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Oligoasthenoteratozoospermia is a human infertility syndrome caused by defects in spermatogenesis, spermiogenesis, and sperm maturation, and its etiology remains unclear. Kelch-like 10 (KLHL10) is a component of ubiquitin ligase E3 10 (KLHL10) and plays an important role in male fertility. Deletion or mutation of the Klhl10 gene in Drosophila or mice results in defects in spermatogenesis or sperm maturation. However, the molecular mechanisms by which KLHL10 functions remain elusive. In this study, we identified a missense mutation (c.1528A→G, p.I510V) in exon 5 of KLHL10, which is associated with oligoasthenoteratozoospermia in humans. To investigate the effects of this mutation on KLHL10 function and spermatogenesis and/or spermiogenesis, we generated mutant mice duplicating the amino acid conversion using the clustered regularly interspaced palindromic repeat/caspase 9 (CRISPR/Cas9) system and designated them Klhl10I510V mice. However, the Klhl10I510V mice did not exhibit any defects in testis development, spermatogenesis, or sperm motility at ten-weeks-of-age, suggesting that this mutation does not disrupt the KLHL10 function, and may not be the cause of male infertility in the affected individual with oligoasthenoteratozoospermia.

Mammalian spermatozoa are highly polarized cells characterized by compartmentalized cellular structures and energy metabolism. Adenylate kinase (AK), which interconverts two ADP molecules into stoichiometric amounts of ATP and AMP, plays a critical role in buffering adenine nucleotides throughout the tail to support flagellar motility. Yet the role of the major AK isoform, AK1, is still not well characterized. Here, by using a proteomic analysis of testis biopsy samples, we found that AK1 levels were significantly decreased in nonobstructive azoospermia patients. This result was further verified by immunohistochemical staining of AK1 on a tissue microarray. AK1 was found to be expressed in post-meiotic round and elongated spermatids in mouse testis and subsequent mature sperm in the epididymis. We then generated Ak1 knockout mice, which showed that AK1 deficiency did not induce any defects in testis development, spermatogenesis, or sperm morphology and motility under physiological conditions. We further investigated detergent-modeled epididymal sperm and included individual or mixed adenine nucleotides to mimic energy stress. When only ADP was available, Ak1 disruption largely compromised sperm motility, manifested as a smaller beating amplitude and higher beating frequency, which resulted in less effective forward swimming. The energy restriction/recover experiments with intact sperm further addressed this finding. Besides, decreased AK activity was observed in sperm of a male fertility disorder mouse model induced by cadmium chloride. These results cumulatively demonstrate that AK1 was dispensable for testis development, spermatogenesis, or sperm motility under physiological conditions, but was required for sperm to maintain a constant adenylate energy charge to support sperm motility under conditions of energy stress.

F-box and WD-40 domain protein 7 (Fbxw7) is a component of the Skp1-Cdc53/Cullin-F-box-protein complex (SCF/β-TrCP), which is an E3 ubiquitin ligase that mediates protein degradation. This complex has recently been shown to negatively regulate spermatogonial stem cell self-renewal; however, its roles in Sertoli cell (SC) proliferation, differentiation, and function remain to be established. In this study, we generated conditional mutant mice with SC-specific deletion of Fbxw7 via the Cre-loxP system. Fbxw7 deficiency in SCs impaired testis development, which is characterized by age-dependent tubular atrophy, excessive germ cell loss, and spermatogenic arrest, and the mutant males were infertile at 7 months old. Fbxw7 ablation also compromised cytoskeletal organization and cell polarity of SCs, as well as integrity of the blood-testis barrier. In addition, the transcript levels of cell markers for germ cells, Leydig cells, and SCs were significantly decreased in Fbxw7 mutant mice. Importantly, protein levels of GATA-4, a transcription factor that plays a crucial role in SC maturation and testis development, were progressively decreased in control SCs after postnatal day 14, whereas levels were aberrantly elevated in Fbxw7-deleted SCs. Interestingly, the Gata-4 messenger RNA levels remained stable following Fbxw7 deletion. Fbxw7 silencing in SCs also induced progressive Leydig cell inefficiency and testosterone insufficiency. Collectively, these results demonstrate that Fbxw7 expression is required for SC maturation and function, potentially through degradation of GATA-4, to support pubertal testis development and spermatogenesis.

In mammals, testis development is triggered by the expression of the sex-determining Y-chromosome gene SRY to commit the Sertoli cell (SC) fate at gonadal sex determination in the fetus. Several genes have been identified to be required to promote the testis pathway following SRY activation (i.e., SRY box 9 (SOX9)) in an embryo; however, it largely remains unknown about the genes and the mechanisms involved in stabilizing the testis pathway after birth and throughout adulthood. Herein, we report postnatal males with SC-specific deletion of Raptor demonstrated the absence of SC unique identity and adversely acquired granulosa cell-like characteristics, along with loss of tubular architecture and scattered distribution of SCs and germ cells. Subsequent genome-wide analysis by RNA sequencing revealed a profound decrease in the transcripts of testis genes (i.e., Sox9, Sox8, and anti-Mullerian hormone (Amh)) and, conversely, an increase in ovary genes (i.e., LIM/Homeobox gene 9 (Lhx9), Forkhead box L2 (Foxl2) and Follistatin (Fst)); these changes were further confirmed by immunofluorescence and quantitative reverse-transcription polymerase chain reaction. Importantly, co-immunofluorescence demonstrated that Raptor deficiency induced SCs dedifferentiation into a progenitor state; the Raptor-mutant gonads showed some ovarian somatic cell features, accompanied by enhanced female steroidogenesis and elevated estrogen levels, yet the zona pellucida 3 (ZP3)-positive terminally feminized oocytes were not observed. In vitro experiments with primary SCs suggested that Raptor is likely involved in the fibroblast growth factor 9 (FGF9)-induced formation of cell junctions among SCs. Our results established that Raptor is required to maintain SC identity, stabilize the male pathway, and promote testis development.

Response surface methodology (RSM) is an effective tool for exploring the relationships between the response and the input factors. Central composite design (CCD) and orthogonal array composite design (OACD) are useful second-order designs in response surface methodology. In this work, we consider the efficiencies of the two classes of composite designs for general case. Assuming the second-order polynomial model, the D-efficiency of CCDs and OACDs are studied for general value of \(\alpha \) in star points. Moreover, the determination of \(\alpha \) is also discussed from the perspective of space-filling criterion.

The minimum variance unbiased estimators (MVUEs) of the parameters for various distributions are extensively studied under ranked set sampling (RSS). However, the results in existing literatures are only locally MVUEs, i.e. the MVUE in a class of some unbiased estimators is obtained. In this paper, the global MVUE of the parameter in a truncated parameter family is obtained, that is to say, it is the MVUE in the class of all unbiased estimators. Firstly we find the optimal RSS according to the character of a truncated parameter family, i.e. arrange RSS based on complete and sufficient statistics of independent and identically distributed samples. Then under this RSS, the global MVUE of the parameter in a truncated parameter family is found. Numerical simulations for some usual distributions in this family fully support the result from the above two-step optimizations. A real data set is used for illustration.

This paper studies a maximum likelihood estimator (MLE) of the parameter for a continuous one-parameter exponential family under ranked set sampling (RSS). The authors first find the optimal RSS according to the character of the family, viz, arrange the RSS based on quasi complete and sufficient statistic of independent and identically distributed (iid) samples. Then under this RSS, some sufficient conditions for the existence and uniqueness of the MLE, which are easily used in practice, are obtained. Using these conditions, the existence and uniqueness of the MLEs of the parameters for some usual distributions in this family are proved. Numerical simulations for these distributions fully support the result from the above two step optimizations of the sampling and the estimation method.

A modified maximum likelihood estimator (MMLE) of scale parameter is considered under moving extremes ranked set sampling (MERSS), and its properties are obtained. For some usual scale distributions, we obtain explicit form of the MMLE and prove the MMLE is an unbiased estimator under MERSS. The simulation results show that the MMLE using MERSS is always more efficient than the MLE using simple random sampling, when the same sample size is used. The simulation results also show that the loss of efficiency in using the MMLE instead of the MLE is very small for small sample.

Stress granules (SGs) are discrete assemblies of stalled messenger ribonucleoprotein complexes (mRNPs) that form when eukaryotic cells encounter environmental stress. RNA-binding proteins (RBPs) mediate their condensation by recruiting populations of mRNPs. However, the cellular and molecular mechanisms underlying the role of ubiquitin-associated protein 2-like (UBAP2L) in the regulation of SG dynamics remain elusive. Here, we show that UBAP2L is required for both SG assembly and disassembly. UBAP2L overexpression nucleated SGs under stress-null conditions. The UBAP2L Arg–Gly–Gly (RGG) motif was required for SG competence, and mediated the recruitment of SG components, including mRNPs, RBPs, and ribosomal subunits. The domain of unknown function (DUF) of UBAP2L-mediated interaction with ras GTPase-activating protein-binding protein (G3BP)1/2, and its deletion caused the cytoplasmic–nuclear transport of UBAP2L and G3BP1/2, thereby compromising SG formation. The protein arginine methyltransferase PRMT1 asymmetrically dimethylated UBAP2L by targeting the RGG motif. Increased arginine methylation blocked, whereas its decrease enhanced UBAP2L interactions with SG components, ablating and promoting SG assembly, respectively. These results provide new insights into the mechanisms by which UBAP2L regulates SG dynamics and RNA metabolism.

Neuroactive steroids exhibit better neuroprotective properties in vitro and in vivo, and will be a potential neuroprotective effect. In this study, polyhydroxy sterone 2β,3α,5-trihydroxy-5α- androst-6-one (YC-10) was designed and synthesized from androst-5-en-3-ol by 6 steps reactions. Its absolute structure was characterized by X-SRD and its structure was characterized by NMR, IR, and MS. Its neuroprotective action was determined by MTT assay with two models of neurotoxicity. The maximum protective effect was at a concentration of 40μM for neurotoxicity induced by glutamate, and showing better cell viability in a dose-dependent manner; Moreover it cloud significantly protect the cerebellar granule neurons against neuronal death mediated by low K + , its effective protective concentration was 50μM.

AKR1B10 is a member of human aldo–keto reductase superfamily, and a promising anti-cancer therapeutic target. In this paper, androst-5-ene-3β-ol, dehydroepiandrosterone, pregnenolone and cholesterol were used as reactants, sixteen products were obtained through Jones reaction and reduction reaction using NaBH4. Their inhibitory activities against AKR1B10 and AKR1B1 were measured. The most active compound (3a) has the IC50 of 0.50 μM for AKR1B10, and the most AKR1B10 selective compound (2a) has the IC50 of 0.81 μM with AKR1B1/AKR1B10 selectivity of 195. In addition, the binding modes of 2a and 3a in the active site of human AKR1B10 were identified by docking.

A modification of ranked set sampling (RSS) called moving extremes ranked set sampling (MERSS) is considered for the estimation of the scale parameter of scale distributions. A maximum likelihood estimator (MLE) is studied and its properties are obtained. We prove the MLE is an equivariant estimator under scale transformation. In order to give more insight into the performance of MERSS with respect to (w.r.t.) simple random sampling (SRS), the asymptotic efficiency of the MLE using MERSS w.r.t. that using SRS is computed for some usual scale distributions. The relative results show that the MLE using MERSS can be real competitors to the MLE using SRS, when the same sample size is used.

Ranked set sample is applicable whenever ranking of a set of sample units can be done easily by a judgement method of the study variable or of the auxiliary variable. This paper considers ranked set sample based on the auxiliary variable X which is correlated with the study variable Y, where (X, Y) follows Morgenstern type bivariate exponential distribution. The authors discuss the optional allocation for unbiased estimators of the correlation coefficient ρ of the random variables X and Y when the auxiliary variable X is used for ranking the sample units and the study variable Y is measured for estimating the correlation coefficient. This paper first gives a class of unbiased estimators of ρ when the mean θ of the study variable Y is known and obtains an essentially complete subclass of this class. Further, the optimal allocation of the unbiased estimators is found in this subclass and is proved to be Bayes, admissible, and minimax. Finally, the unbiased estimator of ρ under the optimal allocation in the case of known θ is reformed for estimating ρ in the case of unknown θ, and the reformed estimator is shown to be strongly consistent.

Riccomagno et al. [1997. Lattice-based D-optimum design for Fourier regression. Ann. Statist. 25, 2313–2317] gave a comprehensive study on D-optimality under a symmetric Fourier regression model and gave a characterization on orthogonality, complete orthogonality and D-optimality of lattice designs under a symmetrical Fourier model. This paper extends their results to asymmetric Fourier regression models. We give some necessary condition for the orthogonality and complete orthogonality of U-type designs under general Fourier regression models that involve symmetrical and asymmetrical Fourier models and prove that a U-type design, which is completely orthogonal, is not D-optimal for an asymmetrical Fourier model. r 2007 Published by Elsevier B.V. MSC: 62K05; 62K15; 62K99

In this paper we consider the problem of estimation of a continuous distribution function under the LINEX loss function. The best invariant estimator is obtained, and proved to be minimax for any sample size n ≥ 1.

This paper considers the estimate problem on the mean matrix of mixture of normals. In order to evaluate estimators of the mean matrix, a fundamental frame of Φ-(general) decision problem is established. Under the frame, a class of Φ-minimax estimators are constructed.

In this paper, we discuss admissibility for linear estimates on regression coefficients in a general multivariate linear model. Eight kinds of definition for admissibility are given. We have proved that they can be divided into three identical subclasses in the class of linear estimates, and got necessary and sufficient conditions for admissible estimates on each subclass. Particularly, the eight kinds of admissibility are identical under a special case of the model.

A new method, called the simplex method, is proposed to generate the uniform design over a convex polyhedron inn-dimensional Euclidean space ℝn.

In this paper, a1ll admissible linear estimates of the mean matrix Θ from the distribution N(Θn×m, Im ⊗ In) are given under each of the several definitions for admissibility.