Protein features fusion using attributed network embedding for predicting protein-protein interaction.

BACKGROUND: Protein-protein interactions (PPIs) hold significant importance in biology, with precise PPI prediction as a pivotal factor in comprehending cellular processes and facilitating drug design. However, experimental determination of PPIs is laborious, time-consuming, and often constrained by technical limitations. METHODS: We introduce a new node representation method based on initial information fusion, called FFANE, which amalgamates PPI networks and protein sequence data to enhance the precision of PPIs' prediction. A Gaussian kernel similarity matrix is initially established by leveraging protein structural resemblances. Concurrently, protein sequence similarities are gauged using the Levenshtein distance, enabling the capture of diverse protein attributes. Subsequently, to construct an initial information matrix, these two feature matrices are merged by employing weighted fusion to achieve an organic amalgamation of structural and sequence details. To gain a more profound understanding of the amalgamated features, a Stacked Autoencoder (SAE) is employed for encoding learning, thereby yielding more representative feature representations. Ultimately, classification models are trained to predict PPIs by using the well-learned fusion feature. RESULTS: When employing 5-fold cross-validation experiments on SVM, our proposed method achieved average accuracies of 94.28%, 97.69%, and 84.05% in terms of Saccharomyces cerevisiae, Homo sapiens, and Helicobacter pylori datasets, respectively. CONCLUSION: Experimental findings across various authentic datasets validate the efficacy and superiority of this fusion feature representation approach, underscoring its potential value in bioinformatics.

Neurovascular anatomy of the developing human fetal penis and clitoris.

The human penile and clitoral development begins from a morphologically indifferent genital tubercle. Under the influence of androgen, the genital tubercle forms the penis by forming a tubular urethra within the penile shaft. Without the effect of the androgen, the genital tubercle differentiates into the clitoris, and a lack of formation of the urethra within the clitoris is observed. Even though there are similarities during the development of the glans penis and glans clitoris, the complex canalization occurring along the penile shaft eventually leads to a morphological difference between the penis and clitoris. Based on the morphological differences, the main goal of this study was to define the vascular and neuronal anatomy of the developing penis and clitoris between 8 and 12 weeks of gestation using laser scanning confocal microscopy. Our results demonstrated there is a co-expression of CD31, which is an endothelial cell marker, and PGP9.5, which is a neuronal marker in the penis where the fusion is actively occurring at the ventral shaft. We also identified a unique anatomical structure for the first time, the clitoral ridge, which is a fetal structure running along the clitoral shaft in the vestibular groove. Contrary to previous anatomical findings which indicate that the neurovascular distribution in the developing penis and clitoris is similar, in this study, laser scanning confocal microscopy enabled us to demonstrate finer differences in the neurovascular anatomy between the penis and clitoris.

Screening Key Sites of Class 2 Integron Integrase that Impact Recombination Efficiency.

By capturing and expressing exogenous resistance gene cassettes through site-specific recombination, integrons play important roles in the horizontal transfer of antimicrobial resistant genes among bacteria. The characteristics of integron integrase make it to be a potential gene editing tool enzyme. In this study, a random mutation library using error-prone PCR was constructed, and amino acid residues mutants that impact on attI2 × attC or attC × attC recombination efficiency were screened and analyzed. Thirteen amino acid mutations were identified to be critical impacted on site-specific recombination of IntI2, including the predicted catalyzed site Y301. Nine of 13 mutated amino acid residues that have critically impacted on IntI2 activity were relative concentrated and near the predicted catalyzed site Y301 in the predicted three-dimensional structure indicated the importance of this area in maintain the activity of IntI2. No mutant with obviously increased recombination activity (more than four-fold as high as that of wild IntI2) was found in library screening, except P95S, R100K slightly increased (within two-fold) the excision activity of IntI2, and S243T slightly increased (within two-fold) both excision and integration activity of IntI2. These findings will provide clues for further specific modification of integron integrase to be a tool enzyme as well as establishing a new gene editing system and applied practically.

Role of mesonephric contribution to mouse testicular development revisited.

The role of the mesonephros in testicular development was re-evaluated by growing embryonic day 11.5 (E11.5) mouse testes devoid of mesonephros for 8-21 days in vivo under the renal capsule of castrated male athymic nude mice. This method provides improved growth conditions relative to previous studies based upon short-term (4-7 days) organ culture. Meticulous controls involved wholemount examination of dissected E11.5 mouse testes as well as serial sections of dissected E11.5 mouse testes which were indeed shown to be devoid of mesonephros. As expected, grafts of E11.5 mouse testes with mesonephros attached formed seminiferous tubules and also contained mesonephric derivatives. Grafts of E11.5 mouse testes without associated mesonephros also formed seminiferous tubules and never contained mesonephric derivatives. The consistent absence of mesonephric derivatives in grafts of E11.5 mouse testes grafted alone is further proof of the complete removal of the mesonephros from the E11.5 mouse testes. The testicular tissues that developed in grafts of E11.5 mouse testes alone contained canalized seminiferous tubules composed of Sox9-positive Sertoli cells as well as GENA-positive germ cells. The seminiferous tubules were surrounded by α-actin-positive myoid cells, and the interstitial space contained 3ßHSD-1-positive Leydig cells. Grafts of E11.5 GFP mouse testes into wild-type hosts developed GFP-positive vasculature indicating that E11.5 mouse testes contain vascular precursors. These results indicate that the E11.5 mouse testis contains precursor cells for Sertoli cells, Leydig cells, myoid cells and vasculature whose development and differentiation are independent of cells migrating from the E11.5 mesonephros.

Ontogeny of mouse Sertoli, Leydig and peritubular myoid cells from embryonic day 10 to adulthood.

We present a comprehensive description of the differentiating somatic cell types (Sertoli, Leydig, and peritubular myoid cells) of the mouse testis from embryonic day 10.5 (E10.5) to adulthood, postnatal day 60 (P60). Immunohistochemistry was used to analyze expression of: Sox9 (a Sertoli cell marker), 3ßHSD-1 (a fetal Leydig cell marker), 3ßHSD-6 (an adult Leydig cell marker), α-actin (a peritubular myoid cell marker), and androgen receptor (a marker of all three somatic cell types). The temporal-spatial expression of these markers was used to interrogate findings of earlier experimental studies on the origin of Sertoli, Leydig and peritubular myoid cells, as well as extend previous descriptive studies across a broader developmental period (E10.5-P60). Such comparisons demonstrate inconsistencies that require further examination and raise questions regarding conservation of developmental mechanisms across higher vertebrate species.

A model to study human ovotesticular syndrome.

Ovotesticular syndrome is a rare disorder of sex development characterized by the presence of testicular and ovarian tissue. The histologic characteristics of human testicular tissue are well defined by the presence of seminiferous cords or tubules containing TSPY-positive germ cells and Sox9-positive Sertoli cells surrounded by interstitial tissue containing cytochrome P450-positive Leydig cells and smooth muscle α-actin-positive peritubular myoid cells. The histological characteristics of the ovary can be defined by germ cell nests and the development of follicles. In contrast to the testis, the ovary has a paucity of defined specific protein markers, with the granulosa cell marker FOXL2 being the most widely used. In practice, defining the ovarian component of the ovotestis can be quite difficult. We developed a model of human ovotesticular syndrome by combining fetal human testis and ovary in a xenograft model. Ovotesticular xenografts were grown under the renal capsules of gonadectomized athymic nude mice for 6-32 weeks along with age matched control grafts of fetal testis and ovary. Forty ovotesticular xenografts and their controls were analyzed by histology, immunohistochemistry, and fluorescent in situ hybridization to determine the protein expression and karyotype of the cells within the grafts. The ovotesticular xenografts exhibited recognizable testicular and ovarian tissue based on testis-specific and ovary-specific markers defined above. The xenografts simulated a bipolar ovotestis in which the testicular and ovarian elements retain their separate histological characteristics and are separated by a well-defined border. This contrasts with the compartmentalized ovotestis previously described in the literature where the testicular tissue is surrounded by ovarian tissue or a mixed histology where testicular and ovarian tissues are interspersed throughout the gonad. In conclusion, we have characterized a human model of ovotestis which will allow a deeper understanding of ovotestis development in humans and facilitate a more accurate diagnosis of the ovotesticular syndrome.

Mouse-human species differences in early testicular development and its implications.

The mouse has been used as a model of human organogenesis with the tacit assumption that morphogenetic and molecular mechanisms in mice are translatable to human organogenesis. While many morphogenetic and molecular mechanisms are shared in mice and humans, many anatomic, morphogenetic, and molecular differences have been noted. Two critical gaps in our knowledge prevent meaningful comparisons of mouse versus human testicular development: (a) human testicular development is profoundly under-represented in the literature, and (b) an absence of a detailed day-by-day ontogeny of mouse testicular development from E11.5 to E16.5 encompassing the ambisexual stage to seminiferous cord formation. To address these deficiencies, histologic and immunohistochemical studies were pursued in comparable stages of mouse and human testicular development with a particular emphasis on Leydig, Sertoli and myoid cells through review of the literature and new observations. For example, an androgen-receptor-positive testicular medulla is present in the developing human testis but not in the developing mouse testis. The human testicular medulla and associated mesonephros were historically described as the source of Sertoli cells in seminiferous cords. Consistent with this idea, the profoundly androgen receptor (AR)-positive human testicular medulla was shown to be a zone of mesenchymal to epithelial transition and a zone from which AR-positive cells appear to migrate into the human testicular cortex. While mouse Sertoli and Leydig cells have been proposed to arise from coelomic epithelium, Sertoli (SOX9) or Leydig (HSD3B1) cell markers are absent from the immediate coelomic zone of the developing human testis, perhaps because Leydig and Sertoli cell precursors are undifferentiated when they egress from the coelomic epithelium. The origin of mouse and human myoid cells remains unclear. This study provides a detailed comparison of the early stages of testicular development in human and mouse emphasizing differences in developmental processes.

Androgenic induction of penile features in postnatal female mouse external genitalia from birth to adulthood: Is the female sexual phenotype ever irreversibly determined?

Female mice were treated for 35 days from birth to 60 days postnatal (P0, [birth], P5, P10, P20 and adult [∼P60]) with dihydrotestosterone (DHT). Such treatment elicited profound masculinization the female external genitalia and development of penile features (penile spines, male urogenital mating protuberance (MUMP) cartilage, corpus cavernosum glandis, corporal body, MUMP-corpora cavernosa, a large preputial space, internal preputial space, os penis). Time course studies demonstrated that DHT elicited canalization of the U-shaped clitoral lamina to create a U-shaped preputial space, preputial lining epithelium and penile epithelium adorned with spines. The effect of DHT was likely due to signaling through androgen receptors normally present postnatally in the clitoral lamina and associated mesenchyme. This study highlights a remarkable male/female difference in specification and determination of urogenital organ identity. Urogenital organ identity in male mice is irreversibly specified and determined prenatally (prostate, penis, and seminal vesicle), whereas many aspects of the female urogenital organogenesis are not irreversibly determined at birth and in the case of external genitalia are not irreversibly determined even into adulthood, the exception being positioning of the female urethra, which is determined prenatally.

Development of the human fetal testis: Morphology and expression of cellular differentiation markers.

A comprehensive immunohistochemical ontogeny of the developing human fetal testis has remained incomplete in the literature to date. We collected human fetal testes from 8 to 21 weeks of fetal age, as well as postnatal human testes at minipuberty, pre-pubertal, and pubertal stages. Immunohistochemistry was performed with a comprehensive panel of antigens targeting gonadocytes, Sertoli cells, fetal Leydig cells, peritubular myoid cells, and other hormonal and developmental targets. Testicular cords, precursor structures to seminiferous tubules, developed from 8 to 14 weeks of fetal age, separating the testis into the interstitial and intracordal compartments. Fetal gonadocytes were localized within the testicular cords and evaluated for Testis-Specific Protein Y, Octamer-binding transcription factor 4, Sal-like protein 4, and placental alkaline phosphatase expression. Fetal Sertoli cells were also localized in the testicular cords and evaluated for SRY-box Transcription Factor 9, inhibin, and anti-Mullerian hormone expression. Fetal Leydig cells were present in the interstitium and stained for cytochrome p450c17 and calretinin, while interstitial peritubular myoid cells were examined using smooth muscle α-actin staining. Androgen receptor expression was localized close to the testicular medulla at 8 weeks and then around the testicular cords in the interstitium as they matured in structure. Postnatal staining showed that Testis-Specific Protein Y remained positive of male gonadocytes throughout adulthood. Anti-Mullerian hormone, SRY-box Transcription Factor 9, and Steroidogenic factor 1 are expressed by the postnatal Sertoli cells at all ages examined. Leydig cell markers cytochrome p450c17 and calretinin are expressed during mini-puberty and puberty, but not expressed during the pre-pubertal period. Smooth muscle α-actin and androgen receptor were not expressed during mini-puberty or pre-puberty, but again expressed during the pubertal period. The ontogenic map of the human fetal and postnatal testicular structure and expression patterns described here will serve as a reference for future investigations into normal and abnormal testicular development.

Development of the human ovary: Fetal through pubertal ovarian morphology, folliculogenesis and expression of cellular differentiation markers.

A definition of normal human fetal and early postnatal ovarian development is critical to the ability to accurately diagnose the presence or absence of functional ovarian tissue in clinical specimens. Through assembling an extensive histologic and immunohistochemical developmental ontogeny of human ovarian specimens from 8 weeks of gestation through 16 years of postnatal, we present a comprehensive immunohistochemical mapping of normal protein expression patterns in the early fetal through post-pubertal human ovary and detail a specific expression-based definition of the early stages of follicular development. Normal fetal and postnatal ovarian tissue is defined by the presence of follicular structures and characteristic immunohistochemical staining patterns, including granulosa cells expressing Forkhead Box Protein L2 (FOXL2). However, the current standard array of immunohistochemical markers poorly defines ovarian stromal tissue, and additional work is needed to identify new markers to advance our ability to accurately identify ovarian stromal components in gonadal specimens from patients with disorders of sexual differentiation.

GKLOMLI: a link prediction model for inferring miRNA-lncRNA interactions by using Gaussian kernel-based method on network profile and linear optimization algorithm.

BACKGROUND: The limited knowledge of miRNA-lncRNA interactions is considered as an obstruction of revealing the regulatory mechanism. Accumulating evidence on Human diseases indicates that the modulation of gene expression has a great relationship with the interactions between miRNAs and lncRNAs. However, such interaction validation via crosslinking-immunoprecipitation and high-throughput sequencing (CLIP-seq) experiments that inevitably costs too much money and time but with unsatisfactory results. Therefore, more and more computational prediction tools have been developed to offer many reliable candidates for a better design of further bio-experiments. METHODS: In this work, we proposed a novel link prediction model based on Gaussian kernel-based method and linear optimization algorithm for inferring miRNA-lncRNA interactions (GKLOMLI). Given an observed miRNA-lncRNA interaction network, the Gaussian kernel-based method was employed to output two similarity matrixes of miRNAs and lncRNAs. Based on the integrated matrix combined with similarity matrixes and the observed interaction network, a linear optimization-based link prediction model was trained for inferring miRNA-lncRNA interactions. RESULTS: To evaluate the performance of our proposed method, k-fold cross-validation (CV) and leave-one-out CV were implemented, in which each CV experiment was carried out 100 times on a training set generated randomly. The high area under the curves (AUCs) at 0.8623 ± 0.0027 (2-fold CV), 0.9053 ± 0.0017 (5-fold CV), 0.9151 ± 0.0013 (10-fold CV), and 0.9236 (LOO-CV), illustrated the precision and reliability of our proposed method. CONCLUSION: GKLOMLI with high performance is anticipated to be used to reveal underlying interactions between miRNA and their target lncRNAs, and deciphers the potential mechanisms of the complex diseases.

Lacticaseibacillus casei T1 attenuates Helicobacter pylori-induced inflammation and gut microbiota disorders in mice.

Probiotics are defined as live microbial food elements that are beneficial to human health. Lacticaseibacillus casei T1 was considered to have potential as a bioactive ingredient in functional foods, which was isolated from kurut. Previous research by our group proved that L. casei T1 could prevent inflammatory responses caused by Helicobacter pylori. This study aimed to investigate whether treatment with L. casei T1 resulted in a suppressive effect on H. pylori-induced oxidative stress and inflammatory responses. The results showed that treatment with L. casei T1 could relieve H. pylori-induced overexpression of inflammatory cytokines in GES-1 cells. Experiments in animals suggested that taking long-term L. casei T1 could reduce oxidative stress and inflammatory cytokines and improve H. pylori-induced gastric mucosal damage. Furthermore, taking L. casei T1 could increase the relative abundance of beneficial intestinal bacterium (Lachnospiraceae and Odoribacter) of H. pylori-infected mice and help in maintaining the balance of intestinal microflora.Collectively, L. casei T1 had certain degrees of therapeutic effect against H. pylori. In the future, it combined with antibiotics for H. pylori eradication deserves further study.

Molecular characterization of class 1 integrons in carbapenem-resistant Enterobacterales isolates.

OBJECTIVE: Carbapenem-resistant Enterobacterales (CRE) infections result in higher treatment costs and mortality rates. Integrons play important roles in emergence and spread of antibiotic resistant genes. To get a better understand on the effects of integron on CRE resistance, distribution of common carbapenemase genes and class 1 integron in clinical CRE isolates were investigated. METHOD: Carbapenemase genes, including blaKPC, blaVIM, blaIMP, blaNDM, blaGES, blaVEB and blaOXA-23, were screened in 161 CRE isolates and subtypes of these genes were confirmed through sequence analysis. Class 1 integron was screened and common promoter and gene cassette arrays were determined by sequencing. The resistant rates to clinical commonly used antibiotics between integron positive and integron negative CRE isolates were compared. RESULTS: Of 161 CRE isolates, the most prevalent carbapenemase gene was blaKPC-2, which was detected in 139 isolates, including 99 Klebsiella pneumoniae. Class 1 integron was detected in 78 isolates. Twenty different gene cassettes, including two carbapenemase genes blaVEB-1 and blaIMP-4, and nine different gene cassette arrays, including blaVEB-1-aadB-arr-2-cmlA5-blaOXA-10-aadA1, aadB-catB8-blaOXA-10-aadA1-dfrA1-aacA4 and blaIMP-4-qacG-aacA4-catB3, were detected. Five types of common promoters were identified. Relative weak promoter PcH1 was the dominant type. Resistant rates of CRE isolates containing class 1 integrons to ceftazidime, amikacin, trimethoprim/sulfamethoxazole and gentamicin were higher than those without class 1 integrons (P < 0.05). CONCLUSION: Class 1 integrons play important roles in the emergence and spread of CRE resistance. To the best of our knowledge, this is the first report of aadB-catB8-blaOXA-10-aadA1-dfrA1-aacA4 and blaIMP-4-qacG-aacA4-catB3 in the same Providencia rettgeri isolate and blaVEB-1-aadB-arr-2-cmlA5-blaOXA-10-aadA1 in P. rettgeri.

SIRT4 in ageing.

Ageing is a phenomenon in which cells, tissues and organs undergo systemic pathological changes as individuals age, leading to the occurrence of ageing-related diseases and the end of life. It is associated with many phenotypes known as ageing characteristics, such as genomic instability, nutritional imbalance, mitochondrial dysfunction, cell senescence, stem cell depletion, and an altered microenvironment. The sirtuin family (SIRT), known as longevity proteins, is thought to delay ageing and prolong life, and mammals, including humans, have seven family members (SIRT1-7). SIRT4 has been studied less among the sirtuin family thus far, but it has been reported that it has important physiological functions in organisms, such as promoting DNA damage repair, participating in the energy metabolism of three substances, inhibiting inflammatory reactions and apoptosis, and regulating mitochondrial function. Recently, some studies have demonstrated the involvement of SIRT4 in age-related processes, but knowledge in this field is still scarce. Therefore, this review aims to analyse the relationship between SIRT4 and ageing characteristics as well as some age-related diseases (e.g., cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer).

Urolithin B alleviates Helicobacter pylori-induced inflammation and oxidative stress in mice.

BACKGROUND: Helicobacter pylori is one of the most common chronic bacterial infections. Active eradication of H. pylori infection is rare due to the fact that most infected patients are asymptomatic and the use of large amounts of antibiotics in eradication therapy leads to severe side effects. Urolithin B (UB) is an additional major intestinal metabolite of ellagic acid (EA), which has been shown to possess anti-inflammatory, antioxidant, and antiapoptotic biological activities. Preventing the incidence of H. pylori-related gastric disease and reducing the damage to the host by H. pylori is a current approach to control H. pylori infection. In this study, we explored the effect of UB on H. pylori infection. MATERIALS AND METHODS: The effects of UB on inflammation and oxidative stress induced by H. pylori in vivo and in vitro were investigated by qPCR, ELISA, HE staining, IHC staining, etc. RESULTS: UB reduced the adhesion and colonization of H. pylori and improved H. pylori-induced inflammation and oxidative stress in vivo and in vitro. Moreover, UB had better anti-inflammatory and antioxidant effects than clarithromycin (CLR) and metronidazole (MET). In addition to inhibiting the secretion of CagA, UB reduced tissue damage by H. pylori infection. CONCLUSIONS: UB was effective in improving damage caused by H. pylori.

Characterization of the complete mitochondrial genomes of five hard ticks and phylogenetic implications.

Ticks are blood-sucking ectoparasites with significant medical and veterinary importance, capable of transmitting bacteria, protozoa, fungi, and viruses that cause a variety of human and animal diseases worldwide. In the present study, we sequenced the complete mitochondrial (mt) genomes of five hard tick species and analyzed features of their gene contents and genome organizations. The complete mt genomes of Haemaphysalis verticalis, H. flava, H. longicornis, Rhipicephalus sanguineus and Hyalomma asiaticum were 14855 bp, 14689 bp, 14693 bp, 14715 bp and 14722 bp in size, respectively. Their gene contents and arrangements are the same as those of most species of metastriate Ixodida, but distinct from species of genus Ixodes. Phylogenetic analyses using concatenated amino acid sequences of 13 protein-coding genes with two different computational algorithms (Bayesian inference and maximum likelihood) revealed the monophylies of the genera Rhipicephalus, Ixodes and Amblyomma, however, rejected the monophyly of the genus Haemaphysalis. To our knowledge, this is the first report of the complete mt genome of H. verticalis. These datasets provide useful mtDNA markers for further studies of the identification and classification of hard ticks.

New pyrrolo[3,2-b]pyrroles with AIE characteristics for detection of dichloromethane and chloroform.

Three new pyrrolo[3,2-b]pyrrole derivatives containing methoxyphenyl, pyrene or tetraphenylethylene (TPE) units (compounds 1-3) have been designed, synthesized and fully characterized. The aggregation-induced emission (AIE) properties of compounds 1-3 were tested in different water fraction (fw ) of tetrahydrofuran (THF). The pyrrolo[3,2-b]pyrrole derivative 3 containing TPE units exhibited typical AIE features with an enhanced emission (∼32-fold) in the solid state versus in solution; compounds 1 and 2 exhibited an aggregation-caused quenching effect. In addition, the steric and electronic effects of the peripheral moieties on the emission behavior, both in solution and in the solid state, have been investigated. Moreover, pyrrolo[3,2-b]pyrrole 1 exhibits high sensitivity and selectivity for dichloromethane and chloroform solvents, with the system displaying a new emission peak and fast response time under ultraviolet irradiation.

Heterogeneity of transposon expression and activation of the repressive network in human fetal germ cells.

Epigenetic resetting in germ cells during development de-represses transposable elements (TEs). piRNAs protect fetal germ cells by targeted mRNA destruction and deposition of repressive epigenetic marks. Here, we provide the first evidence for an active piRNA pathway and TE repression in germ cells of human fetal testis. We identify pre-pachytene piRNAs with features of secondary amplification that map most abundantly to the long interspersed element type 1 (L1) family of TEs. L1-ORF1p expression is heterogeneous in fetal germ cells, peaks at mid-gestation and declines concomitantly with increases in piRNAs, nuclear localization of HIWI2 and an increase in H3K9me3. Surprisingly, the same cells with accumulation of L1-ORF1p display highest levels of HIWI2 and H3K9me3. Conversely, the earliest germ cells with high levels of L1-ORF1p express low levels of the chaperone HSP90α. We propose that a subset of germ cells resists L1 expression, whereas L1-expressing germ cells activate the repression pathway that leads to epigenetic silencing of L1 via H3K9me3.

The cerebrospinal fluid neutrophil to lymphocyte ratio is a sensitive biomarker for bacterial meningitis in children.

BACKGROUND: The cerebrospinal fluid neutrophil-to-lymphocyte ratio (CSF NLR) as a diagnostic biomarker of bacterial meningitis has been reported in adult trials. The aim of this study was to evaluate the CSF NLR as a diagnostic biomarker of bacterial meningitis in children and to define an optimal CSF NLR concentration. METHODS: We performed a retrospective cohort study of children with clinical findings compatible with meningitis. CSF NLR was calculated as the ratio of neutrophil count to lymphocyte count in cerebrospinal fluid (CSF). Initial data included clinical, radiological, and laboratory diagnostics. RESULTS: We determined CSF parameters from children with infectious meningitis (n = 348) and subdivided them into bacterial meningitis (n = 112) and viral meningitis (n = 236). CSF NLR was significantly higher in bacterial meningitis than in viral meningitis (P < 0.001), and its level was higher in Gram-negative bacterial infections than in Gram-positive bacterial infections (P = 0.01). In the receiver operating characteristic curve analysis, CSF NLR was better than CSF protein/sugar/WBC in the ability to distinguish bacterial meningitis from viral meningitis (AUC 0.91 ± 0.02 versus 0.88 ± 0.03/0.87 ± 0.03/0.86 ± 0.03), and using a cutoff point of 0.68, the sensitivity was 0.90, and the specificity was 0.75. Compared with Gram-positive infection, CSF NLR with Gram-negative infection was higher (media, IQR (1.18 (0.19-2.33) versus 3.90 (1.50-8.91), P = 0.01). CONCLUSION: CSF NLR is a more useful diagnostic tool to distinguish between bacterial meningitis and viral meningitis in children. While at a cutoff value of 0.68, CSF NLR has better sensitivity and specificity for bacterial meningitis, and the higher level of CSF NLR could be related to Gram-negative bacterial infection.

Estrogens and development of the mouse and human external genitalia.

The Jost hypothesis states that androgens are necessary for normal development of the male external genitalia. In this review, we explore the complementary hypothesis that estrogens can elicit abnormal development of male external genitalia. Herein, we review available data in both humans and mice on the deleterious effects of estrogen on external genitalia development, especially during the "window of susceptibility" to exogenous estrogens. The male and female developing external genitalia in both the human and mouse express ESR1 and ESR2, along with the androgen receptor (AR). Human clinical data suggests that exogenous estrogens can adversely affect normal penile and urethral development, resulting in hypospadias. Experimental mouse data also strongly supports the idea that exogenous estrogens cause penile and urethral defects. Despite key differences, estrogen-induced hypospadias in the mouse displays certain morphogenetic homologies to human hypospadias, including disruption of urethral fusion and preputial abnormalities. Timing of estrogenic exposure, or the "window of susceptibility," is an important consideration when examining malformations of the external genitalia in both humans and mice. In addition to a review of normal human and mouse external genital development, this article aims to review the present data on the role of estrogens in normal and abnormal development of the mouse and human internal and external genitalia. Based on the current literature for both species, we conclude that estrogen-dependent processes may play a role in abnormal genital development.