REVIEW | doi:10.20944/preprints201809.0217.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Premature ovarian insufficiency, POI; Gene therapy; Menopause; SAL-like 4 genes, SALL4; Follicle-stimulating hormone (FSH); Basonuclin-1; Replication-incompetent adenoviral vector, Ad; Stem cells, SC.
Online: 12 September 2018 (11:06:42 CEST)
Premature ovarian insufficiency (POI) is a highly prevalent disorder, characterized by the development of menopause before age of 40. Most cases are idiopathic; however, in some women the cause of this condition (e.g. anticancer treatment, genetic disorders, and enzymatic defects) may be identified. Although hormone replacement therapy, the principal therapeutic approach for POI, helps to alleviate the related symptoms, this does not effectively solve the issue of fertility. Assisted reproductive techniques also lack efficacy in these women. Thus, the effective approach to manage the patients with POI is highly warranted. Several mechanisms, associated with POI, have been identified, including lack of FSH receptor functioning, alterations in the apoptosis control, mutations in Sal-like 4 genes, thymulin or basonuclin-1 deficiency etc. The above-mentioned may be good targets for gene therapy in order to correct defects, leading to POI. The goal of this review is to summarize the current experience on the POI studies, that employed gene therapy, and to discuss the possible future directions in this field.
REVIEW | doi:10.20944/preprints201711.0096.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Hedgehog signaling; skin; epidermis; hair follicle; development; homeostasis; basal cell carcinoma; signaling crosstalk
Online: 15 November 2017 (07:11:15 CET)
The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.
ARTICLE | doi:10.20944/preprints202306.0539.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: MIA; cytokines; chemokines; colony-stimulating factors; Poly (I:C); neurodevelopmental disorders
Online: 7 June 2023 (10:47:26 CEST)
Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor‐α (PPARα), with the clinically available agonist fenofibrate, attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 hours after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/CTRL group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1 levels were lower than in veh/CTRL group. Notably, MIP-1, TNF-, GRO/KC, GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, indicating the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate the consequences of MIA.
ARTICLE | doi:10.20944/preprints201702.0025.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: congenital hypothyroidism; incidence; neonatal screening; thyroid-stimulating hormone; cutoff level
Online: 8 February 2017 (10:54:10 CET)
Lower cutoff levels in screening programs have led to an increase in the proportion of detected cases with transient hypothyroidism, leading to increase of the overall incidence of primary congenital hypothyroidism (CH) in several countries. We have performed retrospective evaluation on the data from 251,008 (96.72%) neonates screened for thyroid-stimulating hormone (TSH) level in dried blood spot specimens taken 48 hours after birth, between 2002 and 2015, using DELFIA method. A TSH value of 15 mIU/L was used as the cutoff point until 2010 and 10 mIU/L thereafter. Primary CH was detected in 127 newborns (1/1976) of which 81.1% had permanent and 18.9% had transient CH. The incidence of primary CH was increased from 1/2489 until to 2010 to 1/1585 thereafter (p=0.131). However, the incidence of permanent CH was slightly increased (p=0.922), while the transient CH incidence had 8-fold increasing after lowering the TSH cutoff level (p<0.001). In cases with permanent CH, we observed lower frequency for thyroid dysgenesis (82.7 vs. 66.7%) and higher frequency for normal in-situ thyroid gland (17.3 vs. 33.3%), for the period with reduced TSH cutoff value. Our findings support the impact of lower TSH cutoff on the increasing incidence of congenital hypothyroidism.
REVIEW | doi:10.20944/preprints202211.0263.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Thin Endometrium; stem cells; Granulocyte colony-stimulating factor; Acupuncture treatment; Physical therapy
Online: 15 November 2022 (01:12:22 CET)
The endometrium is an important part of the uterus. The human endometrium is a complex and dynamic tissue that goes through phases of growth and regression during any menstrual cycle. A thin endometrium might be relevant to a lower rate of implantation as well as a higher rate of miscarriage. Several treatments have been developed for thin endometrium, such as granulocyte colony-stimulating factor, stem cell therapy, acupuncture and physical therapy, among others. These approaches have been shown to have effects on the endometrium related to reducing the area of fibrosis, increasing the number of glands, promoting angiogenesis, increasing endometrial thickness, improving tissue structure, and increasing pregnancy rates. This review summarizes the key role of these treatments in repairing thin endometrium and improving clinical pregnancy rates
REVIEW | doi:10.20944/preprints202007.0010.v1
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: Primary ovarian insufficiency; ovarian hypofunction; amenorrhea; follicular stimulating hormone; electrophysiological technology; bioelectrical stimulation
Online: 2 July 2020 (13:39:54 CEST)
Ovarian hypofunction or primary ovarian insufficiency (POI) is a common cause in the etiology of female infertility. It is a heterogeneous disorder, affecting approximately 1% of women before the age of 40. The characteristics of POI are menstrual disorders, including amenorrhea and delayed menstruation, accompanied by a raised gonadotrophin level and decreased estradiol level. In recent years, electrophysiology (EP) technology has been advancing rapidly in the diagnosis and treatments of numerous diseases. According to studies, bioelectrical stimulation (BES) therapy is an electrophysiology technology that plays significant roles in numerous diseases, including on the thin endometrium in patients with POI. In this review, the overall research progress of this electrophysiological technology has been discussed in relation to the advancement of primary ovarian insufficiency.
ARTICLE | doi:10.20944/preprints201908.0062.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: dendritic cell; cancer vaccine; vaccination; acquired immunity; granulocyte colony-stimulating factor; tetramer analysis
Online: 5 August 2019 (12:35:50 CEST)
Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16–18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms’ tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.
Subject: Business, Economics And Management, Accounting And Taxation Keywords: early childhood development; stimulating parenting practices; effective early childhood reading practices; rural China; mixed methodology
Online: 8 January 2021 (13:26:49 CET)
Studies have shown that nearly half of rural toddlers in China have cognitive delays due to an absence of stimulating parenting practices, such as early childhood reading, during the critical first three years of life. However, few studies have examined the reasons behind these low levels of stimulating parenting, and no studies have sought to identify the factors that limit caregivers from providing effective early childhood reading practices (EECRP). This mixed-methods study investigates the perceptions, prevalence and correlates of EECRP in rural China, as well as associations with child cognitive development. We use quantitative survey results from 1,720 caregiver-child dyads across 100 rural villages/townships in northwestern China and field observation and interview data with 60 caregivers from these same sites. The quantitative results show significantly low rates of EECRP despite positive perceptions of early reading and positive associations between EECRP and cognitive development. Qualitative results suggest that low rates of EECRP in rural China are not due to the inability to access books, financial or time constraints, or the absence of aspirations. Rather, the low rate of book ownership and absence of reading to young children is driven by the insufficient and inaccurate knowledge of EECRP among caregivers, which leads to their delayed, misinformed reading decisions with their young children, ultimately contributing to developmental delays.
REVIEW | doi:10.20944/preprints202302.0009.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: G-protein-coupled receptor; allosteric site; allosteric modulator; pepducin; heterotrimeric G-protein; autoantibody; thyroid-stimulating hormone receptor; luteinizing hormone receptor; proteinase-activated receptor; chemokine receptor
Online: 1 February 2023 (10:54:07 CET)
A separate group consists of compounds that are able to simultaneously interact with both orthosteric and allosteric sites, which are classified as bitopic GPCR ligands [74, 76-81]. They have two pharmacophores, one of which binds with high affinity to the orthosteric site, while the other, with lower affinity, binds to the allosteric site. If these sites are spatially separated in the receptor, then the pharmacophores in the bitopic ligand must be connected with a flexible linker, the length of which exactly corresponds to the distance between the orthosteric and allosteric sites. At the same time, it is important that the linker does not significantly affect the conformational rearrangements in the receptor caused by its activation by orthosteric and (or) allosteric agonists [74, 79].
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: multiple sclerosis; MS; cause; genes; polygenic; heredity; autoimmune; diet; depression; fatigue; suicide; seizures; bowel disorders; thyroid; mitochondria; chromosome 2; chromosome 5; glial cells; sunlight; vitamin D3; ultraviolet radiation; melanocyte stimulating hormone; melanocyte concentrating hormone; stress
Online: 22 July 2019 (04:37:27 CEST)
The literature on the causation of multiple sclerosis (MS), both genetic and environmental, extends over hundreds of years, with no firm conclusions on the exact role of autoimmunity and lifestyle. The epidemiology of MS was the basis for this review, but with a new, extensive examination of genes pertaining to each disorder, and disease of first, and second, degree relatives of those with MS. The author’s motivation was to discover some relationship between MS, and notable familial conditions, as the heredity of MS is concluded to be 30%, and the disorders had a chronic and/or idiopathic nature. This investigation hoped to further understand the randomness of MS- who acquires it, and what symptoms develop- after the author’s decades of observing several incidences of multiple members developing MS in a single family. Online databases for the human genome were used to link genes to MS, and symptoms, including excessive depression, fatigue and suicide rates, in coordination with linking genes for specific familial conditions including seizures, stroke, mental illness, bowel disorders, and thyroid conditions. Interesting associations were found, notably a cluster of Th2 cytokines, known to cure the animal model of MS, important receptors for neurotransmitters and hormones, a gene specific to Epstein Barr Virus, and potential genes for mitochondrial dysfunction. The results surprised the author, showing polygenic regions of chromosome 2 and 5, especially a cluster at loci 5q31-q33, may be dysregulated. The conclusion agrees with past hypotheses MS results not from a single gene, but from various genes, including those expressed in glial cells. The individual theories to the causation of MS, starting with Charcot may be explained by multiple pathways converging into a single disease outcome. In coordination with a sunlight factor, chromosome 2 appears to mediate the immune system, and inflammation, through ultraviolet radiation producing vitamin D3 in the skin, but additionally through peptides formed in the melanocyte stimulating and concentrating hormone class. The impact of stress in MS could be primary, given the loci of several stress-related and stress-modulated genes on these chromosomes, and calls for more appreciation of, and greater care for, the MS patients’ state of mind.