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In the treatment of central nervous system (CNS) diseases such as glioma, Alzheimer's disease (AD) and Parkinson's disease (PD), drugs are expected to reach specific areas of the brain to achieve the desired effect. Although a growing number of therapeutic targets have been identified in preclinical studies, the ones that can ultimately be used in the clinic are limited. Therefore, the research process and clinical application of drugs for treating CNS diseases are still large challenges. Physiological barriers such as the blood–brain barrier (BBB) act as selective permeable membranes, allowing only certain molecules to enter the brain; this barrier is the major obstacle restricting the arrival of most drugs to brain lesions. Recently, nanoparticles, including lipid-based, cell-derived biomimetic, polymeric and inorganic nanoparticles, have gained increasing attention because of their ability to cross physiological barriers, and could play an important role as delivery carriers and immunomodulators. Additionally, clinical applications of nanoparticles in CNS diseases are underway. This review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases. [ABSTRACT FROM AUTHOR]

Background and Objectives: Elagolix is an orally active, gonadotropin-releasing hormone receptor antagonist approved for the management of endometriosis-associated pain and heavy menstrual bleeding associated with uterine fibroids. Elagolix population pharmacokinetics and factors affecting elagolix exposure in healthy women and women with endometriosis have been reported previously. The purpose of this study was to extend the population pharmacokinetics model with additional modifications to incorporate data from phase III studies of elagolix with hormonal add-back therapy in women with uterine fibroids. Methods: Data from 13 clinical studies (a total of 2168 women) consisting of six phase I studies in healthy premenopausal women, four phase III studies in premenopausal women with endometriosis, and three phase III studies in premenopausal women with uterine fibroids were analyzed using a non-linear mixed-effects modeling approach. Results: Elagolix population pharmacokinetics was best described by a two-compartment model with first-order absorption, lag time in absorption, and first-order elimination. Out of the covariates tested on elagolix apparent clearance, apparent volume of distribution, and/or relative bioavailability, only organic anion transporting polypeptide 1B1 genotype status and body weight had a statistically significant but no clinically meaningful effect on elagolix relative bioavailability and apparent volume of distribution, respectively. There were no clinically meaningful differences in elagolix population pharmacokinetics in healthy women or women with endometriosis or uterine fibroids. Conclusions: Elagolix population pharmacokinetics modeling did not reveal any patient-related factors or clinical parameters that would require dose adjustments for the approved dosage of 300 mg twice daily with estradiol 1 mg /norethindrone acetate 0.5 mg daily, in women with heavy menstrual bleeding associated with uterine fibroids. Clinical Trial Registration: ClinicalTrials.gov identifiers: NCT01620528 (EM-1), NCT01760954 (EM-1-Extend), NCT01931670 (EM-2), NCT02143713 (EM-2-Extend), NCT02654054 (UF-1), NCT02691494 (UF-2), NCT0295494 (UF-Extend). [ABSTRACT FROM AUTHOR]

Centrosomal proteins are necessary components of the centrosome, a conserved eukaryotic organelle essential to the reproductive process. However, few centrosomal proteins have been genetically linked to fertility. Herein we identify a homozygous missense variant of CEP128 (c.665 G > A [p.R222Q]) in two infertile males. Remarkably, male homozygous knock-in mice harboring the orthologous CEP128R222Q variant show anomalies in sperm morphology, count, and motility. Moreover, Cep128 knock-out mice manifest male infertility associated with disrupted sperm quality. We observe defective sperm flagella in both homozygous Cep128 KO and KI mice; the cilia development in other organs is normal—suggesting that CEP128 variants predominantly affected the ciliogenesis in the testes. Mechanistically, CEP128 is involved in male reproduction via regulating the expression of genes and/or the phosphorylation of TGF-β/BMP-signalling members during spermatogenesis. Altogether, our findings unveil a crucial role for CEP128 in male fertility and provide important insights into the functions of centrosomal proteins in reproductive biology. CEP128 is a centrosomal protein important for the organization of centriolar microtubules. Here, the authors show that a CEP128 variant observed in human male siblings causes reduced sperm counts and morphologically abnormal sperm when modeled in mice, suggesting a role for CEP128 in male fertility. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the unknown genetic causes of teratozoospermia, and determine the pathogenicity of candidate variants. Methods: A primary infertile patient and his family members were recruited in the West China Second University Hospital of Sichuan University. Whole-exome sequencing was performed to identify causative genes in a man with teratozoospermia. Immunofluorescence staining and western blotting were applied to assess the pathogenicity of the identified variant. Intracytoplasmic sperm injection (ICSI) was used to assist fertilization for the patient with teratozoospermia. Results: We performed whole-exome sequencing (WES) and detected a novel homozygous frameshift mutation of c.335_336del [p.E112Vfs*3] in DNAJB13 on a primary infertile male patient. Intriguingly, we identified abnormal sperm morphology in this patient, with recurrent respiratory infections and chronic cough. Furthermore, we confirmed that this mutation resulted in negative effects on DNAJB13 expression in the spermatozoa of the affected individual, causing ultrastructural defects in his sperm. Remarkably, our staining revealed that DNAJB13 was expressed in the cytoplasm of primary germ cells and in the flagella of spermatids during spermiogenesis in humans and mice. Finally, we are the first group to report a favorable prognosis using ICSI for a patient carrying this DNAJB13 mutation. Conclusion: Our study revealed a novel homozygous frameshift mutation of c.335_336del [p.E112Vfs*3] in DNAJB13 involved in teratozoospermia phenotype. Our study greatly expands the spectrum of limited DNAJB13 mutations, and is expected to provide a better understanding of genetic counseling diagnoses and subsequent treatment of male infertility. [ABSTRACT FROM AUTHOR]

Due to the changeable brightness outside the tunnel, the lighting brightness at the exit and entrance of the tunnel needs to be adjusted in time, so as to ensure that the driver can feel the difference of light intensity within the range that the human eye can adapt to when passing through the tunnel. In this paper, a tunnel lighting control strategy based on variable reduction factor is proposed, which can ensure that the lighting around the tunnel is within the range that the human eye can adapt to at any time. Through the field data collection and comparison and experiments, it can be shown that the lighting control method not only can improve the lighting quality in the tunnel, but also have better energy-saving effect and can reduce the cost of manual operation and maintenance. [ABSTRACT FROM AUTHOR]

Purpose: There are limited genes known to cause primary ciliary dyskinesia (PCD)–associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD. Methods: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa. Results: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility. Conclusions: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD. [ABSTRACT FROM AUTHOR]

Purpose: Empty follicle syndrome (EFS) refers to the inability to obtain mature oocytes after appropriate ovarian stimulation during the process of in vitro fertilization (IVF). However, the specific cause and mechanism of action underlying EFS remain to be further explored. Herein we aimed to investigate the clinical and genetic characteristics of EFS. Methods: After data were collected in an infertile family, we performed whole-exome sequencing (WES) on the patient and confirmed the pathogenic mutations through Sanger sequencing. Western immunoblotting, immunofluorescence staining, and minigene assay were further used to investigate the negative effects of these mutations. Results: Absence of oocytes was observed over 2 cycles of IVF in the patient, and we evaluated the novel compound heterozygous mutations c.2T>A (p. M1K) and c.1112+1G>T of the zona pellucida glycoprotein 1 gene (ZP1, MIM# 195000) by WES. For the family under study, EFS was classified as an autosomal recessive inheritance pattern. The results of western blotting and immunofluorescence staining analyses confirmed that the missense mutation of c.2T>A [p. M1K] resulted in almost missing protein production. Additionally, using a minigene assay, we demonstrated the deleterious effect on the ZP1 gene of the splice site mutation c.1112+1G>T, which caused truncation of ZP1 protein. Conclusions: The compound heterozygous mutations of ZP1 gene identified in this study by genetic and functional experiments constituted a novel genetic cause of EFS, and further study will expand its use in the clinical and molecular diagnoses of EFS. [ABSTRACT FROM AUTHOR]

Purpose: In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion. Methods: The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500. Results: Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. Conclusions: We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47. [ABSTRACT FROM AUTHOR]

Introduction: Elagolix is a novel, orally active, non-peptide, competitive gonadotropin-releasing hormone (GnRH) receptor antagonist in development for the management of endometriosis with associated pain and heavy menstrual bleeding due to uterine fibroids. The pharmacokinetics of elagolix have been well-characterized in phase I studies; however, elagolix population pharmacokinetics have not been previously reported. Therefore, a robust model was developed to describe elagolix population pharmacokinetics and to evaluate factors affecting elagolix pharmacokinetic parameters.Methods: The data from nine clinical studies (a total of 1624 women) were included in the analysis: five phase I studies in healthy, premenopausal women and four phase III studies in premenopausal women with endometriosis.Results: Elagolix population pharmacokinetics were best described by a two-compartment model with a lag time in absorption. Of the 15 covariates tested for effect on elagolix apparent clearance (CL/F) and/or volume of distribution only one covariate, organic anion transporting polypeptide (OATP) 1B1 genotype status, had a statistically significant, but not clinically meaningful, effect on elagolix CL/F.Conclusion: Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713. [ABSTRACT FROM AUTHOR]

This study aimed to explore the effects of different fertilizers and their combinations on growth and nutrient and Cd uptake of Lolium multiflorum. Compared with control treatment, chemical fertilizer, organic manure, and their conjunctions with biofertilizer increased shoot biomass. Biofertilizers were found to cause significant reductions in shoot biomass of plants grown in organic manure-treated and control soil. Decreased soil-available N and P and shoot N and K concentrations in biofertilizer amendment treatments indicated that plant growth and nutrient absorption might be negatively affected under nutrient deficiency conditions. Elevated shoot biomasses contributed to the highest shoot Cd contents in chemical fertilizer and chemical fertilizer + biofertilizer treatments among all treatments. But the maximum translocation efficiency occurred in biofertilizer + chemical fertilizer + organic manure treatment, followed by organic manure and chemical fertilizer + organic manure treatments. Based on the results, we can conclude that the application of only the biofertilizer Bacillus subtilis should be avoided in nutrient-limited soils. Chemical fertilizer application could benefit the amount of Cd in shoots, and organic manure application and its combinations could result in the higher translocation efficiency. [ABSTRACT FROM AUTHOR]

Temperature data from SABER/TIMED and Empirical Orthogonal Function (EOF) analysis are taken to examine possible modulations of the temperature migrating diurnal tide (DW1) by latitudinal gradients of zonal mean zonal wind ( $$\overline \zeta $$). The result shows that $$\overline \zeta $$ increases with altitudes and displays clearly seasonal and interannual variability. In the upper mesosphere and lower thermosphere (MLT), at the latitudes between 20°N and 20°S, when $$\overline \zeta $$ strengthens (weakens) at equinoxes (solstices) the DW1 amplitude increases (decreases) simultaneously. Stronger maximum in March-April equinox occurs in both $$\overline \zeta $$ and the DW1 amplitude. Besides, a quasi-biennial oscillation of DW1 is also found to be synchronous with $$\overline \zeta $$. The resembling spatial-temporal features suggest that $$\overline \zeta $$ in the upper tropic MLT probably plays an important role in modulating semiannual, annual, and quasi-biennial oscillations in DW1 at the same latitude and altitude. In addition, $$\overline \zeta $$ in the mesosphere possibly affects the propagation of DW1 and produces SAO of DW1 in the lower thermosphere. Thus, SAO of DW1 in the upper MLT may be a combined effect of $$\overline \zeta $$ both in the mesosphere and in the upper MLT, which models studies should determine in the future. [ABSTRACT FROM AUTHOR]

Ten years of SABER/TIMED temperature data are used to analyze the global structure and seasonal variations of the migrating 6-h tide from the stratosphere to the lower thermosphere. The amplitudes of the migrating 6-h tide increase with altitudes. In the stratosphere, the migrating 6-h tide peaks around 35°N/S. The climatologically annual mean of the migrating 6-h tide clearly shows the manifestation of the (4, 6) Hough mode between 70 and 90 km that peaks at the equator and near 35°N/S. Above 90 km, the 6-h tide shows more than one Hough mode with the (4, 6) mode being the dominant one. The migrating 6-h tide is stronger in the southern hemisphere. Annual, semiannual, 4-, and 3-month oscillations are the four dominant seasonal variations of the tidal amplitude. In the stratosphere and stratopause, the spring enhancement of the 6-h tide at middle latitudes is the most conspicuous feature. From the mesosphere to the lower thermosphere, the tidal amplitude at low latitudes is gradually in the scale of that at middle latitudes and exhibits different temporal variations at different altitudes and latitudes. Both ozone heating in the stratosphere and the background atmosphere probably affect the generation and the seasonal variations of the migrating 6-h tide. In addition, the non-linear interaction between different tidal harmonics is another possible mechanism. [ABSTRACT FROM AUTHOR]

This study examined the current changes of human ether-a-go-go-related gene (hERG) mutation derived from a LQT2 Chinese family with a highly penetrating phenotype. Mutation was identified and site-directed mutagenesis was performed to induce the mutation in wild-type (WT) hERG. WT hERG and mutated V535M were cloned and transiently expressed in HEK293 cells. At the 48th and 72nd h after transfection, membrane currents were recorded using whole cell patch-clamp procedures. An A>G transition at 1605 resulting in replacement of V535M was identified. Compared to WT, V535M mutation significantly decreased tail currents of hERG. At test potential of −40 mV after depolarizing at +50 mV, tail current densities were 83.35±7.06 pA/pF in WT and 50.38±7.74 pA/pF in V535M respectively ( n=20, P<0.01). Gating kinetics of hERG revealed that V of steady-state inactivation shifted to negative potential in the mutant ( V: −61.81±1.7 mV vs. V: −43.1±0.71 mV). The time constant of recovery from inactivation was markedly prolonged in the mutant compared to WT among test potentials. V535M hERG mutation demonstrated markedly decreased tail current densities, which suggests that V535M is a new loss-of-function mutation of hERG channel responsible for LQT2. [ABSTRACT FROM AUTHOR]

Aberrant sperm flagella impair sperm motility and cause male infertility, yet the genes which have been identified in multiple morphological abnormalities of the flagella (MMAF) can only explain the pathogenic mechanisms of MMAF in a small number of cases. Here, we identify and functionally characterize homozygous loss-of-function mutations of QRICH2 in two infertile males with MMAF from two consanguineous families. Remarkably, Qrich2 knock-out (KO) male mice constructed by CRISPR-Cas9 technology present MMAF phenotypes and sterility. To elucidate the mechanisms of Qrich2 functioning in sperm flagellar formation, we perform proteomic analysis on the testes of KO and wild-type mice. Furthermore, in vitro experiments indicate that QRICH2 is involved in sperm flagellar development through stabilizing and enhancing the expression of proteins related to flagellar development. Our findings strongly suggest that the genetic mutations of human QRICH2 can lead to male infertility with MMAF and that QRICH2 is essential for sperm flagellar formation. Multiple morphological abnormalities of the sperm flagella (MMAF) is a cause of male infertility. Here the authors identify homozygous nonsense mutations of the glutamine rich 2 (QRICH2) gene in two MMAF patients from 2 consanguineous families and show using QRICH2 knockout mice that the protein is required for sperm flagellar formation and motility. [ABSTRACT FROM AUTHOR]