Bmal1 regulates female reproduction in mice via the hypothalamic-pituitary-ovarian axis.

The hypothalamic-pituitary-gonadal axis (HPG) is the key neuroendocrine axis involved in reproductive regulation. Brain and muscle ARNT-like protein 1 (Bmal1) participates in regulating the metabolism of various endocrine hormones. However, the regulation of Bmal1 on HPG and female fertility is unclear. This study aims to explore the regulation of female reproduction by Bmal1 via the HPG axis in mice. Bmal1-knockout (Ko) mice were generated using the CRISPR/Cas9 technology. The structure, function, and estrous cycle of ovarian in Bmal1 Ko female mice were measured. The key genes and proteins of the HPG axis involved in regulating female reproduction were examined through transcriptome analysis and then verified by RT-PCR, immunohistochemistry, and western blot. Furthermore, the fertility of female mice was detected after intervening prolactin (PRL) and progesterone (Pg) in Bmal1 ko mice. The number of offspring and ovarian weight were significantly lower in Bmal1-Ko mice than in wild-type (Wt) mice. In Bmal1-Ko mice, ovarian cells were arranged loosely and irregularly, and the total number of follicles was significantly reduced. No corpus luteum was found in the ovaries. Vaginal smears revealed that Bmal1-Ko mice had an irregular estrus cycle. In Bmal1-Ko mice, Star expression was decreased, PRL and luteinizing hormone (LH) levels were increased, and dopamine (DA) and Pg levels were decreased. Inhibition of PRL partially recovered the estrous cycle, corpus luteum formation, and Star expression in the ovaries. Pg supplementation promoted embryo implantation in Bmal1-Ko female mice. Bmal1 Ko increases serum PRL levels in female mice likely by reducing DA levels, thus affecting luteal formation, resulting in decreased Star expression and Pg production, hindering female reproduction. Inhibition of PRL or restoration of Pg can partially restore reproductive capacity in female Bmal1-Ko mice. Thus, Bmal1 may regulate female reproduction via the HPG axis in mice, suggesting that Bmal1 is a potential target to treat female infertility.

A metagenomic catalog of the early-life human gut virome.

Early-life human gut microbiome is a pivotal driver of gut homeostasis and infant health. However, the viral component (known as "virome") remains mostly unexplored. Here, we establish the Early-Life Gut Virome (ELGV), a catalog of 160,478 non-redundant DNA and RNA viral sequences from 8130 gut virus-like particles (VLPs) enriched or bulk metagenomes in the first three years of life. By clustering, 82,141 viral species are identified, 68.3% of which are absent in existing databases built mainly from adults, and 64 and 8 viral species based on VLPs-enriched and bulk metagenomes, respectively, exhibit potentials as biomarkers to distinguish infants from adults. With the largest longitudinal population of infants profiled by either VLPs-enriched or bulk metagenomic sequencing, we track the inherent instability and temporal development of the early-life human gut virome, and identify differential viruses associated with multiple clinical factors. The mother-infant shared virome and interactions between gut virome and bacteriome early in life are further expanded. Together, the ELGV catalog provides the most comprehensive and complete metagenomic blueprint of the early-life human gut virome, facilitating the discovery of pediatric disease-virome associations in future.

Influence of age, socioeconomic status, and location on the infant gut resistome across populations.

Antibiotic resistance is a growing global concern, with many ecological niches showing a high abundance of antibiotic resistance genes (ARGs), including the human gut. With increasing indications of ARGs in infants, this study aims to investigate the gut resistome profile during early life at a wider geographic level. To achieve this objective, we utilized stool samples data from 26 studies involving subjects aged up to 3 years from different geographical locations. The 32,277 Metagenome Assembled Genomes (MAGs) previously generated from shotgun sequencing reads from these studies were used for resistome analysis using RGI with the CARD database. This analysis showed that the distribution of ARGs across the countries in our study differed in alpha diversity and compositionally. In particular, the abundance of ARGs was found to vary by socioeconomic status and healthcare access and quality (HAQ) index. Surprisingly, countries having lower socioeconomic status and HAQ indices showed lower ARG abundance, which was contradictory to previous reports. Gram-negative genera, including Escherichia, Enterobacter, Citrobacter, and Klebsiella harbored a particularly rich set of ARGs, which included antibiotics that belong to the Reserve, Access or Watch category, such as glycopeptides, fluoroquinolones, sulfonamides, macrolides, and tetracyclines. We showed that ARG abundance exponentially decreased with time during the first 3 years of life. Many highly ARG-abundant species including Escherichia, Klebsiella, Citrobacter species that we observed are well-known pathobionts found in the infant gut in early life. High abundance of these species and a diverse range of ARGs in their genomes point toward the infant gut, acting as an ARG reservoir. This is a concern and further studies are needed to examine the causal effect and its consequences on long-term health.

Neurodevelopmental outcomes in preterm or low birth weight infants with germinal matrix-intraventricular hemorrhage: a meta-analysis.

BACKGROUND: This meta-analysis aimed to identify the near- and long-term neurodevelopmental prognoses of preterm or low birth weight (LBW) infants with different severities of intraventricular hemorrhage (IVH). METHODS: Four databases were searched for observational studies that were qualified using the Newcastle-Ottawa Scale. RESULTS: 37 studies involving 32,370 children were included. Compared to children without IVH, children with mild IVH had higher incidences of neurodevelopmental impairment (NDI), cerebral palsy (CP), motor/cognitive delay, hearing impairment and visual impairment, as well as lower scores of the mental development index (MDI) and psychomotor development (PDI). Moreover, compared to mild IVH, severe IVH increased susceptibilities of children to NDI, motor delay, CP, hearing impairment and visual impairment, with worse performances in MDI, PDI, motor score and IQ. Mild IVH was not associated with seizures or epilepsy. CONCLUSIONS: Adverse neurodevelopmental outcomes positively associated with the occurrence and severity of IVH in preterm or LBW infants, providing evidence for counseling and further decisions regarding early therapeutic interventions. IMPACT: Adverse neurodevelopmental outcomes later in life were closely associated with the occurrence and severity of IVH in preterm or LBW infants. Our results highlight the importance to make prediction of the neurodevelopmental outcomes of children born preterm or LBW with a history of IVH, which will guide affected parents when their children need clinical interventions to reach the full potential. We emphasize the importance of identifying specific developmental delays that may exist in children with IVH, providing detailed information for the development of comprehensive intervention measures.

Generalized heterophily graph data augmentation for node classification.

Graph data augmentations have demonstrated remarkable performance on homophilic graph neural networks (GNNs). Nevertheless, when transferred to a heterophilic graph, these augmentations are less effective for GNN models and lead to reduced performance. To address this issue, we propose a unified augmentation approach called GePHo, a regularization technique for heterophilic graph neural networks based on self-supervised learning, leveraging graph data augmentation to acquire extra information to guide model learning. Specifically, we propose to generate a pseudo-homophily graph that is type-agnostic, enabling us to apply GePHo to both homophilic and heterophilic graphs. Then, we regularize the neighbors with a sharpening technique for data augmentation and generate the auxiliary pseudo-labels to classify the original GNN's output, whose operations are to constrain the local and global node representation, respectively. Extensive experiments on three homophilic graph and six heterophilic graph datasets demonstrate the competitive effectiveness of GePHo in node classification task, and the ablation experiments verify the efficacy of our GePHo in graph data augmentation.

The RNA m6A modification might participate in microglial activation during hypoxic-ischemic brain damage in neonatal mice.

BACKGROUND: The RNA m6A modification has been implicated in multiple neurological diseases as well as macrophage activation. However, whether it regulates microglial activation during hypoxic-ischemic brain damage (HIBD) in neonates remains unknown. Here, we aim to examine whether the m6A modification is involved in modulating microglial activation during HIBD. We employed an oxygen and glucose deprivation microglial model for in vitro studies and a neonatal mouse model of HIBD. The brain tissue was subjected to RNA-seq to screen for significant changes in the mRNA m6A regulator. Thereafter, we performed validation and bioinformatics analysis of the major m6A regulators. RESULTS: RNA-seq analysis revealed that, among 141 m6A regulators, 31 exhibited significant differential expression (FC (abs) ≥ 2) in HIBD mice. We then subjected the major m6A regulators Mettl3, Mettl14, Fto, Alkbh5, Ythdf1, and Ythdf2 to further validation, and the results showed that all were significantly downregulated in vitro and in vivo. GO analysis reveals that regulators are mainly involved in the regulation of cellular and metabolic processes. The KEGG results indicate the involvement of the signal transduction pathway. CONCLUSIONS: Our findings demonstrate that m6A modification of mRNA plays a crucial role in the regulation of microglial activation in HIBD, with m6A-associated regulators acting as key modulators of microglial activation.

[Association Between Different Modes of Respiratory Support and Feeding Intolerance in Preterm Infants: A Retrospective Cohort Study]. / æ—©äº§å„¿å‘¼å¸æ”¯æŒæ¨¡å¼ä¸Žå–‚å »ä¸è€å—çš„å ³ç³»ï¼šä¸€é¡¹å›žé¡¾æ€§é˜Ÿåˆ—ç ”ç©¶.

Objective: To explore the relationship between different modes of respiratory support and feeding intolerance (FI) in preterm infants over the course of their hospitalization and to provide recommendations for the management of enteral feeding in preterm infants requiring respiratory support. Methods: A retrospective analysis was performed with the preterm infants admitted to the Neonatal Intensive Care Unit (NICU), West China Second University Hospital, Sichuan University between June 2015 and November 2018. The modes of respiratory support were used as independent variables and FI was used as the outcome indicator. The preterm infants were grouped according to the specific modes of respiratory support they were on over the course of their hospitalization and the relationship between each mode of respiratory support and FI was compared. Results: A total of 272 preterm infants were enrolled in the study. After adjusting for confounding factors, findings from logistics regression suggested that, compared with normobaric oxygen, high flow nasal cannula (HFNC) might reduce the incidence of FI (odds ratio [OR]=0.53, 95% confidence interval [CI]: 0.06-4.77), while other modes of respiratory support might increase the incidence of FI. Compared with nasal continuous positive airway pressure (NCPAP), bilevel positive airway pressure (BIPAP) and invasive ventilation might increase the incidence of FI, with the adjusted OR being 1.31 and 1.69, and 95% CI being 0.67-2.55 and 0.65-4.41, respectively. The incidence of FI in BIPAP and invasive ventilation was similar (adjusted OR=1.00, 95% CI: 0.41-2.42). However, the P-values of the above results were all greater than 0.05. Conclusion: HFNC has the lowest incidence of FI in the respiratory support modes examined in this study. Attention should be paid to enteral feeding management when using NCPAP, BIPAP, and invasive ventilation to avoid the occurrence of FI. Given the limited sample size, further research is warranted to confirm the conclusion.

Diagnostic performance of adenosine deaminase for abdominal tuberculosis: A systematic review and meta-analysis.

Background and aim: Abdominal tuberculosis (TB) is a common type of extrapulmonary TB with an insidious onset and non-specific symptoms. Adenosine deaminase (ADA) levels increase rapidly in the early stages of abdominal TB. However, it remains unclear whether ADA serves as a diagnostic marker for abdominal TB. Methods: We performed a systematic literature search for relevant articles published in PubMed, Web of Science, Cochrane Library, and Embase up to April 2022. First, we used the Quality Assessment of Diagnostic Accuracy Studies tool-2 (QUADAS-2), to evaluate the quality of the included articles. Bivariate and hierarchical summary receiver operating characteristic (HSROC) models were then utilized to analyze pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the receiver operating characteristic curve (AUROC). In addition, we explored a subgroup analysis for potential heterogeneity and publication bias among the included literature. Results: Twenty-four articles (3,044 participants, 3,044 samples) which met the eligibility criteria were included in this study. The pooled sensitivity and specificity of ADA for abdominal TB detection were 93% [95% confidence interval (CI): 0.89-0.95] and 95% (95% CI: 0.93-0.96), respectively. PLR and NLR were 18.6 (95% CI: 14.0-24.6) and 0.08 (95% CI: 0.05-0.12), respectively. DOR and AUROC were 236 (95% CI: 134-415) and 0.98 (95% CI: 0.96-0.99), respectively. Furthermore, no heterogeneity or publication bias was found. Conclusions: Our meta-analysis found ADA to be of excellent diagnostic value for abdominal TB and could be used as an auxiliary diagnostic tool. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022297931.

A compendium of 32,277 metagenome-assembled genomes and over 80 million genes from the early-life human gut microbiome.

Age-specific reference genomes of the human gut microbiome can provide higher resolution for metagenomic analyses including taxonomic classification, strain-level genomic investigation and functional characterization. We present the Early-Life Gut Genomes (ELGG) catalog with 32,277 genomes representing 2172 species from 6122 fecal metagenomes collected from children under 3 years old spanning delivery mode, gestational age, feeding pattern, and geography. The ELGG substantially expanded the phylogenetic diversity by 38% over the isolate microbial genomes, and the genomic landscape of the early-life microbiome by increasing recruitment of metagenomic reads to 82.8%. More than 60% of the ELGG species lack an isolate representative. The conspecific genomes of the most abundant species from children differed in gene diversity and functions compared to adults. The ELGG genomes encode over 80 million protein sequences, forming the Early-Life Gut Proteins (ELGP) catalog with over four million protein clusters, 29.5% of which lacked functional annotations. The ELGG and ELGP references provided new insights into the early-life human gut microbiome and will facilitate studies to understand the development and mechanisms of disturbances of the human gut microbiome in early life.

First 1000 Days and Beyond After Birth: Gut Microbiota and Necrotizing Enterocolitis in Preterm Infants.

Preterm birth remains a major maternal and infant health issue worldwide particularly with an increase in the global preterm birth rate, which requires more interventions to manage the consequences of preterm birth. In addition to traditional complications, recent studies have shown that the succession of gut microbiota of preterm infants is disordered due to the systemic physiological immaturity, which confers negative influences on the growth, development, and health of infants. In the present study, we briefly discussed the prevalence of preterm birth worldwide and then highlighted the signatures of gut microbiota in preterm infants within the first 1000 days of life after the birth categorized into birth, infancy, and childhood. Afterward, we focused on the potential association of clinical phenotypes typically associated with preterm birth (i.e., necrotizing enterocolitis) with gut microbiota, and the potential directions for future studies in this field are finally discussed.

The road not taken: host genetics in shaping intergenerational microbiomes.

The early-life gut microbiome is linked to human phenotypes as an imbalanced microbiome of this period is implicated in diseases throughout life. Several determinants of early-life gut microbiome are explored, however, mechanisms of acquisition, colonization, and stability of early-life gut microbiome and their interindividual variability remain elusive. Host genetics play a vital role to shape the gut microbiome and interact with it to modulate individual phenotypes in human studies and animal models. Given the microbial linkage between host generations, we discuss the current state of roles of host genetics in forming intergenerational microbiomes associated with mothers, offspring, and those vertically transmitted, providing a basis for taking into account host genetics in future early-life microbiome research. We further expand our discussion to the bidirectional interactions between host gene expression and microbiome in human health.

Metagenomic analysis of mother-infant gut microbiome reveals global distinct and shared microbial signatures.

Emerging evidence indicates maternal microbiota as one major reservoir for pioneering microbes in infants. However, the global distinct and identical features of mother-infant gut microbiota at various taxonomic resolutions and metabolic functions across cohorts and potential of infant microbial prediction based on their paired mother's gut microbiota remain unclear. Here, we analyzed 376 mother-infant dyads (468 mother and 1024 infant samples) of eight studies from six countries and observed higher diversity at species and strain levels in maternal gut microbiota but not their metabolic functions. A number of 290 species were shared in at least one mother-infant dyad, with 26 species (five at strain level) observed across cohorts. The profile of mother-infant shared species and strains was further influenced by delivery mode and feeding regimen. The mother-sourced species in infants exhibited similar strain heterogeneity but more metabolic functions compared to other-sourced species, suggesting the comparable stability and fitness of shared and non-shared species and the potential role of shared species in the early gut microbial community, respectively. Predictive models showed moderate performance accuracy for shared species and strains occurrences in infants. These generalized mother-infant shared species and strains may be considered as the primary targets for future work toward infant microbiome development and probiotics exploration.

A good start in life is important-perinatal factors dictate early microbiota development and longer term maturation.

Maternal health status is vital for the development of the offspring of humans, including physiological health and psychological functions. The complex and diverse microbial ecosystem residing within humans contributes critically to these intergenerational impacts. Perinatal factors, including maternal nutrition, antibiotic use and maternal stress, alter the maternal gut microbiota during pregnancy, which can be transmitted to the offspring. In addition, gestational age at birth and mode of delivery are indicated frequently to modulate the acquisition and development of gut microbiota in early life. The early-life gut microbiota engages in a range of host biological processes, particularly immunity, cognitive neurodevelopment and metabolism. The perturbed early-life gut microbiota increases the risk for disease in early and later life, highlighting the importance of understanding relationships of perinatal factors with early-life microbial composition and functions. In this review, we present an overview of the crucial perinatal factors and summarise updated knowledge of early-life microbiota, as well as how the perinatal factors shape gut microbiota in short and long terms. We further discuss the clinical consequences of perturbations of early-life gut microbiota and potential therapeutic interventions with probiotics/live biotherapeutics.

Dynamic Deformation Measurement of Specular Surface with Deflectometry and Speckle Digital Image Correlation.

The deformation measurement of a specular surface is of great importance during the quality inspection and installation of optical elements or wafers, especially those with large apertures. We propose a deflectometry method with speckle digital image correlation (DeSDIC) to realize the dynamic and high-accuracy measurement of the deformation on specular surfaces, with a simple system structure and robustness to noises and environmental vibrations. Random speckle pattern displayed on liquid crystal display is reflected by the original surface under test (SUT), and the distorted pattern is recorded by a camera. This originally distorted pattern is taken as the reference image, and the patterns captured afterwards are digitally correlated with the reference image to calculate the gradient change and deformation of the SUT. The theoretical relationships and an experimental one-step calibration scheme are proposed. Both static and dynamic deformations of a deformable mirror were experimentally measured to demonstrate the feasibility and accuracy of DeSDIC, which is comparable to phase-measuring deflectometry and interferometry.

Maternal Vertical Transmission Affecting Early-life Microbiota Development.

The association of the human microbiome with health outcomes has attracted much interest toward its therapeutic manipulation. The likelihood of modulating the human microbiome in early life is high and offers great potential to exert profound effects on human development since the early microbiota shows more flexibility compared to that of adults. The human microbiota, being similar to human genetics, can be transmitted from mother to infant, providing insights into early microbiota acquisition, subsequent development, and potential opportunities for intervention. Here, we review adaptations of the maternal microbiota during pregnancy, birth, and infancy, the acquisition and succession of early-life microbiota, and highlight recent efforts to elucidate mother-to-infant microbiota transmission. We further discuss how the mother-to-infant microbial transmission is shaped; and finally we address potential directions for future studies to promote our understanding within this field.

Effect of supplementation of pelleted hazel (Corylus avellana) leaves on blood antioxidant activity, cellular immune response, and heart beat parameters in sheep1.

Hazel leaves (Corylus avellana) fed to sheep resulted in decreased methane emissions without negatively affecting feed intake and were found to have antioxidant properties in vitro. The objective of this study was to evaluate effects of hazel leaves, rich in tannins, on blood antioxidant activity, cellular immune response, and heart beat parameters in sheep. Four experimental pellets were produced by mixing alfalfa and hazel leaves in different proportions, including alfalfa alone as a control, 30% and 60% of hazel leaves, the latter also with 3.8% polyethylene glycol (PEG). Six adult, nonpregnant, nonlactating female sheep (71 ± 5.7 kg of body weight) were allocated to 4 treatments in a 6 × 4 crossover design with four 18-d periods. The diet consisted of experimental pellets and ryegrass-dominated hay (ratio 80% to 20% in dry matter), resulting in hazel leaf proportions of approximately 0%, 25%, and 50% in the total diet. Blood samples were collected at the end of each period to determine plasma total phenol concentration and markers of oxidative status as well as peripheral blood mononuclear cells (PBMC) activation and proliferation response in vitro. Heart rate (HR) and HR variability parameters were measured for 2 consecutive days in each period, during different activities (i.e., eating pellets or hay, or lying). Treatments were compared with multiple comparisons and contrast analysis was used to test for linear and quadratic relations. Compared with control, feeding a high dosage of hazel leaves enhanced (P = 0.006) the plasma total antioxidant capacity, which linearly (P = 0.016) increased with increasing level of hazel leaves in the diet. The total phenol concentration and activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione reductase in the plasma were not different (P ≥ 0.23) among the treatments; however, the latter slightly increased linearly (P = 0.047) with increasing hazel leaves proportion. No differences were observed in the activation and proliferation of PBMC among treatments. The HR decreased linearly (P ≤ 0.009) during pellet eating and lying and the root mean square of successive differences of interbeat intervals (RMSSD) increased linearly (P = 0.037) when lying with increasing level of hazel leaves in the diet. In conclusion, our findings indicate that hazel leaves are a promising supplement to improve oxidative status with no effect on cellular immune response and cardiac stress level of sheep.

Two-step carrier-wave stitching method for aspheric and freeform surface measurement with a standard spherical interferometer.

Measurement of aspheric and freeform surfaces remains challenging due to the various shapes of the surface under test (SUT), especially when the SUT has a large aperture and strong deviation from the spherical surface. This paper proposes a two-step carrier-wave stitching method to enlarge the measurement bandwidth of a digital Moiré interferometry. Then, measurements of aspheric and freeform surfaces with a standard spherical interferometer without a phase-shifting mechanism are demonstrated. Experimental results with a root-mean-square repeatability of better than 1/200λ present good consistency to UA3P contact measurement results. Further simulation results with different residual wavefronts confirm measurement accuracies of peak-to-valley value of 10-3λ. The method is effective for large residual wavefronts and thus has potential for flexible measurement of aspheric and freeform surfaces.

Effect of immune modulators on in vitro activation and proliferation of peripheral blood mononuclear cells from multiparous Holstein cows peripartum.

This in vitro study examined the ability of important immune modulators [ß-hydroxybutyrate (BHB), cortisol, prolactin, isoproterenol and insulin] to influence the responsiveness of peripheral blood mononuclear cells (PBMC) from multiparous dairy cows 29 ± 2 days before and 14 ± 3 days after calving. The activation and proliferation of PBMC in response to the mitogen phytohemagglutinin was estimated by the oxygen consumption rate after 24 hr and the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5diphenyl tetrazolium bromide) method after 72 hr respectively. In early lactation, the presence of 2 compared to 0.5 mmol/L BHB reduced PBMC activation (p < 0.05) and proliferation (p < 0.10), and the presence of 0.7 compared to 0.2 ng/ml insulin enhanced (p < 0.10) PBMC proliferation. In dry cows, the presence of low concentrations of BHB and insulin and both concentrations of prolactin (20 vs. 300 ng/ml) and isoproterenol (70 vs. 130 ng/L) enhanced activation (p < 0.10), but not proliferation (p ≥ 0.10) compared to cultures with no modulator addition. The presence or absence of high or low concentrations of hydrocortisone (20 vs. 45 nmol/L) did not (p ≥ 0.10) influence the activation and proliferation of PBMC from dry and early lactating cows. It is tempting to speculate that in antepartum PBMC the modulators represented an energy source or positive extrinsic signals to use nutrients for the activation process. On the other hand, PBMC from postpartum cows are known to be exposed to a metabolic challenging endocrine background. Under such conditions, high BHB concentrations and high insulin concentrations seem to act as negative and positive signals for PBMC, respectively, to utilize nutrients for activation and proliferation.

Partial compensation interferometry measurement system for parameter errors of conicoid surface.

Surface parameters, such as vertex radius of curvature and conic constant, are used to describe the shape of an aspheric surface. Surface parameter errors (SPEs) are deviations affecting the optical characteristics of an aspheric surface. Precise measurement of SPEs is critical in the evaluation of optical surfaces. In this paper, a partial compensation interferometry measurement system for SPE of a conicoid surface is proposed based on the theory of slope asphericity and the best compensation distance. The system is developed to measure the SPE-caused best compensation distance change and SPE-caused surface shape change and then calculate the SPEs with the iteration algorithm for accuracy improvement. Experimental results indicate that the average relative measurement accuracy of the proposed system could be better than 0.02% for the vertex radius of curvature error and 2% for the conic constant error.