bluuebunny/crossref_metadata_2025_split huggingface dataset:
The prognostic value of nonlinear indices of blood pressure variability in mouse models of sepsis
Authors: Vandendriessche Benjamin H , Rogge Elke , Brouckaert Peter , Cauwels Anje 
Published: June 2021

Sepsis is associated with high mortality despite decades of research. A lack of validated biomarkers prevents the extrapolation of experimental data to the clinic. It has been well established that the sympathetic/parasympathetic balance is altered in critically ill patients, and that assessment of autonomic function has prognostic value that can be used to direct treatment.We used implantable telemetry devices to monitor blood pressure (BP) in conscious mice and developed a system in Matlab that implements a number of analysis algorithms, including multiscale entropy (MSE). These algorithms model the dataset as a nonlinear system and are capable of uncovering underlying regulating patterns. This approach allows us to do semiautomatic analysis of large amounts of data. In order to overcome the fact that interpretation of MSE results is time consuming, we developed a scoring algorithm that summarizes the output in a single numerical value, which can be plotted in function of time to follow disease progression.As proof of principle, BP measurements from mice that received a lethal or sublethal dose of TNF (tumor necrosis factor), a simple model for inflammatory shock, were analyzed. We found that the MSE parameter can distinguish between lethal/non‐lethal outcome already in the first 2 hours post‐TNF. Preliminary data indicates that this observation can be expanded towards other sepsis models and ICU patients.
Fabrication of Three dimensional porous matrix and bone tissue regeneration
Authors: Zo Sunmi , Singh Deepti , Lee Juhyun , Ki Saetbyul , Han Sungsoo 
Published: June 2021

Ideal scaffold for tissue engineering are often tailor‐made to mimic the micro‐environment and have to act similar to the extracellular matrix of the tissue which has very defined role such as to provide appropriate structural, chemical and mechanical support. The fabrication of three‐dimensional (3‐D) scaffold with highly open porous structure is one of the most important issues in tissue engineering. The aim of the study was to demonstrate potentiality of 3‐D macroporous scaffolds in bone tissue engineering. Scaffold was synthesized with varying pore morphology by freeze‐drying the polymer solution and chemically crosslinking by using CaCl2. The resulting scaffolds were characterized by SEM, tensile strength, and DSC. The biocompatibility and bioactivity were evaluated using differentiation of mesenchymal stem cells into osteoblasts MTT assay, ALP activity, ALP stain test. DNA measurement showed that the differentiated osteoblasts multiplied into several layers on three dimensional porous matrix. Histological analysis for in vivo biocompatibility were performed. The in vitro analysis of the scaffold showed excellent for cell penetration, growth and it is promising for bone repair application.Powered by
Canadians are concerned about dietary sodium, report barriers to sodium reduction, and highly support government interventions to lower sodium intakes: Results of a national survey
Authors: Arcand JoAnne , Mendoza Julio , Qi Ying , Henson Spencer , Lou Wendy , L'Abbe Mary R 
Published: June 2021

Population‐wide dietary sodium reduction is considered a priority intervention to address sodium‐related chronic diseases. In Canada, a national Sodium Reduction Strategy was adopted in 2010; however, there has been a lack of coordinated action in its implementation. We conducted a survey of Canadians (20–69 yrs) to evaluate concern, action, barriers to sodium reduction, and support for government policy interventions. Of the 2603 respondents, 67.2% were concerned about dietary sodium, which increased with age (p<0.001), among men (p=0.012), and in hypertensives (p<0.001). In total, 59.0% were actively limiting their sodium consumption, which was more common in older people (p<0.001) and in hypertensives (p<0.001). Significant barriers to sodium reduction were lack of variety of lower sodium processed (55.5%) and restaurant (65.8%) foods. Respondents highly supported government actions to lower sodium levels in processed foods (86.6%), to set maximum sodium levels for foods served in public institutions (81.8% to 82.3%), and for public education interventions (80.4% to 83.1%); but not financial incentives and disincentives for high/low sodium foods. Based on Canadians’ concern and support for population‐wide sodium reduction, there is a need for multi‐sectoral action to aid Canadians in lowering their sodium intakes to levels consistent with dietary recommendations.Grant Funding Source: Canadian Institute for Health Research
Establishing and maintaining the complex adhesions of the testes: a role for the omega‐3 DHA
Authors: Abbott Timothy L , Hess Rex A. , Sivaguru Mayandi , Nakamura Manabu T. 
Published: June 2021

Spermatid maturation and retention in the testis depend on the establishment and maintenance of a cell adhesion complex formed between spermatids and Sertoli cells. Deficiency in docosahexaenoic acid (DHA) was recently shown to disrupt postmeiotic germ cell maturation and result in infertility; however a role for DHA in germ cell adhesion has yet to be defined. Here, we use Fads2−/− mice to investigate the effect of a DHA deficiency on this adhesion process. We show impaired retention of immature spermatids in the seminiferous epithelium and their abnormal appearance in the nearest distal tissue, the epididymis. With immunohistochemistry we show that an essential adhesion protein expressed in spermatids (nectin‐3), and its binding partner in Sertoli cells (nectin‐2), each fail to organize at the sites of spermatid‐Sertoli contact, whereas both proteins organize normally in other regions of these cells. Further, vesicular transport proteins golgin‐97 and VAMP4, normally redistributed to the spermatid‐Sertoli adhesion at the initiation of its assembly, failed to do so under a DHA deficiency. In conclusion, spermatid retention is impaired under DHA deficiency due to a failure of spermatid‐Sertoli adhesion construction; the selective mislocalization of nectin‐2 and nectin‐3 suggests a role for DHA in certain specialized systems of complex adhesion assembly.Grant Funding Source: Hatch project ILLU‐971–354 through the Division of Nutritional Sciences Vision 20/20 program
Microbiota‐Dependent Th17 and Foxp3+ Regulatory T Cell Differentiation in the Intestinal Lamina Propria
Authors: Geem Duke , Medina‐Contreras Oscar , Newberry Rodney , Denning Timothy Luke 
Published: June 2021

The intestinal microbiota regulates the development and function of mucosal and systemic immune responses. Segmented filamentous bacteria (SFB) and Clostridium strains have been implicated in the development of intestinal Th17 cells and Foxp3+ regulatory T (Treg) cells, respectively, yet the mechanisms and location of their differentiation remains incompletely understood. Using lymphotoxin‐alpha knockout mice, which are deficient in secondary lymphoid organs (SLO)‐including gut‐associated lymphoid structures, we examined the influence of the microbiota on CD4+ T cell differentiation directly in the intestinal lamina propria. Our data demonstrate that CD4 single‐positive thymocytes adoptively transferred into congenic recipients were capable of rapidly migrating to the intestinal lamina propria. Consistent with these observations, naïve CD4+ T cells were abundant in the intestines of both adult gnotobiotic mice and early postnatal SPF mice, and bacterial colonization of either group induced differentiation of Foxp3+ Treg cells, as detected by flow cytometry. Oral gavage of SFB‐containing microbiota into SFB‐free mice was also sufficient to drive Th17 differentiation in mice void of SLO. Collectively, these data suggest that specific components of the microbiota are capable of inducing the development of effector and regulatory T cell subsets directly in the intestinal lamina propria.Supported by an Emory Children's Pediatric Center Seed Grant to T.L.D. a Research Fellowship Award from the Crohn's and Colitis Foundation of America to O.M.C. and a F30 NIH NRSA Fellowship to D.G.
IFN‐γ‐mediated Induction of an Apical IL‐10 Receptor on Polarized Intestinal Epithelia
Authors: Kominsky Douglas J , Campbell Eric L , Kelly Caleb J , Glover Louise E , Bowers Brittelle E , Bayless Amanda J , Dobrinskikh Evgenia , Ehrentraut Stefan F , Colgan Sean P 
Published: June 2021

OBJECTIVEInvestigation of potential anti‐inflammatory mechanisms of IFN‐ in intestinal epithelial cells (IEC) in models of inflammatory bowel disease (IBD).METHODSGuided by microarray analysis, we utilized qPCR, western blot, and confocal microscopy to characterize epithelial IL‐10 receptor (IL‐10R) expression in vitro. Next, the functional consequences of receptor expression were examined. Finally, IL‐10R expression was investigated in a murine IBD model and in human IBD patient samples.RESULTSIn vitro studies revealed that IFN‐ selectively induced the expression of IL‐10R1 on IEC. Further analysis revealed that IL‐10R1 was expressed predominantly on the apical membrane of polarized IEC. Receptor activation functionally induced canonical IL‐10 target gene expression in IEC, concomitant with enhanced barrier restitution. Colonic tissue isolated from murine colitis revealed that levels of IL‐10R1 and SOCS3 were increased in the epithelium and coincided with increased tissue IFN‐ and IL‐10 cytokines. Immunofluorescent staining revealed apical expression of the IL‐10R in colitic mouse tissue. Finally, diseased human tissue demonstrated increased IL‐10R1 transcript with apical IEC localization.CONCLUSIONSThese results provide novel insight into an anti‐inflammatory role for IFN‐ in intestinal inflammation through the induction of a polarized IL‐10 receptor complex.
Resolvin D1 and Resolvin D5 Lower Antibiotic Doses in Infection
Authors: Chiang Nan , Fredman Gabrielle , Oh Sungwhan , Serhan Charles N 
Published: June 2021

Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we carried out LM‐metabololipidomics following Escherichia coli (E. coli) infections in mice for temporal identification of pro‐inflammatory (prostaglandins and leukotrienes) and specialized pro‐resolving mediators (SPM). In self‐resolving E. coli exudates (105 CFU), the dominant SPM were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were significantly greater than levels in exudates from higher titer E. coli (107 CFU) challenged mice. RvD1 and RvD5 (100 ng) each reduced bacterial titers, prevented hypothermia and increased survival, demonstrating the first actions of RvD5. With human macrophages, RvD1 and RvD5 each enhanced phagocytosis of E. coli via human G protein‐coupled receptor (GPR) 32, and countered a panel of pro‐inflammatory genes, including NF‐κB and TNF‐α. During E. coli infections, SPM (RvD1, RvD5, PD1) and the antibiotic ciprofloxacin accelerated resolution and heightened host antimicrobial responses. In skin infections, SPM enhanced vancomycin clearance of S. aureus. Therefore, specific SPM are temporally and differentially regulated during infections. They are anti‐phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance. These results illustrate new opportunities to address antibiotic resistance.[This work was supported in part by NIH grants P01GM095467 and R01GM38765 (CNS).]
Reprogramming of Vascular Smooth Muscle Cells into Calcifying Cells: What Can We Learn from the Embryo?
Authors: Kempf Hervé 
Published: June 2021

Vascular calcifications are widespread in aged individuals and patients with atherosclerosis, diabetes or chronic renal failure. These calcifications of the blood vessels are mostly due to a phenotypic switch of vascular smooth muscle cells (VSMCs) that reprogram into calcifying cells through mechanisms and gene regulations that mimic embryonic bone formation.Over the years, a regiment of systemic factors has been shown to induce VSMCs to trans‐differentiate into cartilage or bone cells and eventually calcify. However, in vivo, vascular calcifications do not form in a randomized pattern, suggesting that intrinsic properties of VSMCs happen to play a role in the occurrence of the calcified lesions. As VSMCs derive from various independent origins during development, evidence will be put forward to prove that VSMCs are differentially prone to calcify within the vascular wall upon their heterogeneous embryological origin.
The Pitx2:miR‐200 Family Axis Regulates WNT and BMP Signaling During Tooth Morphogenesis and Renewal
Authors: Li Xiao , Cao Huojun , Jheon Andrew , Sun Zhao , Wang Jianbo , Klein Ophir , Amendt Brad A 
Published: June 2021

The mouse incisor is a remarkable tooth that grows throughout the animal's lifetime. This continuous renewal is fueled by epithelial stem cells and little is known about the function of specific miRNAs in this process. We describe a novel Pitx2:miR‐200c/141:Noggin regulatory pathway in dental epithelial cell differentiation. miR‐200c represses Noggin, an antagonist of Bmp signaling. Pitx2 expression caused an up‐regulation of miR‐200c and ChIP assays reveal endogenous Pitx2 binding to the miR‐200c/141 promoter. A positive feedback loop was discovered between miR‐200c and Bmp signaling. miR‐200c/141 induced expression of E‐cadherin and the dental epithelial cell differentiation marker, amelogenin. miR‐200c/141 knockout mice show defects in enamel formation and decreases in E‐cadherin and amelogenin. Wnt/β‐catenin signaling is regulated by miR‐200a,b/429 under the control of Pitx2. A negative feedback loop was identified between miR‐200a and Pitx2 and includes β‐ catenin. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR‐200c/141:Noggin regulatory pathway and a Pitx2:miR‐200a,b/429 Wnt/β‐catenin pathway that is important in tooth development. Support for this research was provided from grants DE13941 and DE18885 from the National Institute of Dental and Craniofacial Research.Grant Funding Source: National Institute of Dental and Craniofacial Research
Mechanism of Eukaryotic Helicase Loading and Activation
Authors: Bell Stephen P , Kang Sukhyun , Ticau Simina , Chan Bena Sze Ham 
Published: June 2021

The Mcm2–7 helicase is the only eukaryotic DNA replication protein that participates in all steps of this essential process. Loading of the Mcm2–7 complex at origin DNA licenses replication origins during the G1 phase. Assembly of the Cdc45 and GINS helicase‐activating proteins onto the Mcm2–7 helicase is a central event during the replication origin activation. The resulting Cdc45/Mcm2–7/GINS (CMG) complex is the replicative DNA helicase during replication elongation.We are using a combination of genetic screens and biochemical assays that recapitulate the events of replication initiation to investigate the mechanism of Mcm2–7 loading and activation. Contrary to previous studies, we find that the majority of mutations predicted to inhibit Mcm2–7 helicase function (e.g. mutations in the ATP binding and hydrolysis motifs) are defective for helicase loading. This has led us to hypothesize that the process of Mcm2–7 helicase loading requires one or more activities that are also required for helicase activity of this complex. We will report on our latest studies investigating this connection. We have identified new lethal mutations in proteins predicted to activate the Mcm2–7 helicase. We will report on what we have learned from studying the corresponding mutant proteins using biochemical‐complementation assays for helicase activation and replication initiation.
Breastmilk is a novel source of stem cells with multi‐lineage differentiation potential
Authors: Hassiotou Foteini , Filgueira Luis , Hartmann Peter E. 
Published: June 2021

The breast undergoes extensive remodelling at each pregnancy/lactation, based on mammary stem cell (MaSC) expansion and differentiation. Most of our knowledge on MaSCs comes from the resting breast, where these cells are quiescent and in low numbers. In our laboratory we examine the lactating breast that contains higher numbers of MaSCs, which we access non‐invasively via breastmilk. Here, we describe the presence of MaSCs (CD49f+/CD29+) in breastmilk, which were able to self‐renew and differentiate into mammary cells. In addition, a cell population was identified expressing pluripotency markers (OCT4, SOX2, NANOG) and being able to self‐renew and differentiate into various lineages, including: mammary cells, neuron‐like and glia‐like cells, hepatocyte‐like cells expressing albumin, pancreatic beta‐like cells expressing insulin, osteoblasts, chondrocytes, adipocytes and cardiomyocytes. These findings strongly suggest the existence of a cellular hierarchy in the human lactating breast, at the top of which sits a cell population with potential pluripotency, which can be easily accessed via breastmilk.Grant Funding Source: Women and Infants Research Foundation; and Medela AG (Switzerland)
Genetic dissection of Treacher Collins Syndrome: Polr1c and Polr1d
Authors: Achilleos Annita , Watt Kristin , Trainor Paul 
Published: June 2021

Treacher Collins Syndrome (TCS) is a congenital disorder characterized by craniofacial deformities including external and middle ear defects, cleft palate and hypoplasia of facial bones. TCOF1 underlies TCS in humans and a mouse model was generated to investigate its developmental causes. Tcof1+/− mice show phenotypes similar to human TCS caused by a decrease in cranial neural crest cells (CNCC) that give rise to the majority of bone in the head and face. Tcof1 encodes the nucleolar phosphoprotein Treacle which functions in ribosomal DNA (rDNA) transcription. Tcof1+/− mice exhibit death of CNCC precursors due to a reduction in mature ribosomes. Recently, two more genes involved in rDNA transcription have been identified in TCS patients: POLR1C and POLR1D. To investigate the role of these genes in TCS we turned to zebrafish and mouse. Disruption of polr1c or polr1d in zebrafish results in specific craniofacial defects including loss of facial structures such as the ceratobranchials, hypoplasia of the cranial skeleton and deformed ethmoid plate. Similar to tcof mice, these defects arise from a reduction in CNCC caused by cell death. Further, neural crest specific knock out of Polr1c in mice leads to craniofacial defects similar to human TCS, including hypoplasia of the mandible and severe defects in the inner and middle ear bones. Our analysis suggests that both animal models can be used to dissect out the etiology of TCS.Grant Funding Source: AAA Postdoctoral Fellowship
Gene and nutrient interaction in obesity: trans fatty acid intake and genetic risk score interaction in a multiethnic sample of children
Authors: Brown Michelle M Bohan , Rodriguez‐Cruz Maricela , Fernandez Jose R. 
Published: June 2021

Associations of trans fatty acids (TFA) consumption with obesity may be mediated by individual's genetic background. We hypothesized that adiposity in children may be explained by the interaction of TFA intake and obesity genetic risk score. Fat mass index (FMI = fat mass/height2) and BMI were calculated for 279 children of European‐, African‐ and Hispanic‐American background (EA, AA, HA, respectively). Fat mass was determined using dual x‐ray absorptiometry, TFA intake was obtained from 24 hour dietary recall. Genetic risk score (GRS) was calculated from 16 single nucleotide polymorphisms by counting the number of obesity‐risk alleles. Association models evaluating the interaction of GRS and TFA were adjusted by standard covariates and genetic admixture. Significant GRS × TFA interactions were obtained for BMI and FMI (p= 0.0203 and 0.0055 respectively) in the total sample. In EA children, interaction of GRS and TFA intake was significantly associated with BMI and FMI (p=0.0433 and 0.0215 respectively); however, the interaction was not significant in AA or HA children. In the entire sample, the interaction model explained more of the variability for FMI and BMI (2.54% and 1.9% respectively) than a model with GRS alone. Our results support that dietary contributions to adiposity may be dependent on genetic background, a relevant finding for obesity prevention strategies.Grant Funding Source: NIDDK DK067426 and T32DK062710
Silencing of the Menkes Copper‐Transporting ATPase (Atp7a) in Intestinal Epithelial Cells Impairs Cell Growth and Cell Cycle Control
Authors: Gulec Sukru , Collins James F. 
Published: June 2021

The Menkes copper‐transporting ATPase (Atp7a) is induced in the rodent duodenum during iron deficiency, suggesting that copper influences iron homeostasis. To understand the role of Atp7a in intestinal iron & copper metabolism, we generated an Atp7a knockdown (KD) IEC‐6 cell line using shRNA technology. Atp7a protein was reduced >;70% and KD cells accumulated copper, consistent with defective copper efflux mediated by Atp7a. Unexpectedly, Atp7a KD impaired growth rate as compared to negative control shRNA‐transfected cells (~40% at 96 hours; p<0.0001). Further experiments were thus designed to elucidate the role of Atp7a in cell growth. Western blot analysis demonstrated that cyclin D1 (CD1) expression increased in KD cells while PCNA expression was unchanged. CD1 induces cell cycle arrest while PCNA promotes cell division. This suggested that Atp7a KD perturbed progression through the cell cycle. CD1 expression was not further enhanced by copper loading, implicating Atp7a in regulation of cell growth independent of its documented role in maintaining cellular copper homeostasis. Subsequent experiments showed that expression of additional markers of cell cycle control (p53, p21 & Ki67) was consistent with decreased cell growth. Overall, these novel findings support the hypothesis that Atp7a function is important for regulation of intestinal epithelial cell proliferation and differentiation.Grant Funding Source: NIH
Status of Selected Iron‐Status Biomarkers in Juvenile End‐ Stage Renal Disease in a Guatemalan Context: Comparative Aspects by Mode of Dialysis
Authors: Casimiro Juliana , Lou‐Meda Randall , Olbert Marion , Weiss Günter , Swinkels Dorine W , Tjalsma Harold , Solomons Noel W , Schümann Klaus 
Published: June 2021

BackgroundAnemia is common in end‐stage renal disease (ESRD) with both inflammation and reduced erythropoietin exerting an important role.ObjectiveTo assess selected iron (Fe) biomarkers in Guatemalan low‐income patients on hemodialysis (HD) and peritoneal dialysis (PD).MethodsIron biomarkers were determined in 27 juveniles after HD and 27 on PD therapy (7–20 y).ResultsHb mean was 9.0±1.9 g/dL in HD and 9.9±2.7 g/dL in PD (p=0.17). Respective ranges for serum Fe were 24–148 and 30–175 μg/dL (p=0.29); for transferrin were 7–63 and 12–103 ng/mL (p=0.23); for sTfR were 1.8–6.1 and 0.3–7.1 mg/L (p=0.14); for ferritin 193–4,113 and 17–1,506 ng/mL (p=0.01) and hepcidin‐25 (hep‐25) median values were 36 and 43 nM (p=0.68). Ferritin correlated significantly with hep‐25 in PD (r=0.72; p<0.001), but not in HD (r=0.04; p=0.82).ConclusionsHigher ferritin status and its low correlation with hep‐25 in HD may in part be due to high parenteral Fe vs. oral Fe administration in PD. Overall levels of ferritin and hep‐25 in juvenile, Guatemalan ESRD patients were 4–5 times higher than Dutch adults (Peters et al, Nephrol Dial Transplant, 2010; 25: 848–53). This is possibly related to an inflammatory overlay of the low‐income setting that leads to high hep‐25 associated and to macrophage iron withholding and Fe‐restricted erythropoiesis.Funded by Hildegard Grunow Foundation, Munich and MBR Optical Systems, Wuppertal