bluuebunny/crossref_metadata_2025 huggingface dataset:
USDA Special Supplemental Nutrition Program for Women, Infants and Children (WIC) Vendor Criteria: An Examination of US Administrative Agency Variations
Authors: Landry Matthew J. , Phan Kim , McGuirt Jared T. , Ostrander Alek , Ademu Lilian , Seibold Mia , McCallops Kathleen , Tracy Tara , Fleischhacker Sheila E. , Karpyn Allison
Published: March 2021

The food retail environment has been directly linked to disparities in dietary behaviors and may in part explain racial and ethnic disparities in pregnancy-related deaths. The Special Supplemental Nutrition Program for Women, Infants and Children (WIC), administered by the United States Department of Agriculture, is associated with improved healthy food and beverage access due to its requirement for minimum stock of healthy foods and beverages in WIC-eligible stores. The selection and authorization criteria used to authorize WIC vendors varies widely from state to state with little known about the specific variations. This paper reviews and summarizes the differences across 16 of these criteria enacted by 89 WIC administrative agencies: the 50 states, the District of Columbia, five US Territories, and 33 Indian Tribal Organizations. Vendor selection and authorization criteria varied across WIC agencies without any consistent pattern. The wide variations in criteria and policies raise questions about the rational for inconsistency. Some of these variations, in combination, may result in reduced access to WIC-approved foods and beverages by WIC participants. For example, minimum square footage and/or number of cash register criteria may limit vendors to larger retail operations that are not typically located in high-risk, under-resourced communities where WIC vendors are most needed. Results highlight an opportunity to convene WIC stakeholders to review variations, their rationale, and implications thereof especially as this process could result in improved policies to ensure and improve healthy food and beverage access by WIC participants. More work remains to better understand the value of state WIC vendor authorization authority, particularly in states that have provided stronger monitoring requirements. This work might also examine if and how streamlining WIC vendor criteria (or at least certain components of them) across regional areas or across the country could provide an opportunity to advance interstate commerce and promote an equitable supply of food across the food system, while ensuring the protection for local, community-oriented WIC vendors.
Iodine Excretion and Intake in Women of Reproductive Age in South Australia Eating Plant-Based and Omnivore Diets: A Pilot Study
Authors: Whitbread Jane S. , Murphy Karen J. , Clifton Peter M. , Keogh Jennifer B.
Published: March 2021

Women consuming a strictly vegan/plant-based diet may be at increased risk of low iodine intake due to avoidance of animal products containing iodine. The aim of this pilot study was to determine the iodine excretion and intake in women consuming vegan/plant based diets compared with women consuming omnivore diets. Fifty-seven women (n = 31 plant-based, n = 26 omnivores), provided two spot urine samples to assess urinary iodine concentration (UIC). Two days of dietary intake were also recorded by participants. As the data were not normally distributed results are reported as median (IQR). UIC was significantly different between groups, 44 (26–66) µg/L in the vegan/plant-based group versus 64 (40–88) µg/L in omnivores (p < 0.05). UIC did not meet the >100 µg/L level recommended by the World Health Organization. Iodine intake was also significantly different, 78 (62–91) µg/day in the vegan/plant-based group and 125 (86–175) µg/day in the omnivores (p = 0.000). Iodine intake and bread intake were correlated with iodine excretion (CC 0.410–4.11, p = 0.003). These data indicate iodine insufficiency in both groups of women as the median values were below the minimum WHO recommendation. A larger study assessing iodine excretion in the Australian women of reproductive age who are not pregnant or breastfeeding is needed to confirm these findings.
Observational Study Regarding the Relationship between Nutritional Status, Dental Caries, Mutans Streptococci, and Lactobacillus Bacterial Colonies
Authors: Bud Eugen Silviu , Bica Cristina Ioana , Stoica Oana Elena , Vlasa Alexandru , Eșian Daniela , Bucur Sorana-Maria , Bud Anamaria , Chibelean Manuela , Păcurar Mariana
Published: March 2021

The prevalence of dental caries and obesity is high as both raise significant health problems. The objective of this study was to evaluate the relationship between dental caries, the number of salivary colonies forming units of Mutans Streptococci (MS) and Lactobacillus (LB), and the nutritional status in a group of children from Transylvania. This observational study used a sample of 154 school children, aged 9 to 12 years. The prevalence of caries was measured using the decayed, missing, and filled teeth index for deciduous teeth (dmft index) and for permanent teeth (DMFT index). Height and weight were assessed for each subject, and their body mass index (BMI) percentile was calculated. Salivary levels of Mutans Streptococci (MS) and Lactobacillus (LB) were determined using the CRT Bacteria Test from Ivoclar Vivadent. In our study, we found a positive association between the BMI percentile, MS count, LB count, tooth brushing frequency, and the incidence of dental caries in children aged 9 to 12 years old. Future preventive programs should include nutrition control in order to prevent both the apparition of dental caries and obesity in children.
Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma
Authors: Lookian Pashayar P. , Zhao David , Medina Rogelio , Wang Herui , Zenka Jan , Gilbert Mark R. , Pacak Karel , Zhuang Zhengping
Published: March 2021

The foundation of precision immunotherapy in oncology is rooted in computational biology and patient-derived sample sequencing to enrich for and target immunogenic epitopes. Discovery of these tumor-specific epitopes through tumor sequencing has revolutionized patient outcomes in many types of cancers that were previously untreatable. However, these therapeutic successes are far from universal, especially with cancers that carry high intratumoral heterogeneity such as glioblastoma (GBM). Herein, we present the technical aspects of Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) vaccine immunotherapy, an investigational therapeutic that potentially circumvents the need for in silico tumor-neoantigen enrichment. We then review the most promising GBM vaccination strategies to contextualize the MBTA vaccine. By reviewing current evidence using translational tumor models supporting MBTA vaccination, we evaluate the underlying principles that validate its clinical applicability. Finally, we showcase the translational potential of MBTA vaccination as a potential immunotherapy in GBM, along with established surgical and immunologic cancer treatment paradigms.
Therapeutic Evaluation of Antibody-Based Targeted Delivery of Interleukin 9 in Experimental Pulmonary Hypertension
Authors: Gouyou Baptiste , Grün Katja , Kerschenmeyer Anne , Villa Alessandra , Matasci Mattia , Schrepper Andrea , Pfeil Alexander , Bäz Laura , Jung Christian , Schulze P. Christian , Neri Dario , Franz Marcus
Published: March 2021

Background and Aims: Pulmonary hypertension (PH) is a heterogeneous disorder associated with poor prognosis. For the majority of patients, only limited therapeutic options are available. Thus, there is great interest to develop novel treatment strategies focusing on pulmonary vascular and right ventricular remodeling. Interleukin 9 (IL9) is a pleiotropic cytokine with pro- and anti-inflammatory functions. The aim of this study was to evaluate the therapeutic activity of F8IL9F8 consisting of IL9 fused to the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin, which is abundantly expressed in pulmonary vasculature and right ventricular myocardium in PH. Methods: The efficacy of F8IL9F8 in attenuating PH progression in the monocrotaline mouse model was evaluated in comparison to an endothelin receptor antagonist (ERA) or an IL9 based immunocytokine with irrelevant antibody specificity (KSFIL9KSF). Treatment effects were assessed by right heart catheterization, echocardiography as well as histological and immunohistochemical tissue analyses. Results: Compared to controls, systolic right ventricular pressure (RVPsys) was significantly elevated and a variety of right ventricular echocardiographic parameters were significantly impaired in all MCT-induced PH groups except for the F8IL9F8 group. Both, F8IL9F8 and ERA treatments lead to a significant reduction in RVPsys and an improvement of echocardiographic parameters when compared to the MCT group not observable for the KSFIL9KSF group. Only F8IL9F8 significantly reduced lung tissue damage and displayed a significant decrease of leukocyte and macrophage accumulation in the lungs and right ventricles. Conclusions: Our study provides first pre-clinical evidence for the use of F8IL9F8 as a new therapeutic agent for PH in terms of a disease-modifying concept addressing cardiovascular remodeling.
PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects
Authors: Mishra Rosalin , Patel Hima , Alanazi Samar , Kilroy Mary Kate , Garrett Joan T.
Published: March 2021

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.
Exercise—A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights
Authors: Raun Steffen H. , Buch-Larsen Kristian , Schwarz Peter , Sylow Lykke
Published: March 2021

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.
Proof-of-Concept: Antisense Oligonucleotide Mediated Skipping of Fibrillin-1 Exon 52
Authors: Cale Jessica M. , Greer Kane , Fletcher Sue , Wilton Steve D.
Published: March 2021

Marfan syndrome is one of the most common dominantly inherited connective tissue disorders, affecting 2–3 in 10,000 individuals, and is caused by one of over 2800 unique FBN1 mutations. Mutations in FBN1 result in reduced fibrillin-1 expression, or the production of two different fibrillin-1 monomers unable to interact to form functional microfibrils. Here, we describe in vitro evaluation of antisense oligonucleotides designed to mediate exclusion of FBN1 exon 52 during pre-mRNA splicing to restore monomer homology. Antisense oligonucleotide sequences were screened in healthy control fibroblasts. The most effective sequence was synthesised as a phosphorodiamidate morpholino oligomer, a chemistry shown to be safe and effective clinically. We show that exon 52 can be excluded in up to 100% of FBN1 transcripts in healthy control fibroblasts transfected with PMO52. Immunofluorescent staining revealed the loss of fibrillin 1 fibres with ~50% skipping and the subsequent re-appearance of fibres with >80% skipping. However, the effect of exon skipping on the function of the induced fibrillin-1 isoform remains to be explored. Therefore, these findings demonstrate proof-of-concept that exclusion of an exon from FBN1 pre-mRNA can result in internally truncated but identical monomers capable of forming fibres and lay a foundation for further investigation to determine the effect of exon skipping on fibrillin-1 function.
Bio-Engineered Nisin with Increased Anti-Staphylococcus and Selectively Reduced Anti-Lactococcus Activity for Treatment of Bovine Mastitis
Authors: Field Des , Considine Kiera , O’Connor Paula M. , Ross R. Paul , Hill Colin , Cotter Paul D.
Published: March 2021

Bovine mastitis is a significant economic burden for dairy enterprises, responsible for premature culling, prophylactic and therapeutic antibiotic use, reduced milk production and the withholding (and thus wastage) of milk. There is a desire to identify novel antimicrobials that are expressly directed to veterinary applications, do not require a lengthy milk withholding period and that will not have a negative impact on the growth of lactic acid bacteria involved in downstream dairy fermentations. Nisin is the prototypical lantibiotic, a family of highly modified antimicrobial peptides that exhibit potent antimicrobial activity against many Gram-positive microbes, including human and animal pathogens including species of Staphylococcus and Streptococcus. Although not yet utilized in the area of human medicine, nisin is currently applied as the active agent in products designed to prevent bovine mastitis. Over the last decade, we have harnessed bioengineering strategies to boost the specific activity and target spectrum of nisin against several problematic microorganisms. Here, we screen a large bank of engineered nisin derivatives to identify novel derivatives that exhibit improved specific activity against a selection of staphylococci, including mastitis-associated strains, but have unchanged or reduced activity against dairy lactococci. Three such peptides were identified; nisin A M17Q, nisin A T2L and nisin A HTK.
Interleukin-13 Propagates Prothrombin Kringle-2-Induced Neurotoxicity in Hippocampi In Vivo via Oxidative Stress
Authors: Jeong Jae Yeong , Wi Rayul , Chung Young Cheul , Jin Byung Kwan
Published: March 2021

The present study investigated expression of endogenous interleukin-13 (IL-13) and its possible function in the hippocampus of prothrombin kringle-2 (pKr-2)-lesioned rats. Here we report that intrahippocampal injection of pKr-2 revealed a significant loss of NeuN-immunopositive (NeuN+) and Nissl+ cells in the hippocampus at 7 days after pKr-2. In parallel, pKr-2 increased IL-13 levels, which reached a peak at 3 days post pKr-2 and sustained up to 7 days post pKr-2. IL-13 immunoreactivity was seen exclusively in activated microglia/macrophages and neutrophils, but not in neurons or astrocytes. In experiments designed to explore the involvement of IL-13 in neurodegeneration, IL-13 neutralizing antibody (IL-13Nab) significantly increased survival of NeuN+ and Nissl+ cells. Accompanying neuroprotection, immunohistochemical analysis indicated that IL-13Nab inhibited pKr-2-induced expression of inducible nitric oxide synthase and myeloperoxidase within activated microglia/macrophages and neutrophils, possibly resulting in attenuation of reactive oxygen species (ROS) generation and oxidative damage of DNA and protein. The current findings suggest that the endogenous IL-13 expressed in pKr-2 activated microglia/macrophages and neutrophils might be harmful to hippocampal neurons via oxidative stress.
The Role of CXCL16 in the Pathogenesis of Cancer and Other Diseases
Authors: Korbecki Jan , Bajdak-Rusinek Karolina , Kupnicka Patrycja , Kapczuk Patrycja , Simińska Donata , Chlubek Dariusz , Baranowska-Bosiacka Irena
Published: March 2021

CXCL16 is a chemotactic cytokine belonging to the α-chemokine subfamily. It plays a significant role in the progression of cancer, as well as the course of atherosclerosis, renal fibrosis, and non-alcoholic fatty liver disease (NAFLD). Since there has been no review paper discussing the importance of this chemokine in various diseases, we have collected all available knowledge about CXCL16 in this review. In the first part of the paper, we discuss background information about CXCL16 and its receptor, CXCR6. Next, we focus on the importance of CXCL16 in a variety of diseases, with an emphasis on cancer. We discuss the role of CXCL16 in tumor cell proliferation, migration, invasion, and metastasis. Next, we describe the role of CXCL16 in the tumor microenvironment, including involvement in angiogenesis, and its significance in tumor-associated cells (cancer associated fibroblasts (CAF), microglia, tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), mesenchymal stem cells (MSC), myeloid suppressor cells (MDSC), and regulatory T cells (Treg)). Finally, we focus on the antitumor properties of CXCL16, which are mainly caused by natural killer T (NKT) cells. At the end of the article, we summarize the importance of CXCL16 in cancer therapy.
GC-MS-Based Metabolomics Study of Single- and Dual-Species Biofilms of Candida albicans and Klebsiella pneumoniae
Authors: Galdiero Emilia , Salvatore Maria Michela , Maione Angela , de Alteriis Elisabetta , Andolfi Anna , Salvatore Francesco , Guida Marco
Published: March 2021

Candida albicans and Klebsiella pneumoniae frequently co-exist within the human host as a complex biofilm community. These pathogens are of interest because their association is also related to significantly increased morbidity and mortality in hospitalized patients. With the aim of highlighting metabolic shifts occurring in the dual-species biofilm, an untargeted GC-MS-based metabolomics approach was applied to single and mixed biofilms of C. albicans and K. pneumoniae. Metabolomic results showed that among the extracellular metabolites identified, approximately 40 compounds had significantly changed relative abundance, mainly involving central carbon, amino acid, vitamin, and secondary metabolisms, such as serine, leucine, arabitol, phosphate, vitamin B6, cyclo-(Phe-Pro), trehalose, and nicotinic acid. The results were related to the strict interactions between the two species and the different microbial composition in the early and mature biofilms.
Dietary Influences on the Microbiota–Gut–Brain Axis
Authors: Barber Thomas M. , Valsamakis Georgios , Mastorakos George , Hanson Petra , Kyrou Ioannis , Randeva Harpal S. , Weickert Martin O.
Published: March 2021

Over unimaginable expanses of evolutionary time, our gut microbiota have co-evolved with us, creating a symbiotic relationship in which each is utterly dependent upon the other. Far from confined to the recesses of the alimentary tract, our gut microbiota engage in complex and bi-directional communication with their host, which have far-reaching implications for overall health, wellbeing and normal physiological functioning. Amongst such communication streams, the microbiota–gut–brain axis predominates. Numerous complex mechanisms involve direct effects of the microbiota, or indirect effects through the release and absorption of the metabolic by-products of the gut microbiota. Proposed mechanisms implicate mitochondrial function, the hypothalamus–pituitary–adrenal axis, and autonomic, neuro-humeral, entero-endocrine and immunomodulatory pathways. Furthermore, dietary composition influences the relative abundance of gut microbiota species. Recent human-based data reveal that dietary effects on the gut microbiota can occur rapidly, and that our gut microbiota reflect our diet at any given time, although much inter-individual variation pertains. Although most studies on the effects of dietary macronutrients on the gut microbiota report on associations with relative changes in the abundance of particular species of bacteria, in broad terms, our modern-day animal-based Westernized diets are relatively high in fats and proteins and impoverished in fibres. This creates a perfect storm within the gut in which dysbiosis promotes localized inflammation, enhanced gut wall permeability, increased production of lipopolysaccharides, chronic endotoxemia and a resultant low-grade systemic inflammatory milieu, a harbinger of metabolic dysfunction and many modern-day chronic illnesses. Research should further focus on the colony effects of the gut microbiota on health and wellbeing, and dysbiotic effects on pathogenic pathways. Finally, we should revise our view of the gut microbiota from that of a seething mass of microbes to one of organ-status, on which our health and wellbeing utterly depends. Future guidelines on lifestyle strategies for wellbeing should integrate advice on the optimal establishment and maintenance of a healthy gut microbiota through dietary and other means. Although we are what we eat, perhaps more importantly, we are what our gut microbiota thrive on and they thrive on what we eat.
The Significance of Targeting Poly (ADP-Ribose) Polymerase-1 in Pancreatic Cancer for Providing a New Therapeutic Paradigm
Authors: Jeong Keun-Yeong , Park Min Hee
Published: March 2021

Genome-wide studies focusing on elucidating the effects on cancer progression have enabled the consequent identification of a distinct subpopulation of pancreatic cancer cells with unstable genomic characteristics. Based on this background, deleterious changes by poly (adenosine diphosphate (ADP)-ribose) polymerase-1 (PARP)-1 have been concentrated in oncology. One of the critical functions of PARP-1 is the response to DNA damage, which plays a pivotal role in DNA repair in cancers. PARP-1 also has widespread functions that are essential for the survival and growth of cancer cells. It regulates oxidative stress in mitochondria through the regulation of superoxide and oxidation. PARP-1 is in charge of regulating mitosis, which is a crucial role in tumorigenesis and remodels histones and chromatin enzymes related to transcriptional regulation, causing alterations in epigenetic markers and chromatin structure. Given the significance of these processes, it can be understood that these processes in cancer cells are at the frontline of the pathogenetic changes required for cancer cell survival, and these contributions can result in malignant transformation. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 in pancreatic cancer related to the aforementioned roles, along with the summary of recent approaches with PARP-1 inhibition in clinical studies targeting pancreatic cancer. This understanding could help to embrace the importance of targeting PARP-1 in the treatment of pancreatic cancer, which may present the potential to find out a variety of research topics that can be both challenged clinically and non-clinically.
Vitamin A and Retinoids in Bladder Cancer Chemoprevention and Treatment: A Narrative Review of Current Evidence, Challenges and Future Prospects
Authors: Tratnjek Larisa , Jeruc Jera , Romih Rok , Zupančič Daša
Published: March 2021

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.
Reconstruction of Critical Nerve Defects Using Allogenic Nerve Tissue: A Review of Current Approaches
Authors: Kornfeld Tim , Borger Anton , Radtke Christine
Published: March 2021

Regardless of the nerve defect length, nerve injury is a debilitating condition for the affected patient that results in loss of sensory and motor function. These functional impairments can have a profound impact on the patient’s quality of life. Surgical approaches for the treatment of short segment nerve defects are well-established. Autologous nerve transplantation, considered the gold standard, and the use of artificial nerve grafts are safe and successful procedures for short segment nerve defect reconstruction. Long segment nerve defects which extend 3.0 cm or more are more problematic for repair. Methods for reconstruction of long defects are limited. Artificial nerve grafts often fail to regenerate and autologous nerve grafts are limited in length and number. Cadaveric processed/unprocessed nerve allografts are a promising alternative in nerve surgery. This review gives a systematic overview on pre-clinical and clinical approaches in nerve allograft transplantation.
The Application of Mesenchymal Stromal Cells and Their Homing Capabilities to Regenerate the Intervertebral Disc
Authors: Croft Andreas S. , Illien-Jünger Svenja , Grad Sibylle , Guerrero Julien , Wangler Sebastian , Gantenbein Benjamin
Published: March 2021

Chronic low back pain (LBP) remains a challenging condition to treat, and especially to cure. If conservative treatment approaches fail, the current “gold standard” for intervertebral disc degeneration (IDD)-provoked back pain is spinal fusion. However, due to its invasive and destructive nature, the focus of orthopedic research related to the intervertebral disc (IVD) has shifted more towards cell-based therapeutic approaches. They aim to reduce or even reverse the degenerative cascade by mimicking the human body’s physiological healing system. The implementation of progenitor and/or stem cells and, in particular, the delivery of mesenchymal stromal cells (MSCs) has revealed significant potential to cure the degenerated/injured IVD. Over the past decade, many research groups have invested efforts to find ways to utilize these cells as efficiently and sustainably as possible. This narrative literature review presents a summary of achievements made with the application of MSCs for the regeneration of the IVD in recent years, including their preclinical and clinical applications. Moreover, this review presents state-of-the-art strategies on how the homing capabilities of MSCs can be utilized to repair damaged or degenerated IVDs, as well as their current limitations and future perspectives.
Tau Is Truncated in Five Regions of the Normal Adult Human Brain
Authors: Friedrich Michael G. , Skora Amanda , Hancock Sarah E. , Mitchell Todd W. , Else Paul L. , Truscott Roger J. W.
Published: March 2021

The truncation of Tau is thought to be important in promoting aggregation, with this feature characterising the pathology of dementias such as Alzheimer disease. Antibodies to the C-terminal and N-terminal regions of Tau were employed to examine Tau cleavage in five human brain regions: the entorhinal cortex, prefrontal cortex, motor cortex, hippocampus, and cerebellum. These were obtained from normal subjects ranging in age from 18 to 104 years. Tau fragments of approximately 40 kDa and 45 kDa with an intact N-terminus retained were found in soluble and insoluble brain fractions. In addition, smaller C-terminal Tau fragments ranging in mass from 17 kDa to 25 kDa were also detected. These findings are consistent with significant Tau cleavage taking place in brain regions from 18 years onwards. It appears that site-specific cleavage of Tau is widespread in the normal human brain, and that large Tau fragments that contain the N-terminus, as well as shorter C-terminal Tau fragments, are present in brain cells across the age range.
NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging
Authors: Tannous Cynthia , Deloux Robin , Karoui Ahmed , Mougenot Nathalie , Burkin Dean , Blanc Jocelyne , Coletti Dario , Lavery Gareth , Li Zhenlin , Mericskay Mathias
Published: March 2021

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the Nmrk2 gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the Nampt gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. Nmrk2-KO mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The α7 integrin was repressed at both transcript and protein level at 24 months. Nmrk2 gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.
Integrated in Silico and Experimental Approach towards the Design of a Novel Recombinant Protein Containing an Anti-HER2 scFv
Authors: Santos Joana , Cardoso Miguel , Moreira Irina S. , Gonçalves João , Correia João D. G. , Verde Sandra Cabo , Melo Rita
Published: March 2021

Biological therapies, such as recombinant proteins, are nowadays amongst the most promising approaches towards precision medicine. One of the most innovative methodologies currently available aimed at improving the production yield of recombinant proteins with minimization of costs relies on the combination of in silico studies to predict and deepen the understanding of the modified proteins with an experimental approach. The work described herein aims at the design and production of a biomimetic vector containing the single-chain variable domain fragment (scFv) of an anti-HER2 antibody fragment as a targeting motif fused with HIV gp41. Molecular modeling and docking studies were performed to develop the recombinant protein sequence. Subsequently, the DNA plasmid was produced and HEK-293T cells were transfected to evaluate the designed vector. The obtained results demonstrated that the plasmid construction is robust and can be expressed in the selected cell line. The multidisciplinary integrated in silico and experimental strategy adopted for the construction of a recombinant protein which can be used in HER2+-targeted therapy paves the way towards the production of other therapeutic proteins in a more cost-effective way.
The Role of Cholesterol and Fatty Acids in the Etiology and Diagnosis of Autism Spectrum Disorders
Authors: Esposito Cecilia Maria , Buoli Massimiliano , Ciappolino Valentina , Agostoni Carlo , Brambilla Paolo
Published: March 2021

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders whose pathogenesis seems to be related to an imbalance of excitatory and inhibitory synapses, which leads to disrupted connectivity during brain development. Among the various biomarkers that have been evaluated in the last years, metabolic factors represent a bridge between genetic vulnerability and environmental aspects. In particular, cholesterol homeostasis and circulating fatty acids seem to be involved in the pathogenesis of ASDs, both through the contribute in the stabilization of cell membranes and the modulation of inflammatory factors. The purpose of the present review is to summarize the available data about the role of cholesterol and fatty acids, mainly long-chain ones, in the onset of ASDs. A bibliographic research on the main databases was performed and 36 studies were included in our review. Most of the studies document a correlation between ASDs and hypocholesterolemia, while the results concerning circulating fatty acids are less univocal. Even though further studies are necessary to confirm the available data, the metabolic biomarkers open to new treatment options such as the modulation of the lipid pattern through the diet.
The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression
Authors: Cheriyamundath Sanith , Kumar Anmol , Gavert Nancy , Brabletz Thomas , Ben-Ze’ev Avri
Published: March 2021

The overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-κB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment.
Congenitally Malformed Hearts: Aspects of Teaching and Research Involving Medical Students
Authors: Pickin Catherine C. , Castle James , Shaji Vibha , Banjoko Adeolu , Chambault Aimee-Louise , Seale Anna N. , Lander Anthony , Mehta Chetan , Crucean Adrian
Published: March 2021

To appreciate congenital heart disease fully, a detailed understanding of the anatomical presentation, as well as the physiology, is required. This is often introduced at an advanced stage of training. Professor Anderson has been influential in the Clinical Anatomy Intercalated BSc programme at the University of Birmingham, in particular in his teaching on Sequential Segmental Analysis. This article describes the experiences of the latest cohort of students on this programme, who undertook varying research projects using the Birmingham Cardiac Archive, with the guidance of Professor Anderson. The projects outlined include various aspects of isomerism, encompassing both the cardiac and abdominal manifestations, as well as details of congenitally corrected transposition of the great arteries and prenatally diagnosed right aortic arch and double arch. These studies all aimed to increase the knowledge base of their respective cardiac malformations and provide a basis for further research.
Acute Kidney Injury Post-Percutaneous Nephrolithotomy (PNL): Prospective Outcomes from a University Teaching Hospital
Authors: Pillai Sunil , Kriplani Akshay , Chawla Arun , Somani Bhaskar , Pandey Akhilesh , Prabhu Ravindra , Choudhury Anupam , Pandit Shruti , Taori Ravi , Hegde Padmaraj
Published: March 2021

Acute Kidney Injury (AKI) after percutaneous nephrolithotomy (PNL) is a significant complication, but evidence on its incidence is bereft in the literature. The objective of this prospective observational study was to analyze the incidence of post-PNL AKI and the potential risk factors and outcomes. Demographic data collected included age, gender, body mass index (BMI), comorbidities (hypertension, diabetes mellitus), and drug history—particularly angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers and beta blockers. Laboratory data included serial serum creatinine measured pre- and postoperation (12, 24, and 48 h), hemoglobin (Hb), total leucocyte count (TLC), Prothrombin time (PT), serum uric acid and urine culture. Stone factors were assessed by noncontrast computerized tomography of kidneys, ureter and bladder (NCCT KUB) and included stone burden, location and Hounsfield values. Intraoperative factors assessed were puncture site, tract size, tract number, operative time, the need for blood transfusion and stone clearance. Postoperative complications were documented using the modified Clavien–Dindo grading system and patients with postoperative AKI were followed up with serial creatinine measurements up to 1 year. Among the 509 patients analyzed, 47 (9.23%) developed postoperative AKI. Older patients, with associated hypertension and diabetes mellitus, those receiving ACE inhibitors and with lower preoperative hemoglobin and higher serum uric acid, had higher incidence of AKI. Higher stone volume and density, staghorn stones, multiple punctures and longer operative time were significantly associated with postoperative AKI. Patients with AKI had an increased length of hospital stay and 17% patients progressed to chronic kidney disease (CKD). Cut-off values for patient age (39.5 years), serum uric acid (4.05 mg/dL) and stone volume (673.06 mm3) were assessed by receiver operating characteristic (ROC) curve analysis. Highlighting the strong predictors of post-PNL AKI allows early identification, proper counseling and postoperative planning and management in an attempt to avoid further insult to the kidney.
Eutrophication Driven by Aquaculture Fish Farms Controls Phytoplankton and Dinoflagellate Cyst Abundance in the Southern Coastal Waters of Korea
Authors: Kang Yoonja , Kim Hyun-Jung , Moon Chang-Ho
Published: March 2021

We examined the dynamics of dinoflagellate cyst and phytoplankton assemblages in eutrophic coastal waters of Korea, adjacent to fish and shellfish farms. Water temperature showed seasonality, whereas salinity and pH remained relatively consistent. Dissolved inorganic nutrient levels were higher in September and at the inner stations, where aquaculture fish farms are located than those in May and at the outer stations. Canonical correspondence analysis and artificial neural network analysis revealed multiple environmental factors that affect the distribution of phytoplankton and dinoflagellate cysts. Diatoms dominated in the phytoplankton assemblages, while the protoperidinioid group dominated in the dinoflagellate cyst assemblages. Cyst abundance was higher at the outer stations than at the inner stations due to transport by fast currents, and phytoplankton abundance was positively correlated with cyst abundance. An increase in diatom abundance led to an increase in heterotrophic/mixotrophic cyst abundance, indicating that excessive uneaten food and urinary waste from the fish farms caused eutrophication in the study region and fast growth of diatoms, thereby contributing to the growth of heterotrophic/mixotrophic dinoflagellates and consequently, high abundance of heterotrophic/mixotrophic dinoflagellate cysts.
Innovations and Analogies in the Legal Regulation of Withdrawal from a Limited Liability Company under Current Russian Law
Authors: Mikryukov Viktor A.
Published: March 2021

The purpose of the study is to highlight the most significant legal gaps in the mechanism under study, find doctrinally relevant ways to overcome them casually in law enforcement, and propose options for generally filling the gaps in rulemaking. It is equally important to test the effectiveness of the analogy as a means to combat legal gaps. The methodological framework was formed by general (analysis, synthesis, abstraction, and concretization) and specific (comparative, formal, and technical legal) scientific research methods. The positive role of analogy as a method of combating legal uncertainty and the formation of legislative innovations was confirmed. The conclusion was made about the absence of a formal need for additional legislative authorization for Limited Liability Companies’ members to create a conditional or individualized withdrawal procedure. Backed by the legal analogy, the necessity to extend the freedom-of-contract doctrine in determining the fair value of a withdrawing shareholder’s share was argued. The achievements provided the basis for specific practical proposals to enhance existing Russian legislation and harmonize corporate relationships, which should improve Russia’s business climate.
Radionuclides Transfer from Soil to Tea Leaves and Estimation of Committed Effective Dose to the Bangladesh Populace
Authors: Absar Nurul , Abedin Jainal , Rahman Md. Mashiur , Miah Moazzem Hossain , Siddique Naziba , Kamal Masud , Chowdhury Mantazul Islam , Sulieman Abdelmoneim Adam Mohamed , Faruque Mohammad Rashed Iqbal , Khandaker Mayeen Uddin , Bradley David Andrew , Alsubaie Abdullah
Published: March 2021

Considering the probable health risks due to radioactivity input via drinking tea, the concentrations of 226Ra, 232Th,40K and 137Cs radionuclides in the soil and the corresponding tea leaves of a large tea plantation were measured using high purity germanium (HPGe) γ-ray spectrometry. Different layers of soil and fresh tea leaf samples were collected from the Udalia Tea Estate (UTE) in the Fatickchari area of Chittagong, Bangladesh. The mean concentrations (in Bq/kg) of radionuclides in the studied soil samples were found to be 34 ± 9 to 45 ± 3 for 226Ra, 50 ± 13 to 63 ± 5 for 232Th, 245 ± 30 to 635 ± 35 for 40K and 3 ± 1 to 10 ± 1 for 137Cs, while the respective values in the corresponding tea leaf samples were 3.6 ± 0.7 to 5.7 ± 1.0, 2.4 ± 0.5 to 5.8 ± 0.9, 132 ± 25 to 258 ± 29 and <0.4. The mean transfer factors for 226Ra, 232Th and 40K from soil to tea leaves were calculated to be 0.12, 0.08 and 0.46, respectively, the complete range being 1.1 × 10−2 to 1.0, in accordance with IAEA values. Additionally, the most popularly consumed tea brands available in the Bangladeshi market were also analyzed and, with the exception of 40K, were found to have similar concentrations to the fresh tea leaves collected from the UTE. The committed effective dose via the consumption of tea was estimated to be low in comparison with the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) reference ingestion dose limit of 290 μSv/y. Current indicative tea consumption of 4 g/day/person shows an insignificant radiological risk to public health, while cumulative dietary exposures may not be entirely negligible, because the UNSCEAR reference dose limit is derived from total dietary exposures. This study suggests a periodic monitoring of radiation levels in tea leaves in seeking to ensure the safety of human health.
Prediction of Insulin Resistance by Modified Triglyceride Glucose Indices in Youth
Authors: Song Kyungchul , Park Goeun , Lee Hye Sun , Choi Youngha , Oh Jun Suk , Choi Han Saem , Suh Junghwan , Kwon Ahreum , Kim Ho-Seong , Chae Hyun Wook
Published: March 2021

The triglyceride glucose (TyG) index, derived from a combination of fasting glucose and triglycerides, has been suggested as a useful marker for insulin resistance (IR), in addition to modified TyG indices that combine obesity parameters. This study investigated the association and utility of TyG and modified TyG indices for IR prediction in youth. Based on the Korea National Health and Nutritional Examination Survey, the data of 3728 youth aged 10–19 years were analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) of tertiles 2 and 3 for each parameter were calculated and compared with tertile 1 as a reference. To compare the parameters for identifying IR, receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. The ORs and 95% CIs for insulin resistance (IR) progressively increased across tertiles of each parameter. Overall, all modified TyG indices presented higher ORs and AUC than the TyG index. The TyG-body mass index standard deviation score showed the largest AUC for IR detection in all subjects. In conclusion, TyG and modified TyG indices could be used as valuable markers for the prediction of IR in youth. Moreover, modified TyG indices had better diagnostic accuracy than the TyG index.
Full-Length Transcriptome Sequencing Provides Insights into Flavonoid Biosynthesis in Fritillaria hupehensis
Authors: Guo Kunyuan , Chen Jie , Niu Yan , Lin Xianming
Published: March 2021

One of the most commonly utilized medicinal plants in China is Fritillaria hupehensis (Hsiao et K.C. Hsia). However, due to a lack of genomic resources, little is known about the biosynthesis of relevant compounds, particularly the flavonoid biosynthesis pathway. A PacBio RS II sequencing generated a total of 342,044 reads from the bulb, leaf, root, and stem, of which 316,438 were full-length (FL) non-redundant reads with an average length of 1365 bp and a N50 of 1888 bp. There were also 38,607 long non-coding RNAs and 7914 simple sequence repeats detected. To improve our understanding of processes implicated in regulating secondary metabolite biosynthesis in F. hupehensis tissues, we evaluated potential metabolic pathways. Overall, this study provides a repertoire of FL transcripts in F. hupehensis for the first time, and it will be a valuable resource for marker-assisted breeding and research into bioactive compounds for medicinal and pharmacological applications.
In Vitro Evaluation of the Activity of Terpenes and Cannabidiol against Human Coronavirus E229
Authors: Chatow Lior , Nudel Adi , Nesher Iris , Hayo Hemo David , Rozenberg Perri , Voropaev Hanna , Winkler Ilan , Levy Ronnie , Kerem Zohar , Yaniv Zohara , Eyal Nadav
Published: March 2021

The activity of a new, terpene-based formulation, code-named NT-VRL-1, against Human Coronavirus (HCoV) strain 229E was evaluated in human lung fibroblasts (MRC-5 cells), with and without the addition of cannabidiol (CBD). The main constituents in the terpene formulation used for the experiment were beta caryophyllene, eucalyptol, and citral. The tested formulation exhibited an antiviral effect when it was pre-incubated with the host cells prior to virus infection. The combination of NT-VRL-1 with CBD potentiated the antiviral effect better than the positive controls pyrazofurin and glycyrrhizin. There was a strong correlation between the quantitative results from a cell-viability assay and the cytopathic effect seen under the microscope after 72 h. To the best of our knowledge, this is the first report of activity of a combination of terpenes and CBD against a coronavirus.