Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.

Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer's disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis.

The role of immunologic tests for subfertility in the clinical environment.

Unexplained subfertility and implantation failures not only are emotionally and physically distressing but also become a significant obstacle to reproductive-age couples who wish to build their family. Often, the currently recommended evaluation for these couples is significantly limited, and many of causes remain unexplained. To obtain an accurate diagnosis and treatment, proper evidence-based laboratory evaluation should be performed.

Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures.

Peripheral blood NK cytotoxicity assay (NKC) is one of the commonly utilized diagnostic tools for recurrent pregnancy losses (RPL) and repeated implantation failures (RIF). In this retrospective cohort study, we aimed to assess the cutoff values of NKC for RPL and RIF. A total of 883 women were included in this study; 24 nonpregnant fertile women, 604 nonpregnant women with three or more RPL, 163 nonpregnant women with two or more of RIF, 48 normal pregnant women, and 44 pregnant women with a history of RPL.

T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells.

During pregnancy, various immune effectors and molecules participating in the immune-microenvironment establish specific maternal tolerance toward the semi-allogeneic fetus. Activated maternal immune effectors by the trophoblast antigens, such as T helper (Th), T cytotoxic (Tc), T regulatory (Treg), and B cells, are involved in the regulation of adaptive immunity. Recognition of active signal through the T cell receptors stimulate the differentiation of naive CD3CD4 T cells into specific T cell subsets, such as Th1, Th2, Th9, Th17, Th22, and follicular Th cells (Tfh).

In vivo anti-V-ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses.

Tumor acidity is the key metabolic feature promoting cancer progression and is modulated by pH regulators on a cancer cell's surface that pump out excess protons/lactic acid for cancer cell survival. Neutralizing tumor acidity improves the therapeutic efficacy of current treatments including immunotherapies. Vacuolar-ATPase (V-ATPase) proton pumps encompass unique plasma membrane-associated subunit isoforms, making this molecule an important target for anticancer therapy.

Clinical molecular genetics evaluation in women with reproductive failures.

Molecular diagnostics is a rapidly growing branch of the clinical laboratory and has accelerated the advance of personalized medicine in the fields of pharmacogenomics, pharmacogenetics, and nutrigenomics. The versatility of molecular biology allows it to be effective in several medical fields that include reproduction, immunogenetics, and virology. Implementation of molecular and sequencing technology in reproductive medicine can add another layer of understanding to better define the causes behind infertility and recurrent reproductive loss.

PD-1 and PD-L1 expression on T-cell subsets in women with unexplained recurrent pregnancy losses.

Problem: Does programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) expression on the T-cell subsets such as T helper (Th) 1, Th17, and Treg cells differentiate women with recurrent pregnancy losses (RPL) from normal fertile women?

Method Of Study: The study was designed as a prospective cohort study. Forty-five women with two or more RPL of unknown etiology and twenty fertile women who had at least one or more live-born infants were enrolled prospectively from Jan 2017 to Jul 2019. PD-1 and PD-L1 expression on T-cell subsets were measured by flow cytometric analysis.

Poor ovarian response is associated with serum vitamin D levels and pro-inflammatory immune responses in women undergoing in-vitro fertilization.

Poor ovarian response (POR) limits the success of infertility treatment modality. In this study, we aim to investigate if POR is associated with serum 25(OH) vitamin D (VD) levels and pro-inflammatory immune responses in infertile women with a history of in-vitro fertilization and embryo transfer failures. A retrospective cross-sectional study included 157 women with IVF failures.

Ovarian and endometrial immunity during the ovarian cycle.

Immune tolerance is crucial for the successful pregnancy, while immune effectors and their products are required to safeguard a fetus from the infectious pathogens. The key immune effectors, such as T, B, and natural killer (NK) cells, monocytes, macrophages, and dendritic cells take part in regulating the immune responses at the maternal-fetal interface. The immune effectors become involved in intraovarian reproductive processes as well, such as ovulation, production of corpus luteum (CL) and its degeneration and determine the quality and evolution of the oocyte during the folliculogenesis.

Mast cell-induced immunopathology in recurrent pregnancy losses.

Problem: Mast cells (MC) have been known to play an important role in inflammation and angiogenesis by secreting numerous mediators, such as proteases, gelatinases, and proteoglycans. Three different MC subtypes were found in the endometrial layers of the uterus. In this study, we aim to investigate the role of endometrial MCs in recurrent pregnancy losses (RPL).

Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses.

Problem: Angiogenesis and vascular remodeling in secretory endometrium represent one of the crucial steps in pregnancy establishment, for which uterine NK (uNK) cells have an important role. Impairment of these steps may proceed to implantation and instigate initial pathology of recurrent pregnancy losses (RPL). In this study, we aim to investigate vascular development and density of uNK cells in secretory endometrium of women with RPL.

Inflammation induced preterm labor and birth.

Preterm birth which occurs before 37 weeks gestation is one of the most common obstetrical complication in humans. After many studies, it appears that "not one answer fits all" regarding the risk factors, causes and the treatments for this syndrome. However, it is becoming more evident that one of the major risk factors is inflammation and/or infection in the fetoplacental unit.

Interleukin 22 prevents lipopolysaccharide- induced preterm labor in mice.

Preterm birth is widespread and causes 35% of all neonatal deaths. Infants who survive face potential long-term complications. A major contributing factor of preterm birth is infection.

A Role for Iodide and Thyroglobulin in Modulating the Function of Human Immune Cells.

Iodine is an essential element required for the function of all organ systems. Although the importance of iodine in thyroid hormone synthesis and reproduction is well known, its direct effects on the immune system are elusive. Human leukocytes expressed mRNA of iodide transporters (NIS and PENDRIN) and thyroid-related proteins [thyroglobulin (TG) and thyroid peroxidase (TPO)].

Mammary epithelium-specific inactivation of V-ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer.

Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell-associated vacuolar ATPase 'a2' isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis.

Identification of Novel Bisbenzimidazole Derivatives as Anticancer Vacuolar (H⁺)-ATPase Inhibitors.

The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents.

Predicting NK cell subsets using gene expression levels in peripheral blood and endometrial biopsy specimens.

Problem: In molecular analysis of tissue biopsy specimens, one crucial aspect is characterization of immune cell populations. This is especially important for evaluation of uterine receptivity by assessing levels of lymphocyte populations including CD56 CD16- uterine NK cells and CD56 CD16+ conventional NK cells. Our objective was to investigate whether measuring total RNA transcripts from a tissue specimen would accurately reflect immune cell levels and be a new technique to assess immune cell subsets.

The immune response in pregnancy and in cancer is active and supportive of placental and tumor cell growth not their destruction.

While many investigators have described the biochemical and physiological similarities between tumor cells and trophoblast cells, in this discourse we will compare primarily their leucocytes, which constitute a large portion of the tumor and its microenvironment as well as the placenta and its microenvironment. There is a remarkable similarity between the cells that support placental growth and development and tumor growth and development. In many cases over half of the cells present in the tumor and the placenta are non-tumor or nontrophoblast cells, immune cells.

Low-dose prednisone and immunoglobulin G treatment for woman at risk for neonatal alloimmune thrombocytopenia and T helper 1 immunity.

Problem: Fetal and neonatal alloimmune thrombocytopenia is an alloimmune disorder resulting from platelet opsonization by maternal antibodies that destroy fetal platelets. As there is no antenatal screening or immunization to prevent sensitization, selection of high-risk population or the prevention of antenatal sensitization is significantly limited.

Method Of Study: (i) A case report of ante- and postnatal management of a woman with paternal homozygosity for human platelet antigen-1(HPA) incompatibility.

Zika virus infection and biological treatment for reproductive medicine.

The recent Zika virus (ZIKV) epidemic is particularly challenging in the field of reproductive medicine as various biological tissues and byproducts, such as intravenous immunoglobulin G or cells are utilized during reproductive cycles, and an infected mother has an increased risk of having babies with fetal microcephaly and other congenital brain anomalies. In this review, current guidelines for prevention of sexual transmission of ZIKV, ZIKV testing, and tissue and blood product usages are summarized for physicians caring for those planning pregnancy or going through infertility treatment.

The V-ATPase a2 isoform controls mammary gland development through Notch and TGF-β signaling.

Among all tissues and organs, the mammary gland is unique because most of its development occurs in adulthood. Notch signaling has a major role in mammary gland development and has been implicated in breast cancer. The vacuolar-ATPase (V-ATPase) is a proton pump responsible for the regulation and control of pH in intracellular vesicles and the extracellular milieu.

Gonadotropin-releasing hormone analogues lead to pro-inflammatory changes in T lymphocytes.

Problem: We aimed to investigate the effect of gonadotropin-releasing hormone (GnRH) analogues on T-cell immunity.

Method Of Study: TNF-α(+) -, INF-ɣ(+) -, IL-10(+) -, and IL-17(+) -expressing T cells in peripheral blood mononuclear cells (PBMCs) were treated with various concentrations (0.1, 1, 5, and 10 μm) of GnRH agonist (buserelin acetate) and antagonist (cetrorelix acetate) for 4 hours in vitro and they were analyzed with flow cytometry.

Pregnancy is a model for tumors, not transplantation.

Nearly 65 years have passed since Peter Medawar posed the following question: "How does the pregnant mother contrive to nourish within itself, for many weeks or months, a fetus that is an antigenically foreign body." Now, understanding of reproductive immunology has demonstrated that the HLA antigens in the placenta are non-classical and do not induce rejection. In the placenta and in tumors, 50% or more of the cells are cells of the immune system and were once thought to be primed and ready for killing tumors or the "fetal transplant" but these cells are not potential killers but abet the growth of either the tumor or the placenta.

Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles.

Problem: Association between PAI-1 4G/5G polymorphism and reproductive failures has been postulated. We aimed to investigate its impact on metabolic, hormonal, and immune profiles of women with reproductive failures.

Method Of Study: A retrospective study was carried out in 208 women with a history of reproductive failure.