan Dandan , Zhu Yao , Zang Feifei , Tan Chang , Zhang Shaoke , Shu Hao , Zhang Zhijun , Feng Haixia , Wang Zan , Xie Chunming
Published: February 2021

Objective: To investigate variation in the characteristics of regional cerebral blood flow (rCBF), brain activity, and intrinsic functional connectivity (FC) across the Alzheimer's disease spectrum (ADS).

Methods: The study recruited 20 individuals in each of the following categories: Alzheimer's disease (AD), mild cognitive impairment (MCI), subjective cognitive decline (SCD), and healthy control (HC). All participants completed the 3.0T resting-state functional MRI (rs-fMRI) and arterial spin labeling scans in addition to neuropsychological tests. Additionally, the normalized CBF, regional homogeneity (ReHo), and amplitude of low-frequency fluctuation (ALFF) of individual subjects were compared in the ADS. Moreover, the changes in intrinsic FC were investigated across the ADS using the abnormal rCBF regions as seeds and behavioral correlations. Finally, a support-vector classifier model of machine learning was used to distinguish individuals with ADS from HC.

Results: Compared to the HC subjects, patients with AD showed the poorest level of rCBF in the left precuneus (LPCUN) and right middle frontal gyrus (RMFG) among all participants. In addition, there was a significant decrease in the ALFF in the bilateral posterior cingulate cortex (PCC) and ReHo in the right PCC. Moreover, RMFG- and LPCUN-based FC analysis revealed that the altered FCs were primarily located in the posterior brain regions. Finally, a combination of altered rCBF, ALFF, and ReHo in posterior cingulate cortex/precuneus (PCC/PCUN) showed a better ability to differentiate ADS from HC, AD from SCD and MCI, but not MCI from SCD.

Conclusions: The study demonstrated the significance of an altered rCBF and brain activity in the early stages of ADS. These findings, therefore, present a potential diagnostic neuroimaging-based biomarker in ADS. Additionally, the study provides a better understanding of the pathophysiology of AD.
Resilience and Psychobiological Response to Stress in Older People: The Mediating Role of Coping Strategies
Authors: Zapater-Fajarí Mariola , Crespo-Sanmiguel Isabel , Pulopulos Matias M. , Hidalgo Vanesa , Salvador Alicia
Published: February 2021

Resilience, the ability to overcome adversity and face stressful demands and experiences, has been strongly associated with successful aging, a low risk of diseases and high mental and physical functioning. This relationship could be based on adaptive coping behaviors, but more research is needed to gain knowledge about the strategies employed to confront social stress. Thus, we aimed to investigate the role of the use of active or passive coping strategies by resilient people in dealing with stressful situations. For this purpose, we measured resilience, coping strategies, and perceived stress in 66 healthy older adults (31 men and 35 women) between 56 and 75 years old who were exposed to stress (Trier Social Stress Test, TSST) or a control situation. The stress response was analyzed at endocrine (cortisol) and psychological (anxiety) levels. In the stress condition, moderated mediation analysis showed a conditional indirect effect of resilience on cortisol reactivity through active coping. However, passive coping strategies did not mediate the resilience-cortisol relationship. In addition, neither active nor passive coping mediated the relationship between resilience and the anxiety response. These results suggest that resilience is associated with active coping strategies, which in turn could explain, at least in part, individual differences in the cortisol response to a psychosocial laboratory stressor. These factors may prevent the development of stress-related pathologies associated with aging and facilitate healthy and satisfactory aging.
Ventromedial Prefrontal Cortex Activity and Sympathetic Allostasis During Value-Based Ambivalence
Authors: Dundon Neil M. , Shapiro Allison D. , Babenko Viktoriya , Okafor Gold N. , Grafton Scott T.
Published: February 2021

Anxiety is characterized by low confidence in daily decisions, coupled with high levels of phenomenological stress. Ventromedial prefrontal cortex (vmPFC) plays an integral role in maladaptive anxious behaviors via decreased sensitivity to threatening vs. non-threatening stimuli (fear generalization). vmPFC is also a key node in approach-avoidance decision making requiring two-dimensional integration of rewards and costs. More recently, vmPFC has been implicated as a key cortical input to the sympathetic branch of the autonomic nervous system. However, little is known about the role of this brain region in mediating rapid stress responses elicited by changes in confidence during decision making. We used an approach-avoidance task to examine the relationship between sympathetically mediated cardiac stress responses, vmPFC activity and choice behavior over long and short time-scales. To do this, we collected concurrent fMRI, EKG and impedance cardiography recordings of sympathetic drive while participants made approach-avoidance decisions about monetary rewards paired with painful electric shock stimuli. We observe first that increased sympathetic drive (shorter pre-ejection period) in states lasting minutes are associated with choices involving reduced decision ambivalence. Thus, on this slow time scale, sympathetic drive serves as a proxy for “mobilization” whereby participants are more likely to show consistent value-action mapping. In parallel, imaging analyses reveal that on shorter time scales (estimated with a trial-to-trial GLM), increased vmPFC activity, particularly during low-ambivalence decisions, is associated with decreased sympathetic state. Our findings support a role of sympathetic drive in resolving decision ambivalence across long time horizons and suggest a potential role of vmPFC in modulating this response on a moment-to-moment basis.
Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice
Authors: Minakova Elena , Sarafinovska Simona , Mikati Marwa O. , Barclay Kia M. , McCullough Katherine B. , Dougherty Joseph D. , Al-Hasani Ream , Maloney Susan E.
Published: February 2021

Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioidsin uterogoes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact ofin uteroand prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth,in uterooxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in uteroOxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in uteroVeh) or biologically reared (prolonged Veh) controls.In uteroOxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits.
Semantic Relatedness Emerges in Deep Convolutional Neural Networks Designed for Object Recognition
Authors: Huang Taicheng , Zhen Zonglei , Liu Jia
Published: February 2021

Human not only can effortlessly recognize objects, but also characterize object categories into semantic concepts with a nested hierarchical structure. One dominant view is that top-down conceptual guidance is necessary to form such hierarchy. Here we challenged this idea by examining whether deep convolutional neural networks (DCNNs) could learn relations among objects purely based on bottom-up perceptual experience of objects through training for object categorization. Specifically, we explored representational similarity among objects in a typical DCNN (e.g., AlexNet), and found that representations of object categories were organized in a hierarchical fashion, suggesting that the relatedness among objects emerged automatically when learning to recognize them. Critically, the emerged relatedness of objects in the DCNN was highly similar to the WordNet in human, implying that top-down conceptual guidance may not be a prerequisite for human learning the relatedness among objects. In addition, the developmental trajectory of the relatedness among objects during training revealed that the hierarchical structure was constructed in a coarse-to-fine fashion, and evolved into maturity before the establishment of object recognition ability. Finally, the fineness of the relatedness was greatly shaped by the demand of tasks that the DCNN performed, as the higher superordinate level of object classification was, the coarser the hierarchical structure of the relatedness emerged. Taken together, our study provides the first empirical evidence that semantic relatedness of objects emerged as a by-product of object recognition in DCNNs, implying that human may acquire semantic knowledge on objects without explicit top-down conceptual guidance.
Case Report: Decompressive Craniectomy for COVID-19 Malignant Cerebral Artery Infarction. Is Surgery a Good Option?
Authors: Sáez-Alegre Miguel , García-Feijoo Pablo , Millán Pablo , Vivancos Sánchez Catalina , Rodríguez Domínguez Víctor , García Nerín Jorge , Isla Guerrero Alberto , Gandía-González María Luisa
Published: February 2021

SARS-CoV2 infection can lead to a prothrombotic state. Large vessel occlusion, as well as malignant cerebral stroke have been described in COVID-19 patients. In the following months, given the increase in COVID-19 cases, an increase in malignant cerebral SARS-CoV2 associated strokes are expected. The baseline situation of the patients as well as the risk of evolution to a serious disease due to the virus, depict a unique scenario. Decompressive craniectomy is a life-saving procedure indicated in patients who suffer a malignant cerebral stroke; however, it is unclear whether the same eligibility criteria should be used for patients with COVID-19. To our knowledge seven cases of decompressive craniectomy and malignant cerebral stroke have been described to date. We report on a 39-year-old female with no major risk factors for cerebrovascular disease, apart from oral contraception, and mild COVID-19 symptoms who suffered from left hemispheric syndrome. The patient underwent endovascular treatment with stenting and afterward decompressive craniectomy due to a worsening neurological status with unilateral unreactive mydriasis. We present the case and provide a comprehensive review of the available literature related to the surgical treatment for COVID-19 associated malignant strokes, to establish whether the same eligibility criteria for non-COVID-19 associated strokes should be used. Eight patients, including our case, were surgically managed due to malignant cerebral stroke. Seven of these patients received decompressive craniectomy, and six of them met the eligibility criteria of the current stroke guidelines. The mortality rate was 33%, similar to that described in non-COVID-19 cases. Two patients had a left middle cerebral artery (MCA) and both survived after decompressive craniectomy. Our results support that decompressive craniectomy, using the current stroke guidelines, should be considered an effective life-saving treatment for COVID-19-related malignant cerebral strokes.
The 1,000th Transplant for Multiple Sclerosis and Other Autoimmune Disorders at the HSCT-México Program: A Myriad of Experiences and Knowledge
Authors: Murrieta-Álvarez Iván , Cantero-Fortiz Yahveth , León-Peña Andrés A. , Olivares-Gazca Juan C. , Priesca-Marín José Manuel , Ruiz-Delgado Guillermo J. , Gómez-De-León Andrés , Gonzalez-Lopez Elías Eugenio , Jaime-Pérez José Carlos , Gómez-Almaguer David , Ruiz-Argüelles Guillermo J.
Published: February 2021

After gaining experience conducting both auto and allografts in persons with hematological diseases in the HSCT programs in Puebla and Monterrey, México, this study outlines subsequent program autografting patients with autoimmune conditions. The first transplant in multiple sclerosis was conducted in Puebla on July 5, 2006. From 2015 we increased activity autografting persons with autoimmune conditions in the two campuses of the HSCT-México program: Puebla and Monterrey. By December 6, 2020, patient number 1,000 in the program was autografted. In our experience, a significant reduction in the expanded disability status scale score was achieved in all of the three phenotypes of the disease (from a median of 5.1 to 4.5 points), whereas the response rate (defined as a decrease of at least 0.5 of EDSS score regardless of baseline EDSS, or unchanged EDSS) was 83, 78, and 73% after 12 months in the relapsing-remitting, primary-progressive and secondary-progressive forms of multiple sclerosis, respectively. In addition to analyzing the viability, safety, and efficacy of our method, this study contributes new knowledge to the field of both stem cell transplantation and multiple sclerosis.
Optimal Model Mapping for Intravoxel Incoherent Motion MRI
Authors: Liao Yen-Peng , Urayama Shin-ichi , Isa Tadashi , Fukuyama Hidenao
Published: February 2021

In general, only one diffusion model would be applied to whole field-of-view voxels in the intravoxel incoherent motion-magnetic resonance imaging (IVIM-MRI) study. However, the choice of the applied diffusion model can significantly influence the estimated diffusion parameters. The quality of the diffusion analysis can influence the reliability of the perfusion analysis. This study proposed an optimal model mapping method to improve the reliability of the perfusion parameter estimation in the IVIM study. Six healthy volunteers (five males and one female; average age of 38.3 ± 7.5 years). Volunteers were examined using a 3.0 Tesla scanner. IVIM-MRI of the brain was applied at 17 b-values ranging from 0 to 2,500 s/mm2. The Gaussian model, the Kurtosis model, and the Gamma model were found to be optimal for the CSF, white matter (WM), and gray matter (GM), respectively. In the mean perfusion fraction (fp) analysis, the GM/WM ratios were 1.16 (Gaussian model), 1.80 (Kurtosis model), 1.94 (Gamma model), and 1.54 (Optimal model mapping); in the mean pseudo diffusion coefficient (D*) analysis, the GM/WM ratios were 1.18 (Gaussian model), 1.19 (Kurtosis model), 1.56 (Gamma model), and 1.24 (Optimal model mapping). With the optimal model mapping method, the estimated fp and D* were reliable compared with the conventional methods. In addition, the optimal model maps, the associated products of this method, may provide additional information for clinical diagnosis.
Pupil Reactions to Tactile Stimulation: A Systematic Review
Authors: Gusso Mariana de Mello , Serur Gabriele , Nohama Percy
Published: February 2021

Pupil dynamics can represent an indirect measure of perception; thus, it has been broadly explored in the auditory and visual fields. Although it is crucial for experiencing the outside world, tactile perception is not well-explored. Considering that, we sought to answer the following question via a systematic review: does normal tactile perception processing modulate pupil dilation in mammals (human or not)? The review process was conducted according to PRISMA Statement. We searched on Periódicos CAPES (Brazil) for the following terms: [(touch) OR (cutaneous stimulation) OR (tactile perception) OR (somatosensory) AND (pupil OR pupillary) NOT blind NOT reflex NOT pain NOT fear NOT noxious NOT autism NOT nerve NOT (pupillary block) NOT glaucoma NOT cataract NOT aneurysm NOT syndrome NOT treatment NOT special education]. From the 6,488 papers found, 4,568 were duplicates, and nine fulfilled the inclusion criteria. All papers found a positive relationship between pupil diameter and tactile perception. We found that the pupil is a reliable indirect measure of brain states and can evaluate norepinephrine (NE)/locus coeruleus (LC) action, stimulus inhibition, arousal, cognitive processes, and affection independently of the stimuli category (visual, auditory, or tactile). We also found that the perceptual tactile processing occurs in similar ways as the other perceptual modalities. We verified that more studies should be done, mostly avoiding low sampling rate recording systems, confounders as cue signs, not automated stimulation, and concurrent stimulus and using more reliable equipment.