bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Mediterranean Dietary Intervention on Metabolic and Hormonal Parameters According to BRCA1/2 Variant Type
Authors: Oliverio Andreina , Radice Paolo , Colombo Mara , Paradiso Angelo , Tommasi Stefania , Daniele Antonella , Terribile Daniela Andreina , Magno Stefano , Guarino Donatella , Manoukian Siranoush , Peissel Bernard , Bruno Eleonora , Pasanisi Patrizia
Published: March 2022

The female carriers of BRCA1/2 pathogenic variants (mutations) face a high lifetime risk of developing breast and/or ovarian cancer. However, the risk may differ depending on various genetic and non-genetic elements, including metabolic and hormonal factors. We previously showed that a 6-month Mediterranean dietary intervention trial reduced body weight and the levels of insulin-like growth factor I and other metabolic factors in BRCA mutation carriers. We also found that higher baseline levels of glucose and insulin were significantly associated with BRCA loss-of-function (LOF) variants. In this study, we evaluated whether the BRCA mutation type influences in a different way the metabolic and hormonal response to the dietary intervention in 366 female carriers. The LOF variant carriers randomized in the intervention group (IG) showed significantly higher changes in most considered parameters compared to the control group (CG). The nonsynonymous variant carriers in the IG showed similar changes, but none of them were statistically significant. Performing the “delta” analysis of differences (intention-to-treat analysis), we observed that in LOF variant carriers, the reduction of insulin levels was significantly more pronounced that in nonsynonymous variant carriers. These findings suggest that the changes in insulin levels might be modulated by a different response to the dietary intervention mediated by BRCA LOF variants.
Heterologous Immune Responses of Serum IgG and Secretory IgA Against the Spike Protein of Endemic Coronaviruses During Severe COVID-19
Authors: Smit Wouter L. , van Tol Sophie , Wal Sanne van der , van Vulpen Femke , la Grouw Shannon , van Lelyveld Lenneke , Limonard Gijs , Bossink Ailko , Godeke Gert-Jan , Shrestha Sandhya , Reimerink Johan , Eggink Dirk , Reusken Chantal , Heron Michiel , Thijsen Steven
Published: March 2022

Defining immune correlates of disease severity is important to better understand the immunopathogenesis in COVID-19. Here we made use of a protein microarray platform to detect IgG- and IgA-reactive antibodies in sera and saliva respectively, and assess cross-reactivity between SARS-CoV-2 and endemic coronaviruses (eCoVs). IgG responses against the full protein of spike, but not the S1 subunit, were significantly higher in convalescent sera of patients with severe disease compared to mild disease and healthy controls. In addition, we detected reactivity of secretory IgA to eCoVs in saliva of patients with severe disease, not present in patients with moderate disease or seropositive healthy controls. These heterologous immune responses are in line with non-protective cross-reactivity, and support a potential role for immune imprinting in the pathogenesis of severe COVID-19.
The Icarus Flight of Perinatal Stem and Renal Progenitor Cells Within Immune System
Authors: Picerno Angela , Castellano Giuseppe , Curci Claudia , Kopaczka Katarzyna , Stasi Alessandra , Pertosa Giovanni Battista , Sabbà Carlo , Gesualdo Loreto , Gramignoli Roberto , Sallustio Fabio
Published: March 2022

Our immune system actively fights bacteria and viruses, and it must strike a delicate balance between over- and under-reaction, just like Daedalus and Icarus in Greek mythology, who could not escape their imprisonment by flying too high or too low. Both human amniotic epithelial and mesenchymal stromal cells and the conditioned medium generated from their culture exert multiple immunosuppressive activities. They have strong immunomodulatory properties that are influenced by the types and intensity of inflammatory stimuli present in the microenvironment. Notably, very recently, the immunomodulatory activity of human adult renal stem/progenitor cells (ARPCs) has been discovered. ARPCs cause a decrease in Tregs and CD3+ CD4− CD8− (DN) T cells in the early stages of inflammation, encouraging inflammation, and an increase in the late stages of inflammation, favoring inflammation quenching. If the inflammatory trigger continues, however, ARPCs cause a further increase in DN T cells to avoid the development of a harmful inflammatory state. As in the flight of Daedalus and Icarus, who could not fly too high or too low to not destroy their wings by the heat of the sun or the humidity of the sea, in response to an inflammatory environment, stem cells seem to behave by paying attention to regulating T cells in the balance between immune tolerance and autoimmunity. Recognizing the existence of both suppressive and stimulatory properties, and the mechanisms that underpin the duality of immune reaction, will aid in the development of active immunotherapeutic approaches that manipulate the immune system to achieve therapeutic benefit.
The Shared Mechanism and Candidate Drugs of Multiple Sclerosis and Sjögren’s Syndrome Analyzed by Bioinformatics Based on GWAS and Transcriptome Data
Authors: Hong Xiangxiang , Wang Xin , Rang Xinming , Yin Xinyue , Zhang Xuemei , Wang Rui , Wang Duo , Zhao Tingting , Fu Jin
Published: March 2022

Objective

This study aimed to explore the shared mechanism and candidate drugs of multiple sclerosis (MS) and Sjögren’s syndrome (SS).

Methods

MS- and SS-related susceptibility genes and differentially expressed genes (DEGs) were identified by bioinformatics analysis based on genome-wide association studies (GWAS) and transcriptome data from GWAS catalog and Gene Expression Omnibus (GEO) database. Pathway enrichment, Gene Ontology (GO) analysis, and protein–protein interaction analysis for susceptibility genes and DEGs were performed. The drugs targeting common pathways/genes were obtained through Comparative Toxicogenomics Database (CTD), DrugBank database, and Drug–Gene Interaction (DGI) Database. The target genes of approved/investigational drugs for MS and SS were obtained through DrugBank and compared with the common susceptibility genes.

Results

Based on GWAS data, we found 14 hub common susceptibility genes (HLA-DRB1, HLA-DRA, STAT3, JAK1, HLA-B, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB5, HLA-DPA1, HLA-DPB1, TYK2, IL2RA, and MAPK1), with 8 drugs targeting two or more than two genes, and 28 common susceptibility pathways, with 15 drugs targeting three or more than three pathways. Based on transcriptome data, we found 3 hub common DEGs (STAT1, GATA3, PIK3CA) with 3 drugs and 10 common risk pathways with 435 drugs. “JAK-STAT signaling pathway” was included in common susceptibility pathways and common risk pathways at the same time. There were 133 overlaps including JAK-STAT inhibitors between agents from GWAS and transcriptome data. Besides, we found that IL2RA and HLA-DRB1, identified as hub common susceptibility genes, were the targets of daclizumab and glatiramer that were used for MS, indicating that daclizumab and glatiramer may be therapeutic for SS.

Conclusion

We observed the shared mechanism of MS and SS, in which JAK-STAT signaling pathway played a vital role, which may be the genetic and molecular bases of comorbidity of MS with SS. Moreover, JAK-STAT inhibitors were potential therapies for MS and SS, especially for their comorbidity.
Load Transfer Law of Anti-Floating Anchor With GFRP Bars Based on Fiber Bragg Grating Sensing Technology
Authors: Zhang Yamei , Bai Xiaoyu , Yan Nan , Sang Songkui , Jing Desheng , Chen Xiaoyu , Zhang Mingyi
Published: March 2022

The glass fiber-reinforced polymer (GFRP) anchor, a new type of composite material anchor, has been widely used in foundation engineering of coastal areas. This study investigated the feasibility of applying the fiber Bragg grating (FBG) sensing technology to monitor the strain of the GFRP anchor during the pull test. Based on an advanced method, the FBG strain sensors were installed in GFRP anchors during the anchor manufacturing process. Then, GFRP anchors were installed into the pre-created borehole with an M30 cement mortar. Meanwhile, the FBG temperature sensors were installed next to the GFRP anchors to monitor the temperature change during the test. The axial force and average shear stress of GFRP anchors along depth during the pull test were analyzed, and the influence of temperature change on strain measurement was studied. The test results showed that the FBG sensing technology and the installation method of FBG strain sensors used in the test were feasible to monitor the mechanical properties of the GFRP anchor during the pull test. Moreover, the effect of temperature change on strain monitoring of FBG strain sensors was negligible.
Gut Microbiota From Sjögren syndrome Patients Causes Decreased T Regulatory Cells in the Lymphoid Organs and Desiccation-Induced Corneal Barrier Disruption in Mice
Authors: Schaefer Laura , Trujillo-Vargas Claudia M. , Midani Firas S. , Pflugfelder Stephen C. , Britton Robert A. , de Paiva Cintia S.
Published: March 2022

Sjögren syndrome (SS) is an autoimmune inflammatory disorder characterized by secretory dysfunction in the eye and mouth; in the eye, this results in tear film instability, reduced tear production, and corneal barrier disruption. A growing number of studies show that homeostasis of the ocular surface is impacted by the intestinal microbiome, and several 16S sequencing studies have demonstrated dysbiosis of the intestinal microbiota in SS patients. In this study, we utilized metagenomic sequencing to perform a deeper analysis of the intestinal microbiome using stools collected from sex- and age-matched healthy (n = 20), dry eye (n = 4) and SS (n = 7) subjects. The observed Operational Taxonomic Units (OTUs) and Shannon alpha diversity were significantly decreased in SS compared to healthy controls, and there was a significant inverse correlation between observed OTUs and ocular severity score. We also identified specific bacterial strains that are differentially modulated in SS vs. healthy subjects. To investigate if the differential composition of intestinal microbiome would have an impact on the immune and eye phenotype, we performed functional studies using germ-free mice colonized with human intestinal microbiota from SS patients and healthy controls. Flow cytometry analysis demonstrated reduced frequency of CD4+ FOXP3+ cells in ocular draining cervical lymph nodes (CLN) in mice colonized with SS patient intestinal microbiota 4 weeks post-colonization. We also found that offspring of SS-humanized mice also have fewer CD4+FOXP3+ cells in the CLN as well as spleen, demonstrating vertical transmission. SS-humanized mice subjected to desiccating stress exhibited greater corneal barrier disruption as compared to healthy control humanized mice under the same conditions. Taken together, these data support the hypothesis that the intestinal microbiota can modulate ocular surface health, possibly by influencing development of CD4+ FOXP3+ regulatory T cells (Tregs) in the ocular draining lymph nodes.
Molecular Characterization of a New Moniliformis sp. From a Plateau Zokor (Eospalax fontanierii baileyi) in China
Authors: Dai Guo-Dong , Yan Hong-Bin , Li Li , Zhang Lin-Sheng , Liu Zhan-Long , Gao Sheng-Zhi , Ohiolei John Asekhaen , Wu Yao-Dong , Guo Ai-Min , Fu Bao-Quan , Jia Wan-Zhong
Published: March 2022

In the present study, a new species of the genus Moniliformis species is described taxonomically in the mitochondrial genomic context. The parasite was found in a plateau zokor captured in a high-altitude area of Xiahe County of Gansu Province, China. The mitochondrial (mt) genome length of this new species was 14,066 bp comprising 36 genes and 2 additional non-coding regions (SNR and LNR), without atp8. The molecular phylogeny inferred by the cytochrome c oxidase subunit I gene (cox1) and the18S ribosomal RNA gene (18S rDNA) sequences showed that the parasite as a sister species to other Moniliformis spp. and was named Moniliformis sp. XH-2020. The phylogeny of the concatenated amino acid sequences of the 12 protein-coding genes (PCGs) showed Moniliformis sp. XH-2020 in the same cluster as Macracanthorhynchus hirudinaceus and Oncicola luehei confirming the cox1 and 18S rDNA phylogenetic inference. In addition, the entire mt genome sequenced in this study represents the first in the order Moniliformida, providing molecular material for further study of the phylogeny of the class Archiacanthocephala. Moreover, the species of this class, use arthropods as intermediate hosts and mammals as definitive hosts and are agents of acanthocephaliasis, a zoonosis in humans. Therefore, this study not only expands the host range among potential wild animal hosts for Archiacanthocephalans which is of great ecological and evolutionary significance but also has important significance for the research of zoonotic parasitic diseases.
Development of an Immunochromatographic Strip for Rapid Detection of Mink Enteritis Virus
Authors: Lin Peng , Wang Jianke , Song Shanshan , Cheng Yuening , Yi Li , Cheng Shipeng , Wang Zhenjun
Published: March 2022

Although mink enteritis virus (MEV) is an acute, virulent, and highly contagious pathogen in minks, there is currently a lack of a quick diagnostic method. By conjugating colloidal gold nanoparticles with the MEV-specific monoclonal antibody, monoclonal antibody (MAb) 14, we developed a single-step competitive immunochromatographic strip (ICS) assay for simple determination of MEV. The optimal concentrations of the colloidal gold-coupled MAb 14 (coating antibody), the capture protein (MEV VP2 protein), and the goat anti-mouse antibody were 1.0, 0.8, and 1.0 mg/ml, respectively. The limit of detection was approximately 512 hemagglutination units/100 μl of MEV B strain. Other common viruses of mink were tested to evaluate the specificity of the ICS, and the results showed no cross-reactivity for other pathogens. In comparison with the Anigen Rapid canine parvovirus (CPV) Ag Test Kit (BioNote, Korea) in testing 289 samples, the percentage of agreement and relative sensitivity and specificity of the MEV ICS assay were 94.1, 93.2, and 97.1%, respectively. The ICS test was found to be a sufficiently sensitive and specific detection method for the convenient and rapid detection of MEV.
Human β-Defensin-3 is Associated With Platelet-Derived Extracellular Vesicles and is a Potential Contributor to Endothelial Dysfunction
Authors: Panigrahi Soumya , Ghosh Santosh K. , Ferrari Brian , Wyrick Jonathan M. , Podrez Eugene A , Weinberg Aaron , Sieg Scott F.
Published: March 2022

While platelets are the essential mediators of hemostasis, they are being increasingly recognized for their potential of contributing to host defenses. Here, using immunofluorescent microscopy, western blot, and ELISA, we found that human β-defensin 3 (hBD-3), an important antimicrobial peptide produced by epithelial cells, can be detected in human platelets and megakaryocytes. Flow cytometry and immuno-electron microscopy revealed hBD-3 on the surface of thrombin activated platelets. Moreover, hBD-3 was also found in platelet derived extracellular vesicles (p-EVs), isolated from platelet poor plasma and from platelet supernatants following thrombin stimulation. Incubation of platelets with hBD-3 peptide resulted in modest platelet activation and pre-incubation of platelets with synthetic hBD-3 prior to exposure to thrombin appeared to increase hBD-3 content in platelet lysates as well as in p-EVs, suggesting that hBD-3 can be initially taken up by platelets, perhaps via their open canalicular system. Interestingly, in vitro exposure of primary human endothelial cells to either hBD-3 peptide or purified p-EVs, caused significant endothelial dysfunction as documented by diminished levels of phosphorylated endothelial nitric oxide synthase (eNOS), Krüppel like factor-2 (KLF-2), and elevated relative expression of von Willebrand Factor (vWF). Pre-incubation of platelets with hBD-3 appeared to augment endothelial dysfunction caused by p-EVs. Overall, the current study provides evidence that hBD-3 enriched EVs can be released by activated platelets and may play a role in positive feedback of platelet activation as well as in endothelial dysfunction. Theoretically, these effects could contribute to both cellular recruitment to the endothelium creating a pro-thrombotic vascular microenvironment which serve as a bridge between innate immunity and hemostasis.
Directed Evolution of Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase Generates a Hyperactive and Highly Selective Variant
Authors: Fischer Jonathan T. , Söll Dieter , Tharp Jeffery M.
Published: March 2022

Pyrrolysyl-tRNA synthetase (PylRS) is frequently used for site-specific incorporation of noncanonical amino acids (ncAAs) into proteins. Recently, the active site of Methanomethylophilus alvus PylRS (MaPylRS) has been rationally engineered to expand its substrate compatibility, enabling the incorporation of difficult ncAAs. However, mutations beyond the active site that enhance the enzymatic properties of MaPylRS have not been reported. We utilized phage-assisted non-continuous evolution (PANCE) to evolve MaPylRS to efficiently incorporate Nε-Boc-l-lysine (BocK). Directed evolution yielded several mutations outside of the active site that greatly improve the activity of the enzyme. We combined the most effective mutations to generate a new PylRS variant (PylRSopt) that is highly active and selective towards several lysine and phenylalanine derivatives. The mutations in PylRSopt can be used to enhance previously engineered PylRS constructs such as MaPylRSN166S, and PylRSopt is compatible in applications requiring dual ncAA incorporation and substantially improves the yield of these target proteins.
Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease
Authors: Fang Yi , Dai Shaobing , Jin Chongyao , Si Xiaoli , Gu Luyan , Song Zhe , Gao Ting , Chen Ying , Yan Yaping , Yin Xinzhen , Pu Jiali , Zhang Baorong
Published: March 2022

Objective

Aquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson’s disease (PD).

Methods

Three-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson’s Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers.

Results

In patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD.

Interpretation

Genetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.
Increased Susceptibility to Cerebral Microhemorrhages Is Associated With Imaging Signs of Microvascular Degeneration in the Retina in an Insulin-Like Growth Factor 1 Deficient Mouse Model of Accelerated Aging
Authors: Miller Lauren R. , Tarantini Stefano , Nyúl-Tóth Ádám , Johnston Morgan P. , Martin Teryn , Bullen Elizabeth C. , Bickel Marisa A. , Sonntag William E. , Yabluchanskiy Andriy , Csiszar Anna , Ungvari Zoltan I. , Elliott Michael H. , Conley Shannon M.
Published: March 2022

Age-related cerebrovascular defects contribute to vascular cognitive impairment and dementia (VCID) as well as other forms of dementia. There has been great interest in developing biomarkers and other tools for studying cerebrovascular disease using more easily accessible tissues outside the brain such as the retina. Decreased circulating insulin-like growth factor 1 (IGF-1) levels in aging are thought to contribute to the development of cerebrovascular impairment, a hypothesis that has been supported by the use of IGF-1 deficient animal models. Here we evaluate vascular and other retinal phenotypes in animals with circulating IGF-1 deficiency and ask whether the retina mimics common age-related vascular changes in the brain such as the development of microhemorrhages. Using a hypertension-induced model, we confirm that IGF-1 deficient mice exhibited worsened microhemorrhages than controls. The retinas of IGF-1 deficient animals do not exhibit microhemorrhages but do exhibit signs of vascular damage and retinal stress such as patterns of vascular constriction and Müller cell activation. These signs of retinal stress are not accompanied by retinal degeneration or impaired neuronal function. These data suggest that the role of IGF-1 in the retina is complex, and while IGF-1 deficiency leads to vascular defects in both the brain and the retina, not all brain pathologies are evident in the retina.
Dynamics of the Brain Functional Network Associated With Subjective Cognitive Decline and Its Relationship to Apolipoprotein E €4 Alleles
Authors: Zhou Baiwan , Wu Xiaojia , Tang Lin , Li Chuanming
Published: March 2022

The aim of our study was to explore the dynamic functional alterations in the brain in patients with subjective cognitive decline (SCD) and their relationship to apolipoprotein E (APOE) €4 alleles. In total, 95 SCD patients and 49 healthy controls (HC) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Then, the mean time series of 90 cortical or subcortical regions were extracted based on anatomical automatic labeling (AAL) atlas from the preprocessed rs-fMRI data. The static functional connectome (SFC) and dynamic functional connectome (DFC) were constructed and compared using graph theory methods and leading eigenvector dynamics analysis (LEiDA), respectively. The SCD group displayed a shorter lifetime (p = 0.003, false discovery rate corrected) and lower probability (p = 0.009, false discovery rate corrected) than the HC group in a characteristic dynamic functional network mainly involving the bilateral insular and temporal neocortex. No significant differences in the SFC were detected between the two groups. Moreover, the lower probability in the SCD group was found to be negatively correlated with the number of APOE ε4 alleles (r = −0.225, p = 0.041) in a partial correlation analysis with years of education as a covariate. Our results suggest that the DFC may be a more sensitive parameter than the SFC and can be used as a potential biomarker for the early detection of SCD.
Endogenous and Exogenous Estrogen Exposures: How Women’s Reproductive Health Can Drive Brain Aging and Inform Alzheimer’s Prevention
Authors: Jett Steven , Malviya Niharika , Schelbaum Eva , Jang Grace , Jahan Eva , Clancy Katherine , Hristov Hollie , Pahlajani Silky , Niotis Kellyann , Loeb-Zeitlin Susan , Havryliuk Yelena , Isaacson Richard , Brinton Roberta Diaz , Mosconi Lisa
Published: March 2022

After advanced age, female sex is the major risk factor for late-onset Alzheimer’s disease (AD), the most common cause of dementia affecting over 24 million people worldwide. The prevalence of AD is higher in women than in men, with postmenopausal women accounting for over 60% of all those affected. While most research has focused on gender-combined risk, emerging data indicate sex and gender differences in AD pathophysiology, onset, and progression, which may help account for the higher prevalence in women. Notably, AD-related brain changes develop during a 10–20 year prodromal phase originating in midlife, thus proximate with the hormonal transitions of endocrine aging characteristic of the menopause transition in women. Preclinical evidence for neuroprotective effects of gonadal sex steroid hormones, especially 17β-estradiol, strongly argue for associations between female fertility, reproductive history, and AD risk. The level of gonadal hormones to which the female brain is exposed changes considerably across the lifespan, with relevance to AD risk. However, the neurobiological consequences of hormonal fluctuations, as well as that of hormone therapies, are yet to be fully understood. Epidemiological studies have yielded contrasting results of protective, deleterious and null effects of estrogen exposure on dementia risk. In contrast, brain imaging studies provide encouraging evidence for positive associations between greater cumulative lifetime estrogen exposure and lower AD risk in women, whereas estrogen deprivation is associated with negative consequences on brain structure, function, and biochemistry. Herein, we review the existing literature and evaluate the strength of observed associations between female-specific reproductive health factors and AD risk in women, with a focus on the role of endogenous and exogenous estrogen exposures as a key underlying mechanism. Chief among these variables are reproductive lifespan, menopause status, type of menopause (spontaneous vs. induced), number of pregnancies, and exposure to hormonal therapy, including hormonal contraceptives, hormonal therapy for menopause, and anti-estrogen treatment. As aging is the greatest risk factor for AD followed by female sex, understanding sex-specific biological pathways through which reproductive history modulates brain aging is crucial to inform preventative and therapeutic strategies for AD.
Vangl2, a Core Component of the WNT/PCP Pathway, Regulates Adult Hippocampal Neurogenesis and Age-Related Decline in Cognitive Flexibility
Authors: Koehl Muriel , Ladevèze Elodie , Montcouquiol Mireille , Abrous Djoher Nora
Published: March 2022

Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing Western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-Gogh like 2 (Vangl2), a core component of the Planar Cell Polarity (PCP) signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this member of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant-negative mutation in the Vangl2 gene, called Looptail (Vangl2Lp), we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of a decrease in cognitive flexibility. The inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.
Age–Period–Cohort Analysis of Long Trend of Mortality for Stroke and Subtypes Attributed to High SBP in Chinese Adults
Authors: Ma Yudiyang , Cao Jinhong , Mubarik Sumaira , Bai Jianjun , Yang Donghui , Zhao Yudi , Hu Qian , Yu Chuanhua
Published: March 2022

Stroke has been found as the leading cause of death in China, and high systolic blood pressure (SBP) has been indicated as a critical risk factor of stroke mortality. Accordingly, in this article, the aims were to investigate the long-term trends of mortality in terms of stroke and subtypes arising from high SBP stratified by age and gender among Chinese adults. The data of this article originated from the global burden of disease (GBD) study database. The age, period, and cohort effects were examined with the age–period–cohort model (APC). The age-standardized mortality of stroke attributed to high SBP in China has been significantly declining from 1990 to 2019. As indicated by the result of APC analysis, substantially rising age effects have been exerted on stroke and subtypes from 25 to 84 years of both genders, whereas the age effect on women increased less rapidly than that on men. As opposed to the above result, the period and cohort effects were reported to show similar monotonous decrease trends, and stroke of women more significantly declined than that of men (significantly with p < 0.05 for all). All types of stroke mortality arising from high SBP were indicated to change. The risk of death was identified to be most remarkably reduced in high SBP-attributable subarachnoid hemorrhage (SAH), whereas intracerebral hemorrhage (ICH) and ischemic stroke (IS) decreased at approximately the same rate. People born in the later birth cohorts or living in recent periods had a lower risk of stroke death, whereas men and elder groups were considered as the high-risk populations for stroke mortality due to high SBP. Although the stroke mortality relating to high SBP in China was declining, ICH and IS would continue to be the first and second lethal subtypes of stroke. In contrast to the above finding, SAH accounted for the minimum proportion of deaths and the maximum reduction in period and cohort effects. Thus, it is of high significance to introduce advanced hypertension control technology and knowledge regarding healthy lifestyles.
Cerebellar and Prefrontal Structures Associated With Executive Functioning in Pediatric Patients With Congenital Heart Defects
Authors: Badaly Daryaneh , Beers Sue R. , Ceschin Rafael , Lee Vincent K. , Sulaiman Shahida , Zahner Alexandria , Wallace Julia , Berdaa-Sahel Aurélia , Burns Cheryl , Lo Cecilia W. , Panigrahy Ashok
Published: March 2022

Objective

Children, adolescents, and young adults with congenital heart defects (CHD) often display executive dysfunction. We consider the prefrontal and cerebellar brain structures as mechanisms for executive dysfunction among those with CHD.

Methods

55 participants with CHD (M age = 13.93) and 95 healthy controls (M age = 13.13) completed magnetic resonance imaging (MRI) of the brain, from which we extracted volumetric data on prefrontal and cerebellar regions. Participants also completed neuropsychological tests of executive functioning; their parents completed ratings of their executive functions.

Results

Compared to healthy controls, those with CHD had smaller cerebellums and lateral, medial, and orbital prefrontal regions, they performed more poorly on tests of working memory, inhibitory control, and mental flexibility, and their parents rated them as having poorer executive functions across several indices. Across both groups, there were significant correlations for cerebellar and/or prefrontal volumes with cognitive assessments of working memory, mental flexibility, and inhibitory control and with parent-completed ratings of task initiation, working memory, and planning/organization. Greater prefrontal volumes were associated with better working memory, among those with larger cerebellums (with group differences based on the measure and the prefrontal region). Greater prefrontal volumes were related to better emotional regulation only among participants with CHD with smaller cerebellar volumes, and with poorer inhibition and emotional regulation only among healthy controls with larger cerebellar volumes.

Conclusion

The cerebellum not only contributes to executive functioning among young individuals with CHD but may also modulate the relationships between prefrontal regions and executive functioning differently for pediatric patients with CHD vs. health controls.
Unrevealing Reliable Cortical Parcellation of Individual Brains Using Resting-State Functional Magnetic Resonance Imaging and Masked Graph Convolutions
Authors: Qiu Wenyuan , Ma Liang , Jiang Tianzi , Zhang Yu
Published: March 2022

Brain parcellation helps to understand the structural and functional organization of the cerebral cortex. Resting-state functional magnetic resonance imaging (fMRI) and connectivity analysis provide useful information to delineate individual brain parcels in vivo. We proposed an individualized cortical parcellation based on graph neural networks (GNN) to learn the reliable functional characteristics of each brain parcel on a large fMRI dataset and to infer the areal probability of each vertex on unseen subjects. A subject-specific confidence mask was implemented in the GNN model to account for the tradeoff between the topographic alignment across subjects and functional homogeneity of brain parcels on individual brains. The individualized brain parcellation achieved better functional homogeneity at rest and during cognitive tasks compared with the group-registered atlas (p-values < 0.05). In addition, highly reliable and replicable parcellation maps were generated on multiple sessions of the same subject (intrasubject similarity = 0.89), while notable variations in the topographic organization were captured across subjects (intersubject similarity = 0.81). Moreover, the intersubject variability of brain parcellation indicated large variations in the association cortices while keeping a stable parcellation on the primary cortex. Such topographic variability was strongly associated with the functional connectivity variability, significantly predicted cognitive behaviors, and generally followed the myelination, cytoarchitecture, and functional organization of the human brain. This study provides new avenues to the precise individualized mapping of the cortical areas through deep learning and shows high potentials in the personalized localization diagnosis and treatment of neurological disorders.
Mechanistic Impact of Zinc Deficiency in Human Development
Authors: Hussain Azhar , Jiang Wenting , Wang Xiukang , Shahid Shumaila , Saba Noreena , Ahmad Maqshoof , Dar Abubakar , Masood Syed Usama , Imran Muhammad , Mustafa Adnan
Published: March 2022

Zinc (Zn) deficiency in humans is an emerging global health issue affecting approximately two billion people across the globe. The situation prevails due to the intake of Zn deficient grains and vegetables worldwide. Clinical identification of Zn deficiency in humans remains problematic because the symptoms do not appear until impair the vital organs, such as the gastrointestinal track, central nervous system, immune system, skeletal, and nervous system. Lower Zn body levels are also responsible for multiple physiological disorders, such as apoptosis, organs destruction, DNA injuries, and oxidative damage to the cellular components through reactive oxygen species (ROS). The oxidative damage causes chronic inflammation lead toward several chronic diseases, such as heart diseases, cancers, alcohol-related malady, muscular contraction, and neuro-pathogenesis. The present review focused on the physiological and growth-related changes in humans under Zn deficient conditions, mechanisms adopted by the human body under Zn deficiency for the proper functioning of the body systems, and the importance of nutritional and nutraceutical approaches to overcome Zn deficiency in humans and concluded that the biofortified food is the best source of Zn as compared to the chemical supplementation to avoid their negative impacts on human.
Infant Formula Supplemented With Milk Fat Globule Membrane, Long-Chain Polyunsaturated Fatty Acids, and Synbiotics Is Associated With Neurocognitive Function and Brain Structure of Healthy Children Aged 6 Years: The COGNIS Study
Authors: Nieto-Ruiz Ana , García-Santos José A. , Verdejo-Román Juan , Diéguez Estefanía , Sepúlveda-Valbuena Natalia , Herrmann Florian , Cerdó Tomás , De-Castellar Roser , Jiménez Jesús , Bermúdez Mercedes G. , Pérez-García Miguel , Miranda M. Teresa , López-Sabater M. Carmen , Catena Andrés , Campoy Cristina
Published: March 2022

Background

Adequate nutrient intake during the first few months of life plays a critical role on brain structure and function development.

Objectives

To analyze the long-term effects of an experimental infant formula (EF) on neurocognitive function and brain structure in healthy children aged 6 years compared to those fed with a standard infant formula or breastfed.

Methods

The current study involved 108 healthy children aged 6 years and participating in the COGNIS Study. At 0–2 months, infants were randomized to receive up to 18 months of life a standard infant formula (SF) or EF enriched with milk fat globule membrane (MFGM), long-chain polyunsaturated fatty acids (LC-PUFAs) and synbiotics. Furthermore, a reference group of breastfed (BF) infants were also recruited. Children were assessed using neurocognitive tests and structural Magnetic Resonance Imaging (MRI) at 6 years old.

Results

Experimental infant formula (EF) children showed greater volumes in the left orbital cortex, higher vocabulary scores and IQ, and better performance in an attention task than BF children. EF children also presented greater volumes in parietal regions than SF kids. Additionally, greater cortical thickness in the insular, parietal, and temporal areas were found in children from the EF group than those fed with SF or BF groups. Further correlation analyses suggest that higher volumes and cortical thickness of different parietal and frontal regions are associated with better cognitive development in terms of language (verbal comprehension) and executive function (working memory). Finally, arachidonic acid (ARA), adrenic acid (AdA), docosahexaenoic acid (DHA) levels in cheek cell glycerophospholipids, ARA/DHA ratio, and protein, fatty acid, and mineral intake during the first 18 months of life seem to be associated with changes in the brain structures at 6 years old.

Conclusions

Supplemented infant formula with MFGM components, LC-PUFAs, and synbiotics seems to be associated to long-term effects on neurocognitive development and brain structure in children at 6 years old.

Clinical Trial Registration

https://www.clinicaltrials.gov/, identifier: NCT02094547.
The Simultaneous Formation of Acrylamide, β-carbolines, and Advanced Glycation End Products in a Chemical Model System: Effect of Multiple Precursor Amino Acids
Authors: Chen Cuyu , Jiao Ye , Zeng Maomao , He Zhiyong , Shen Qingwu , Chen Jie , Quan Wei
Published: March 2022

This study investigated the effect of multiple precursor amino acids on the simultaneous formation of acrylamide, β-carbolines (i. e., harmane and norharmane), and advanced glycation end products (AGEs) [i.e., Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine] via a chemical model system. This model system was established with single or multiple precursor amino acids, including lysine–glucose (Lys/Glu), asparagine–glucose (Asn/Glu), tryptophan–glucose (Trp/Glu), and a combination of these amino acids (Com/Glu). Kinetic parameters were calculated by multiresponse non-linear regression models. We found that the k values of the AGEs and of acrylamide decreased, while those of harmane increased in the Com/Glu model when heated to 170 and 200°C. Our results indicated that the precursor amino acid of acrylamide and AGEs compete for α-dicarbonyl compounds, leading to a decrease in the formation of AGEs and acrylamide. Moreover, compared with asparagine, the precursor amino acid of β-carbolines was more likely to react with acetaldehyde by Pictet–Spengler condensation, which increased the formation of harmane and decreased the formation of acrylamide via the acrolein pathway.
Dynamic Observation of Lung Nodules on Chest CT Before Diagnosis of Early Lung Cancer
Authors: Du Qiaodan , Peng Jia , Wang Xiuyu , Ji MingFang , Liao Yuting , Tang Binghang
Published: March 2022

Objective

Early recognition and diagnosis of lung cancer can help improve the prognosis of patients. However, early imaging patterns of malignant lung nodules are not fully clear. To understand the early imaging signs of malignant lung cancer nodules, the changes of the lung nodules before diagnosis were dynamically observed and analyzed.

Materials and Methods

This retrospective study observed dynamic changes of lung nodules before pathological confirmation with consecutive regular chest CT examination from January 2003 to December 2018. At least 3 follow-up CT scans were performed in all cases, and the interval between each follow-up was about 1 year. The size, density, and morphological signs of the nodules were evaluated based on the CT axial image, and a reverse line chart or scatter plot with the diagnosis time as coordinate origin was constructed.

Results

A total of 55 lung nodules in 53 patients (mean age, 58.40 years ±11.43 [standard deviation]; 20 women) were accessed. The follow-up time was 5.96 ± 2.68 years. The average diameters in maximum slice of the lesion at baseline and last scan were 6.83 ± 2.92 mm and 16.65 ± 7.34 mm, respectively. According to the reverse line chart, the nodule growth curve segments within 4 years from the last scan showed an ascending shape, and those beyond 4 years showed a flat shape. There are 90.9% (50/55) GGN and 9.1% (5/55) SN when the lesion first appears, and 21.8% (12/55) GGN, 38.2% (21/55) PSN, and 40% (22/55) SN in the last scan. There are 12.7% (7/55) and 98.2% (54/55) nodules with poor morphological signs at baseline and last scan, respectively.

Conclusion

At the time node close to the diagnosis, the growth curve showed an upward pattern; the proportion of PSN and SN rose as the main density types; and the appearance of poor morphological signs of nodules increased. When a persistent lung nodule starts to show a malignant change, a further diagnostic workup is warranted.
Mature T-Cell leukemias: Challenges in Diagnosis
Authors: El-Sharkawi Dima , Attygalle Ayoma , Dearden Claire
Published: March 2022

T-cell clones can frequently be identified in peripheral blood. It can be difficult to appreciate whether these are benign and transient or whether they signify a clonal disorder. We review factors that aid in understanding the relevance of T-cell clones. Conversely, obvious pathological T-cell clones can be detected in blood, but there is uncertainty in how to categorize this clonal T cell population, thus, we adopt a multidisciplinary review of the clinical features, diagnostic material and radiology before making the diagnosis. In this review we shall discuss some of these challenges faced when diagnosing mature T-cell leukemias.
Daemonorops draco Blume Induces Apoptosis Against Acute Myeloid Leukemia Cells via Regulation of the miR-216b/c-Jun
Authors: Park Moon Nyeo , Jeon Hee Won , Rahman Md. Ataur , Park Se Sun , Jeong Se Yun , Kim Ki Hyun , Kim Sung-Hoon , Kim Woojin , Kim Bonglee
Published: March 2022

Daemonorops dracoBlume (DD), also called dragon’s blood, has been used as a traditional Korean medicine, especially for relieving pain caused by wound infection. Recently, it has been described that DD has antibacterial and analgesic effects. In this study, the underlying anticancer effect of DD associated with apoptosis was investigated in acute myeloid leukemia cell lines U937 and THP-1. DD exhibited cytotoxic effects and induced apoptosis in U937 and THP-1 cells. Moreover, DD treatment significantly reduced mitochondrial membrane potential (ΔΨ). The protein expression of cleaved poly(ADP-ribose) polymerase, cleaved caspase-3, p-H2A.X, CCAAT/enhancer-binding protein (CHOP), and activating transcription factor 4 was upregulated by DD treatment. Consistently, DD-treated cells had increased reactive oxygen species (ROS) level in a concentration-dependent mannerviamiR-216b activation in association with c-Jun inhibition. N-acetyl-L-cysteine pretreatment reversed the cytotoxic effect of DD treatment as well as prevented ROS accumulation. Collectively, the results of this study suggest that the anticancer effect of DD in AML was mediated by CHOP-dependent apoptosis along with ROS accumulation and included upregulation of miR-216b followed by a decrease in c-Jun.
Risk Stratification Before and During Treatment in Newly Diagnosed Multiple Myeloma: From Clinical Trials to the Real-World Setting
Authors: Bonello Francesca , Cani Lorenzo , D’Agostino Mattia
Published: March 2022

Multiple Myeloma (MM) is a hematologic malignancy characterized by a wide clinical and biological heterogeneity leading to different patient outcomes. Various prognostic tools to stratify newly diagnosed (ND)MM patients into different risk groups have been proposed. At baseline, the standard-of-care prognostic score is the Revised International Staging System (R-ISS), which stratifies patients according to widely available serum markers (i.e., albumin, β 2-microglobulin, lactate dehydrogenase) and high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. Though this score clearly identifies a low-risk and a high-risk population, the majority of patients are categorized as at “intermediate risk”. Although new prognostic factors identified through molecular assays (e.g., gene expression profiling, next-generation sequencing) are now available and may improve risk stratification, the majority of them need specialized centers and bioinformatic expertise that may preclude their broad application in the real-world setting. In the last years, new tools to monitor response and measurable residual disease (MRD) with very high sensitivity after the start of treatment have been developed. MRD analyses both inside and outside the bone marrow have a strong prognostic impact, and the achievement of MRD negativity may counterbalance the high-risk behavior identified at baseline. All these techniques have been developed in clinical trials. However, their efficient application in real-world clinical practice and their potential role to guide treatment-decision making are still open issues. This mini review will cover currently known prognostic factors identified before and during first-line treatment, with a particular focus on their potential applications in real-world clinical practice.
Neutropenic Diet Cannot Reduce the Risk of Infection and Mortality in Oncology Patients With Neutropenia
Authors: Ma Yimei , Lu Xiaoxi , Liu Hanmin
Published: March 2022

Background

The purpose of this systematic review and meta-analysis was to evaluate the effect of a neutropenic diet and a control diet on infection and mortality rates in oncology patients with neutropenia.

Methods

We searched the following English electronic databases: PubMed, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar Engine. Published studies involving neutropenic diets (study group) and control diets (control group) in oncology patients with neutropenia were searched. The focus of the meta-analysis was on the outcomes of infection and mortality rates. A subgroup analysis was also performed.

Results

A total of 6 studies were included, with a total sample size of 1114 patients. The patients in the study group had a similar infection rate compared with the patients in the control group (P = 0.11). The patients in the study group had a similar mortality rate compared with the patients in the control group (P = 0.74). Another subgroup analysis showed that the incidence of infection was also similar for pediatric (P = 0.74) and adult (P = 0.11) oncology patients between the study and control groups.

Conclusions

Based on the current evidence, this meta-analysis showed that the application of a neutropenic diet cannot reduce the risk of infection and mortality in oncology patients with neutropenia. However, more rigorous randomized controlled trials are needed to confirm this conclusion in the future.