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Abstract Background and objectives Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making. Methods In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017–2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses. Results The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P

Abstract As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.

The ongoing evolution of SARS-CoV-2 is a significant concern, especially with the decrease in clinical sequencing efforts, which impedes the ability of public health sectors to prepare for the emergence of new variants and potential COVID-19 outbreaks. Wastewater-based epidemiology (WBE) has been proposed as a surveillance program to detect and monitor the SARS-CoV-2 variants being transmitted in communities. However, research is limited in evaluating the effectiveness of wastewater collection at sentinel sites for monitoring disease prevalence and variant dynamics, especially in terms of inferring the epidemic patterns on a broader scale, such as at the state/province level. This study utilized a multiplexed tiling amplicon-based sequencing (ATOPlex) to track the longitudinal dynamics of variant of concern (VOC) in wastewater collected from municipalities in Queensland, Australia, spanning from 2020 to 2022. We demonstrated that wastewater epidemiology measured by ATOPlex exhibited a strong and consistent correlation with the number of daily confirmed cases. The VOC dynamics observed in wastewater closely aligned with the dynamic profile reported by clinical sequencing. Wastewater sequencing has the potential to provide early warning information for emerging variants. These findings suggest that WBE at sentinel sites, coupled with sensitive sequencing methods, provides a reliable and long-term disease surveillance strategy.

Abstract By means of the techniques of real analysis, applying some basic inequalities and formulas, a new reverse Mulholland’s inequality with one partial sum in the kernel is given. We obtain the equivalent conditions of the parameters related to the best value in the new inequality. As applications, we reduce to the equivalent forms and a few inequalities for particular parameters.

Abstract The anti-foreign tissue (transplant rejection) response, mediated by the immune system, has been the biggest obstacle to successful organ transplantation. There are still many enigmas regarding this process and some aspects of the underlying mechanisms driving the immune response against foreign tissues remain poorly understood. Here, we found that a large number of neutrophils and macrophages were attached to the graft during skin transplantation. Furthermore, both types of cells could autonomously adhere to and damage neonatal rat cardiomyocyte mass (NRCM) in vitro. We have demonstrated that Complement C3 and the receptor CR3 participated in neutrophils/macrophages-mediated adhesion and damage this foreign tissue (NRCM or skin grafts). We have provided direct evidence that the damage to these tissues occurs by a process referred to as trogocytosis, a damage mode that has never previously been reported to directly destroy grafts. We further demonstrated that this process can be regulated by NFAT, in particular, NFATc3. This study not only enriches an understanding of host-donor interaction in transplant rejection, but also provides new avenues for exploring the development of novel immunosuppressive drugs which prevent rejection during transplant therapy.

Abstract Background Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients. Results X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2:

Abstract In this paper, a new reverse half-discrete Mulholland-type inequality with the nonhomogeneous kernel of the form h ( v ( x ) ln n ) $h(v(x)\ln n)$ and the best possible constant factor is obtained by using the weight functions and the technique of real analysis. The equivalent reverses are considered. As corollaries, we deduce some new equivalent reverse inequalities with the homogeneous kernel of the form k λ ( v ( x ) , ln n ) $k_{\lambda }(v(x),\ln n)$ . A few particular cases are provided. Our new reverse half-discrete Mulholland-type inequality which has a nonhomogeneous kernel is more general than in the previous homogeneous kernel work. The harmonized integration will have more applications.

In this paper, by introducing multiple parameters, we establish a discrete version of the Hardy–Littlewood–Polya inequality in the whole plane. For the obtained inequality, we give the equivalent statements of the best possible constant factor linked to the parameters and deal with the equivalent inequalities. Our main result provided a new generalization of Hardy–Littlewood–Polya inequality, and as a consequence, we show that some new inequalities of the Hardy–Littlewood–Polya type can be derived from the current results by taking the special values of parameters.

In this study, we conducted a 16-week feeding trial to investigate the effects of a high-cassava starch diet on growth performance, liver function, and metabolism in largemouth bass (Micropterus salmoides). We formulated five diets containing varying levels of cassava starch: 12%, 9%, 6%, 3%, and 0% (termed M12, M9, M6, M3, and M0, respectively). We distributed these diets among largemouth bass with the initial body weight of 83.33 ± 0.55 g via an in-pond “raceway” aquaculture system. Our findings suggest that high level (12%) of cassava starch dietary inclusion adversely affected growth performance metrics such as weight gain rate and specific growth rate, along with feed utilization efficiency indicators, including protein efficiency, protein deposition rate, and the apparent digestibility of dry matter and protein. This negative impact was accompanied by a decrease in intestinal amylase activity. Through further transcriptomic analysis, we identified several key genes associated with carbohydrate metabolism, which underwent changes influencing liver function. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the involvement of these differentially expressed genes (DEGs) in the tricarboxylic acid cycle (TCA cycle). Comparative metabolomics analysis further indicated that the M9 group showed significant enrichment in pathways related to amino acid metabolism and alterations in the levels of metabolites involved in carbohydrate metabolism. In conclusion, our study demonstrates that incorporating up to 9% cassava starch in the diet can enhance growth performance in largemouth bass by stimulating digestive enzyme activities and promoting glucose utilization.

Abstract By means of the weight functions, the idea of introduced parameters, using the transfer formula and Hermite–Hadamard’s inequality, a more accurate half-discrete multidimensional Hilbert-type inequality with the homogeneous kernel as 1 ( x + ∥ k − ξ ∥ α ) λ + m ( x , λ > 0 ) $\frac{1}{(x + \Vert k - \xi \Vert _{\alpha} )^{\lambda + m}}\ (x,\lambda > 0)$ involving one derivative function of m-order is given. The equivalent conditions of the best possible constant factor related to several parameters are considered. The equivalent forms. the operator expressions and some particular inequalities are obtained.

Background: Preconception or prenatal carrier screening plays an important role in reproductive decision-making, but current research on hereditary deafness is limited. This study aimed to investigate the carrier frequencies of common deafness genes in the Chinese population who underwent carrier screening and to follow up on pregnancy outcomes in high-chance couples.Methods: Individual females or couples in preconception or early pregnancy were recruited from two hospitals in China. Carrier screening for common deafness genes in the Chinese population, including the GJB2 and SLC26A4 genes, was performed using next-generation sequencing technology. Genetic counseling was provided to subjects before and after testing.Results: Of the 9,993 subjects screened, the carrier rate was 2.86% for the GJB2 gene and 2.63% for the SLC26A4 gene. The variant with the highest carrier frequency in GJB2 was c.235delC (1.89%), and c.919–2A>G (1.08%) in SLC26A4. Of the six high-chance couples, four made alternative reproductive decisions (three with prenatal diagnosis and one with preimplantation genetic testing), with consequent termination of the birth of two affected fetuses.Conclusion: These findings confirmed the clinical utility of preconception or prenatal carrier screening for hereditary deafness.

Background and purpose: Intellectual disability-7 (MRD7) is a subtype disorder of intellectual disability (MRD) involving feeding difficulties, hypoactivity, and febrile seizures at an age of early onset, then progressive intellectual and physical development deterioration. We purposed to identify the underlying causative genetic factors of three individuals in each Chinese family who presented with symptoms of intellectual disability and facial dysmorphic features. We provided prenatal diagnosis for the three families and genetic counseling for the prevention of this disease.Methods: We collected retrospective clinical diagnostic evidence for the three probands in our study, which included magnetic resonance imaging (MRI), computerized tomography (CT), electroencephalogram (EEG), and intelligence tests for the three probands in our study. Genetic investigation of the probands and their next of kin was performed by Trio-whole exome sequencing (WES). Sanger sequencing or quantitative PCR technologies were then used as the next step to verify the variants confirmed with Trio-WES for the three families. Moreover, we performed amniocentesis to explore the state of the three pathogenic variants in the fetuses by prenatal molecular genetic diagnosis at an appropriate gestational period for the three families.Results: The three probands and one fetus were clinically diagnosed with microcephaly and exhibited intellectual developmental disability, postnatal feeding difficulties, and facial dysmorphic features. Combining probands’ clinical manifestations, Trio-WES uncovered the three heterozygous variants in DYRK1A: a novel variant exon3_exon4del p.(Gly4_Asn109del), a novel variant c.1159C>T p.(Gln387*), and a previously presented but rare pathogenic variant c.1309C>T p.(Arg437*) (NM_001396.5) in three families, respectively. In light of the updated American College of Medical Genetic and Genomics (ACMG) criterion, the variant of exon3_exon4del and c.1159C>T were both classified as likely pathogenic (PSV1+PM6), while c1309C>T was identified as pathogenic (PVS1+PS2_Moderate+PM2). Considering clinical features and molecular testimony, the three probands were confirmed diagnosed with MRD7. These three discovered variants were considered as the three causal mutations for MRD7. Prenatal diagnosis detected the heterozygous dominant variant of c.1159C>T p.(Gln387*) in one of the fetuses, indicating a significant probability of MRD7, subsequently the gestation was intervened by the parents’ determination and professional obstetrical operation. On the other side, prenatal molecular genetic testing revealed wild-type alleles in the other two fetuses, and their parents both decided to sustain the gestation.Conclusion: We identified two novel and one rare mutation in DYRK1A which has broadened the spectrum of DYRK1A and provided evidence for the diagnosis of MRD7 at the molecular level. Besides, this study has supported the three families with MRD7 to determine the causative genetic factors efficiently and provide concise genetic counseling for the three families by using Trio-WES technology.

BackgroundEpilepsy is characterized by recurrent unprovoked seizures. Mutations in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene are the main monogenic cause of epilepsy. Type and location of variants make a huge difference in the severity of SCN1A disorder, ranging from the mild phenotype (genetic epilepsy with febrile seizures plus, GEFS+) to the severe phenotype (developmental and epileptic encephalopathies, DEEs). Dravet Syndrome (DS) is an infantile-onset DEE, characterized by drug-resistant epilepsy and temperature sensitivity or febrile seizures. Genetic test results reveal SCN1A variants are positive in 80% DS patients and DS is mainly caused by de novo variants.MethodsTrio-whole exome sequencing (WES) was used to detect variants which were associated with clinical phenotype of five probands with epilepsy or twitching. Then, Sanger sequencing was performed to validate the five novel SCN1A variants and segregation analysis. After analyzing the location of five SCN1A variants, the pathogenic potential was assessed.ResultsIn this study, we identified five novel SCN1A variants (c.4224G > C, c.3744_3752del, c.209del, c.5727_5734delTTTAAAACinsCTTAAAAAG and c.5776delT) as the causative variants. In the five novel SCN1A variants, four were de novo and the remaining one was inherited. All novel variants would be classified as “pathogenic” or “likely pathogenic.”ConclusionThe five novel SCN1A variants will enrich the SCN1A mutations database and provide the corresponding reference data for the further genetic counseling.

Abstract By means of the weight functions, the idea of introducing parameters and the technique of real analysis related to the beta and gamma functions, a new reverse Hardy–Hilbert-type integral inequality with the homogeneous kernel as 1 ( x + y ) λ + m + n $\frac{1}{(x + y)^{\lambda + m + n}}$ ( λ > 0 $\lambda > 0$ ) involving two derivative functions of higher order is given. As applications, the equivalent statements of the best possible constant factor related to several parameters are considered, and some particular inequalities are obtained.

Abstract In this paper, by virtue of the symmetry principle, applying the techniques of real analysis and Euler–Maclaurin summation formula, we construct proper weight coefficients and use them to establish a reverse extended Hardy–Hilbert’s inequality with multi-parameters. Then, we obtain the equivalent forms and some equivalent statements of the best possible constant factor related to several parameters. Finally, we illustrate how the obtained results can generate some new reverse Hardy–Hilbert-type inequalities.

Based on the survey results of Spartina alterniflora, sediments, and intertidal benthic organisms in Zhangjiang Estuary Mangrove Reserve in 2019 and 2020, and combined with historical remote sensing image data, this paper analyzed the invasion process of S. alterniflora. The results showed that: The plant height of S. alterniflora in the high tide area of Zhangjiang Estuary Mangrove Reserve was slightly lower than that of mangroves in the same tidal area, and also lower than that of S. alterniflora in the middle tidal area, and it was more inclined to expand to the beach. The contents of total nitrogen, sulfide and organic carbon in the sediments of S. alterniflora in the study area were higher than those of the sand, and the content of total salt was lower than that of the sand. According to the analysis of remote sensing images in the study area, S. alterniflora maintained a high rate of expansion in Zhangjiang Estuary Mangrove Reserve from 2011 to 2019, and the expansion of S. alterniflora entered a stable period in 2020. According to the abundance biomass comparison method, the intertidal benthic community structure in the S. alterniflora area in 2020 was more stable than that in 2019. This study believes that when studying the impact of S. alterniflora invasion on coastal wetlands, in addition to considering the survey method, temporal and spatial factors and the length of the invasion time of S. alterniflora, the different expansion periods of S. alterniflora invasion should also be considered.

Abstract By means of the weight functions, the idea of introducing parameters and the technique of real analysis, a new Hardy–Hilbert-type integral inequality with the homogeneous kernel 1 ( x + y ) λ ( λ > 0 ) $\frac{1}{(x + y)^{\lambda}}\ (\lambda > 0)$ involving two multiple upper-limit functions is obtained. The equivalent statements of the best possible constant factor related to the beta and gamma functions are considered. As applications, the equivalent forms and the case of a nonhomogeneous kernel are deduced. Some particular inequalities and the operator expressions are provided.

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics.

BackgroundMore than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.MethodsThis cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.ResultsHigh-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.ConclusionsOur results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.

Background: Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive disorder of amino acid metabolism and caused by mutations in the phenylalanine hydroxylase (PAH) gene. Without timely and appropriate dietary management, the disturbance of amino acid metabolism may impair cognitive development and neurophysiological function. Newborn screening (NBS) can aid the early diagnosis of PAHD, which can give accurate therapy to PAHD patients in time. In China, the PAHD incidence and PAH mutation spectrum vary enormously across the provinces. A total of 5,541,627 newborns from Jiangxi province were screened by NBS between 1997 and 2021.Method: One seventy one newborns from Jiangxi province were diagnosed with PAHD. By Sanger sequencing and the multiplex ligation-dependent probe amplification (MLPA) analysis, mutation analysis was performed in 123 PAHD patients. Using an arbitrary values (AV)-based model, we compared the observed phenotype with the predicted phenotype based on the genotype.Results: In this study, we speculated the PAHD incidence of Jiangxi province was about 30.9 per 1,000,000 live births (171/5,541,627). We summarized the PAH mutation spectrum in Jiangxi province for the first time. Two novel variants (c.433G > C, c.706 + 2T > A) were found. The most prevalent variant was c.728G > A (14.1%). The overall prediction rate of the genotype-phenotype was 77.4%.Conclusion: This mutation spectrum is very meaningful to improve the diagnostic rate of PAHD and to increase the accuracy genetic counseling. This study offers data for the genotype-phenotype prediction suitable for Chinese population.

Abstract Background Most embryos that spontaneously abort during early pregnancy are found to have chromosomal abnormalities. The purpose of this study is to explore the factors involved in chromosome aberrations during embryogenesis. Methods A case-case study was performed to compare the risk factors for spontaneous abortion with and without embryo chromosome aberration. A total of 160 cases of spontaneous abortion were enrolled from a tertiary general hospital in Kunming. KaryoLite BACs-on-Beads (KL-BoBs) and fluorescence in situ hybridization (FISH) were employed to determine chromosomal constitution of abortion chorion villus samples. Maternal serum levels of homocysteine (Hcy) were detected by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Information about clinical background and environmental exposure was collected through a self-designed questionnaire. To identify the inherited chromosomal abnormalities, couples with chromosomal abnormalities in abortus were recalled for karyotyping. Results The overall rate of chromosomal abnormalities was 62.5% (100/160, KL-BoBs combined with FISH) including 51.9% (83/160) aneuploidies, 6.3% (10/160) polyploidies, and 4.4% (7/160) structural abnormalities. Only one case of structural abnormality was found to be inherited from maternal balanced translocation. Compared to abortus with normal karyotype, abortus with abnormal karyotype showed a positive association with parental age and elevated maternal serum homocysteine (Hcy) level, but negative association with previous miscarriage and perceived noise. Conclusions Embryonic chromosomal aberrations accounted for the majority of spontaneous abortion cases. A combination of internal and external factors may induce spontaneous abortion through fetal chromosomal aberrations or other pathogenic mechanisms.

Abstract In this paper, by virtue of the symmetry principle, applying the techniques of real analysis and Euler–Maclaurin summation formula, we construct proper weight coefficients and use them to establish a reverse Hardy–Hilbert inequality with the power function as intermediate variables. Then, we obtain the equivalent forms and some equivalent statements of the best possible constant factor related to several parameters. Finally, we illustrate how the obtained results can generate some particular reverse Hardy–Hilbert inequalities.

Abstract Background Our previous two-dimensional electrophoresis experiment showed that the expression of LASP1 in patients with endometriosis was significantly higher than that of control endometrium. However, the molecular mechanism by which LASP1 is regulated in endometriosis/adenomyosis is unknown. Methods Herein, qPCR was performed to analyze the expression levels of LASP1 and miR-218-5p between endometriosis (Ems) cells and control cells. Fluorescence in situ hybridization was carried out to measure the expression level of miR-218-5p in ectopic endometrium versus normal endometrium. After miR-218-5p mimic or inhibitor were transfected, the transwell experiment was carried out to see the effect of miR-218-5p on the migration of endometrial stromal cells (ESCs). EdU was used to measure cell proliferation rate. Dual-luciferase reporter assay was used to verify the binding of hsa-miR-218-5p to the 3’UTR of LASP1. Western blot and immunofluorescence analysis were carried out to identify the protein expression pattern of LASP1 and EMT markers in endometrial tissue. Results The miR-218-5p is mainly secreted from blood vessels and expressed in the muscle layer around the endometrium, which inhibits the expression level of LASP1 by binding the 3’UTR region of LASP1 in normal ESCs. Overexpression of miR-218-5p impedes the epithelial-to-mesenchymal transition (EMT) and prevents the migration of ESCs and the expression of Vimentin in Ems. Conclusions Our findings revealed that miR-218-5p in endometrial microenvironment prevents the migration of ectopic endometrial stromal cells by inhibiting LASP1.

A high-quality genome for the parasitic tapeworm, Echinococcus granulosus, provides further insight into the EG95 vaccine target for cystic echinococcosis.

By means of the weight functions, the idea of introduced parameters and the transfer formulas, two multidimensional Hilbert-type integral inequalities with the general nonhomogeneous kernel as H(||x||αλ1||y||βλ2)(λ1,λ2≠0) are given, which are some extensions of the Hilbert-type integral inequalities in the two-dimensional case. Some equivalent conditions of the best value and several parameters related to the new inequalities are provided. Two corollaries regarding the kernel, represented as kλ(||x||αλ1,||y||βλ2)(λ1,λ2≠0), are given, and a few new inequalities for the particular parameters are obtained.

By the use of the techniques of analysis and some useful formulas, we give a new extension of Hilbert-type inequality with two internal variables involving one partial sums, which is a refinement of a published inequality. We provide a few equivalent conditions of the best possible constant related to multi parameters. We obtain the equivalent inequalities, the operator expressions as well as a few inequalities with the particular parameters as applications.

In this article, we construct proper weight coefficients and use them to establish a Hardy-Hilbert-type inequality involving one partial sum. Based on this inequality, the equivalent conditions of the best possible constant factor related to several parameters are discussed. We also consider the equivalent forms and the operator expressions of the obtained inequalities. At the end of the paper, we demonstrate that more new Hardy-Hilbert-type inequalities can be derived from the special cases of the present results.

Prenatal exposure to nicotine that are mainly produced from tobacco smoke has been reported to affect infants. Therefore, nicotine exposure is one of important health concerns for newborn screening. Detecting nicotine and its metabolites such as cotinine in meconium were widely used to evaluate the tobacco exposure of pregnancy. In this study, disposable wooden tips were applied for touch sampling of meconium from newborn infants, and then were directly mounted on mass spectrometer (MS) to perform rapid screening of nicotine and cotinine. Choice of extraction/spray solvents was optimized. The limits of detection, reproducibility, linear response for direct analysis of meconium were also investigated. It is found the limits of detection (S/N = 3) to be as low as 0.36 ng/mg and 1.18 ng/mg for nicotine and cotinine, respectively, while the limits of quantitation (S/N = 10) to be 1.19 ng/mg and 3.94 ng/mg for nicotine and cotinine, respectively. The relative standard deviations (RSD) were found to be at 8.4%–19.8% (n = 6) for nicotine and cotinine, a good linear range from 5–500 ng/mL (R2 > 0.99). These analytical performances are well-accepted levels for ambient mass spectrometer analysis. In this study, evaluation of nicotine and cotinine in 22 puerpera volunteers were conducted by the established wooden-tip spray mass spectrometry (WTS-MS). These results showed that wooden-tip spray mass spectrometry would be useful for newborn screening of nicotine and cotinine in meconium with high reproducibility, speed, sensitivity, and specificity. Owing to the use of disposable wooden tips that involves no sample preparation and no chromatographic separation, our results show that wooden-tip spray mass spectrometry is a powerful tool for determination of nicotine in newborn meconium.

To evaluate the performance of expanded non-invasive prenatal testing (expanded noninvasive prenatal testing, NIPT-Plus) in screening for fetal chromosomal abnormalities includes aneuploidies and copy number variations, a total of 23,116 pregnant women with a singleton pregnancy were recruited for NIPT-Plus. Screening positive results were verified by karyotype analysis and chromosomal microarray analysis after amniocentesis. A total of 264 pregnancies (1.14%) were positive results as predicted by NIPT-Plus, including 233 aneuploidies and 31 copy number variations. Following genetic counseling, 233 (88.26%) pregnant women underwent invasive prenatal diagnosis and 136 were verified as true positives, comprising 72 common trisomies (T21, T18, T13), 47 sex chromosomal abnormalities two rare autosomal aneuploidies (RATs) and 15 copy number variations The positive predictive value for common trisomies, SCAs, RATs and CNVs were 68.57%, 68.12%, 6.67% and 51.72%, respectively. Pregnant women with screen-positive results for common trisomies have higher rates of invasive prenatal diagnosis and pregnancy termination than those with positive results for SCAs, RATs, and CNVs. NIPT-Plus showed a good performance in detecting common trisomies, SCAs and also contributed to detecting pathogenic CNVs, but higher accuracy was required in the detection of RATs. In summary, this study provides a reference for the clinical application of NIPT-Plus for screening fetal chromosomal abnormalities in this region. Therefore, we suggest that NIPT-Plus could be widely used in clinical screening for fetal chromosomal abnormalities in combination with prenatal diagnosis and genetic counseling.

Background: Hyperphenylalaninemia (HPA) is the most common inborn error in amino acid metabolism. It can be primarily classified into phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiency. BH4 deficiency (BH4D) is caused by genetic defects in enzymes involved in the biosynthesis and regeneration of BH4. 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), which is encoded by the PTS gene, participates in the biosynthesis of BH4. PTPS deficiency (PTPSD) is the major cause of BH4D. In this study, we investigated that the prevalence of BH4D in Jiangxi province was approximately 12.5 per 1,000,000 live births (69/5,541,627). Furthermore, the frequency of BH4D was estimated to be 28.8% (69/240) in the HPA population of Jiangxi. In this study, we aimed to characterize the mutational spectrum of the PTS gene in patients with PTPSD from Jiangxi province.Method: Newborn screening data of Jiangxi province from 1997 to 2021 were analyzed and 53 families with PTPSD were enrolled for the analysis of the PTS gene variants by Sanger sequencing.Results: 106 variants were identified in 106 alleles of 53 patients with PTPSD, including 13 types of variants reported previously, and two novel variants (c.164-36A>G and c.146_147insTG). The predominant variant was c.259C>T (47.2%), followed by c.84-291A>G (19.8%), c.155A>G (8.5%), c.286G>A (6.6%) and c.379C>T (4.7%).Conclusion: The results of this study can not only provide guidance for the molecular diagnosis and genetic counseling in cases of PTPS deficiency but also enrich the PTS mutation database.

Abstract By means of the weight functions, Hermite–Hadamard’s inequality, and the techniques of real analysis, a new more accurate reverse half-discrete Mulholland-type inequality involving one higher-order derivative function is given. The equivalent statements of the best possible constant factor related to a few parameters, the equivalent forms, and several particular inequalities are provided. Another kind of the reverses is also considered.

Background and aimsConcurrent hearing and genetic screening of newborns have been widely adopted as an effective strategy in early diagnosis and intervention for hearing loss in many cities in China. Here, we aimed to firstly explore the efficacy of combining conventional hearing screening with genetic screening among the large-scale newborns in Jiangxi Province.MethodsA total of 24,349 newborns from Jiangxi Maternal and Child Health Hospital were enrolled in our study from April 2021 to June 2022. Newborn hearing screening was conducted using otoacoustic emission (OAE) and automated auditory brainstem response (AABR). Meanwhile, newborn dried blood spots were collected and twenty common variants in four genes, including GJB2, SLC26A4, MT-RNR1(12SrRNA), and GJB3, were screened using a BGISEQ-500 next generation sequencing platform. Whole coding regions sequencing of GJB2 and SLC26A4 were performed by Sanger sequencing and NGS, respectively. Following up of hearing for the newborns was undertaken by phone interviews.ResultsAmong the 24,349 newborns, 7.00% (1,704/24,349) were bilaterally or unilaterally referred in their initial hearing screening, whereas 1.30% (316/24,349) exhibited bilateral or unilateral hearing loss in the repeated screening. Genetic screening revealed that 4.813% (1,172/24,349) of the screened newborns were positive for at least one mutant allele (heterozygote, homozygote, or compound heterozygote in one gene, mtDNA homoplasmy or heteroplasmy and combined variants in different genes). A total of 1,146 individuals were identified with mutant allele in one gene, including 525 of GJB2, 371 of SLC26A4, 189 as homoplasmic or heteroplasmic of MT-RNR1, and 61 of GJB3, indicating that GJB2 and SLC26A4 are the most common endemic deafness-associated genes among newborns in Jiangxi Province. Nineteen newborns were detected with combined heterozygous variants in different genes, with “c.235delC heterozygous and c.919-2A > G heterozygous” as the most prevalent genotype. Additionally, seven newborns were screened as homozygotes or compound heterozygotes responsible for congenital or late-onset prelingual hearing loss, including three cases with GJB2 c.235delC homozygous and one with SLC26A4 c.919-2A > G homozygous variant, one case with compound heterozygous variants for GJB2 and two with compound heterozygous variants for SLC26A4. Coding regions sequencing of GJB2 or SLC26A4 for overall 265 infants revealed that 14 individuals were identified as compound heterozygote with a second pathogenic variant not screened by our genetic panel.ConclusionsHerein our study firstly investigated the efficacy of concurrent hearing screening and genetic screening of common hearing impairment variants among large-scale newborns in Jiangxi Province. Concurrent screening provides a more comprehensive approach for management of congenital or delayed onset prelingual hearing loss and prevention of drug-induced hearing impairment for newborns at risk as well as their maternal relatives. An insight into the molecular epidemiology for hearing loss genes among Jiangxi population will also be beneficial to the genetic counseling and birth defect prevention.

Background and aims: Hemoglobinopathy associated with the HBB gene, with its two general subtypes as thalassemia and abnormal hemoglobin (Hb) variants, is one of the most prevalent hereditary Hb disorders worldwide. Herein we aimed to elucidate the prevalence of ß-thalassemia and abnormal hemoglobin variants and the prenatal diagnosis of the HBB gene in Jiangxi Province, southern central China.Methods: Hematological indices and capillary Hb electrophoresis were conducted for 136,149 subjects who were admitted to Jiangxi Maternal and Child Health Hospital and requested for hemoglobinopathy investigation. Routine α- and ß-globin genotyping were performed by gap-polymerase chain reaction (Gap-PCR) and reverse dot-blot (RDB) hybridization for the 11,549 individuals suspected to be thalassemia carriers. For participants whose genotypes could not explain their hematological indices, further Sanger sequencing and Gap-PCR were conducted for the detection of rare or novel variants in related globin genes. Prenatal diagnosis was performed for 77 pregnant couples both carrying ß-thalassemia trait at appropriate gestational ages.Results: Among the 11,549 subjects, 2,548 individuals were identified with HBB-associated hemoglobinopathy based on molecular analysis. A total of 2,358 subjects were identified as ß-thalassemia heterozygous carriers and nine cases were diagnosed as compound heterozygous ß-thalassemia. Additionally, 125 cases were detected with composite α- and ß-thalassemia and the remaining 56 individuals with abnormal Hb variants in the HBB. A total of 35 types of variants were identified in the HBB gene, including 26 types of ß-thalassemia and nine types of abnormal Hb variants. Four novel variants were firstly reported, including one variant in HBA2 and three variants in HBB. Overall, 77 prenatal samples underwent ß-thalassemia molecular diagnosis; 20 fetuses were identified with normal ß-thalassemia genotypes, 30 fetuses as ß-thalassemia heterozygotes, 11 as homozygotes, and 16 as compound heterozygotes in HBB.Conclusion: We have demonstrated a relatively high prevalence rate at 1.872% of ß-hemoglobinopathies including common and rare ß-thalassemia as well as abnormal Hb variants among large child-bearing population in the Jiangxi area of southern central China for the first time. Our data presents that prenatal diagnosis is an effective way to prevent and control birth defects of ß-thalassemia.

In this paper, we address Hardy–Hilbert-type inequality by virtue of constructing weight coefficients and introducing parameters. By using the Euler–Maclaurin summation formula, Abel’s partial summation formula, and differential mean value theorem, a new weighted Hardy–Hilbert-type inequality containing two partial sums can be proven, which is a further generalization of an existing result. Based on the obtained results, we provide the equivalent statements of the best possible constant factor related to several parameters. Also, we illustrate how the inequalities obtained in the main results can generate some new Hardy–Hilbert-type inequalities.

By using the methods of real analysis and the mid-value theorem, we introduce some lemmas and obtain a new reverse extended Hardy–Hilbert’s inequality with two partial sums and multi-parameters. We also give a few equivalent conditions of the best possible constant factor related to several parameters in the new inequality. Some particular inequalities are deduced.

In the present paper, we establish an equivalent form related to a Hilbert-type integral inequality with a non-homogeneous kernel and a best possible constant factor. We also consider the case of homogeneous kernel as well as certain operator expressions.

Using weight functions and parameters, as well as applying real analytic techniques, we derive a new Hardy–Hilbert-type integral inequality with the homogeneous kernel 1(x+y)λ+n involving one multiple upper limit function and one derivative function of higher order. Certain equivalent statements of the optimal constant factor related to some parameters are considered. A few particular inequalities and the case of reverses are also provided.

In this paper, we present a new reverse Mulholland-type inequality with multi-parameters and deal with its equivalent forms. Based on the obtained inequalities, the equivalent statements of the best possible constant factor related to several parameters are discussed. As an application, some interesting inequalities for double series are derived from the special cases of our main results.

Background and PurposeInfantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, neuroregression, and hypotonia followed by generalized spasticity, optic atrophy, and dementia. In this case, we aimed to identify the underlying causative genetic factors of a Chinese family with two siblings who presented with walking difficulty and inability to speak. We provided a prenatal diagnosis for the family and information for the prevention of this genetic disease.MethodsRetrospective clinical information and magnetic resonance imaging (MRI) findings of the proband were collected. Trio-whole exome sequencing (WES) including the proband and his parents was performed to explore the genetic causes, while Sanger sequencing was subsequently used to validate the variants identified by Trio-WES in the pedigree. Furthermore, prenatal molecular genetic diagnosis was carried out through amniocentesis to investigate the status of pathogenic mutations in the fetus by Sanger sequencing at an appropriate gestational age.ResultsThe two siblings were both clinically diagnosed with rapid regression in psychomotor development milestones. Brain MRI showed cerebellar atrophy and typical bilaterally symmetrical T2/FLAIR hyperintense signal changes in periventricular areas, indicating periventricular leukomalacia, and myelin sheath dysplasia. Trio-WES revealed two heterozygous variants in PlA2G6 associated with clinical manifestations in the proband: a novel maternally inherited variant c.217C>T (p.Gln73*) and a previously reported paternally inherited recurrent pathogenic variant c.1894C>T (p.Arg632Trp). These two heterozygous mutations were also detected in the younger brother who had similar clinical features as the proband. The novel variant c.217C>T was classified as “pathogenic (PVS1 + PM2 + PP3),” while the variant c.1894C>T was “pathogenic” (PS1 + PM1 + PM2 + PM3 + PP3) based on the latest American College of Medical Genetics and Genomics (ACMG) guidelines on sequence variants. Combining the molecular evidence and clinical phenotypes, the diagnosis of INAD was established for the two affected siblings. The two variants that were identified were considered the causative mutations for INAD in this family. Prenatal diagnosis suggested compound heterozygous mutations of c.217C>T and c.1894C>T in the fetus, indicating a high risk of INAD, and the parents chose to terminate the pregnancy.ConclusionWe identified a novel pathogenic mutation that broadens the mutation spectrum of PLA2G6 and will provide clues for the molecular diagnosis of INAD. Furthermore, our study has helped to elucidate the causative genetic factors of this Chinese family with INAD effectively and efficiently by using the emerging Trio-WES strategy and providing precise genetic counseling for this family.

Testicular torsion-detorsion is an ischaemia-reperfusion-induced male gonad injury that may lead to male infertility. Oxidative stress plays an important role in the ischaemia-reperfusion injury. Icariside II (ICA II) prevents oxidative stress and has obvious protective effects on spermatogenic function. The present study was aimed to investigate therapeutic potentials of ICA II on testicular torsion. 72 mice were randomly divided into three groups: sham-operated control group (n = 24), testicular ischemia-reperfusion + saline group (n = 24) and testicular ischemia-reperfusion + icariside II treated group (n = 24). Testicular ischemia-reperfusion was induced by the left testis rotated 360 degrees in a clockwise direction for 30 minutes followed by detorsion, the contralateral testis was removed. ICA II in saline (5 mg/kg/day) was administrated by gavage immediately after detorsion. The results demonstrated that ICA II alleviated testicular damage by mitigating spermatogenic cell injury and improving testosterone production in mouse models of testicular torsion. We revealed that ICA II alleviated oxidative stress and apoptosis in the testes, reduced inflammatory infiltration and accelerated angiogenesis. Briefly, ICA II administration ameliorated testicular damage by improving spermatogenic function and testosterone production, which supports its use as a pharmacological treatment of testicular torsion.

Abstract By using the idea of introducing parameters and weight coefficients, a new reverse discrete Mulholland-type inequality in the whole plane with general homogeneous kernel is given, which is an extension of the reverse Mulholland inequality. The equivalent forms are obtained. The equivalent statements of the best possible constant factor related to several parameters and a few applied examples are presented.

Hardy-type integral inequalities play a prominent role in the study of analytic inequalities, which are essential in mathematical analysis and its various applications, such as in the study of symmetry and asymmetry phenomena. In this paper, employing methods of real analysis and using weight functions, we investigate some equivalent conditions of two kinds of reverse Hardy-type integral inequalities with a particular non-homogeneous kernel. A few equivalent conditions of two kinds of reverse Hardy-type integral inequalities with a particular homogeneous kernel are deduced in the form of applications.

By means of the weight functions, the idea of introduced parameters, using the transfer formula and Hermite–Hadamard’s inequality, a more accurate half-discrete multidimensional Hilbert-type inequality with the homogeneous kernel as 1(x+||k−ξ||α)λ(x,λ>0) involving one multiple upper limit function is given, which is a new application of Hilbert-type inequalities. The equivalent conditions of the best possible constant factor related to several parameters are considered. The equivalent forms the operator expressions and some particular inequalities are obtained.

Abstract By the use of the weight coefficients, the idea of introduced parameters and the technique of real analysis, a more accurate Hilbert-type inequality in the whole plane with the general homogeneous kernel is given, which is an extension of the more accurate Hardy–Hilbert’s inequality. An equivalent form is obtained. The equivalent statements of the best possible constant factor related to several parameters, the operator expressions and a few particular cases are considered.

Abstract By applying the weight functions, the idea of introducing parameters and the technique of real analysis, a new multiple Hilbert-type integral inequality involving the upper limit functions is given. The constant factor related to the gamma function is proved to be the best possible in a condition. A corollary about the case of the nonhomogeneous kernel and some particular inequalities are obtained.

Abstract In this article, by using weight functions, the idea of introducing parameters, the reverse extended Hardy–Hilbert integral inequality and the techniques of real analysis, a reverse Hardy–Hilbert-type integral inequality involving one derivative function and the beta function is obtained. The equivalent statements of the best possible constant factor related to several parameters are considered. The equivalent form, the cases of non-homogeneous kernel and some particular inequalities are also presented.

Background: Moxibustion is a traditional Chinese medicine therapy to cure diseases by fumigating meridians or affected parts via burning of moxa floss. Moxa smoke (MS) is one of the key factors in moxibustion. In this study, we adopted digital gene expression profiling, a next-generation gene sequencing technology, to investigate the effect of MS, inhalable particulate matter (PM10), on human lung adenocarcinoma A549 cells. Methods: The effects of MS PM10 on A549 cells, over different treatment durations were investigated in different groups: the 4-h group (4-h MS group and 4-h control group) and the 20-h group (20-h MS group and 20-h control group). Samples collected from the four groups were stored at −80 °C for subsequent digital gene expression analysis. The differentially expressed genes (DEGs), identified after PM10 treatment, were screened, and their expression patterns analyzed by cluster analysis, Gene Ontology term enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results: Compared with two control groups, 1109 DEGs were identified after 4 h of MS intervention and 3565 DEGs were found after 20 h of MS intervention, respectively. Compared with that after 4-h intervention, 2149 DEGs were identified after 20-h intervention. Cluster analysis demonstrated that PM10 can significantly inhibit cell cycle process with the prolongation of intervention time. Significant pathway enrichment analysis showed that MS PM10 can inhibit A549 cell cycle process at all phases. When MS PM10 exposure time prolongs, the inhibitory effect on cell cycle process becomes more obvious. Conclusion: MS PM10 has many biological activities, and may cause differential expression of genes involved in various biological processes. Nevertheless, further research on MS is warranted for better understanding of the mechanistic details.