Connexin26 Gap Junction Mediates miRNA Intercellular Genetic Communication in the Cochlea and Is Required for Inner Ear Development

Organ development requires well-established intercellular communication to coordinate cell proliferations and differentiations. MicroRNAs (miRNAs) are small, non-coding RNAs that can broadly regulate gene expression and play a critical role in the organ development. In this study, we found that miRNAs could pass through gap junctions between native cochlear supporting cells to play a role in the cochlear development. Connexin26 (Cx26) and Cx30 are predominant isoforms and co-express in the cochlea. Cx26 deficiency but not Cx30 deficiency can cause cochlear developmental disorders. We found that associated with Cx26 deletion induced the cochlear developmental disorders, deletion of Cx26 but not Cx30 disrupted miRNA intercellular transfer in the cochlea, although inner ear gap junctions still retained permeability after deletion of Cx26. Moreover, we found that deletion of Cx26 but not Cx30 reduced miR-96 expression in the cochlea during postnatal development. The reduction is associated with the cochlear tunnel developmental disorder in Cx26 knockout (KO) mice. These data reveal that Cx26-mediated intercellular communication is required for cochlear development and that deficiency of Cx26 can impair miRNA-mediated intercellular genetic communication in the cochlea, which may lead to cochlear developmental disorders and eventually congenital deafness as previously reported

Gap Junction Mediated miRNA Intercellular Transfer and Gene Regulation: A Novel Mechanism for Intercellular Genetic Communication

Intercellular genetic communication is an essential requirement for coordination of cell proliferation and differentiation and has an important role in many cellular processes. Gap junction channels possess large pore allowing passage of ions and small molecules between cells. MicroRNAs (miRNAs) are small regulatory RNAs that can regulate gene expression broadly. Here, we report that miRNAs can pass through gap junction channels in a connexin-dependent manner. Connexin43 (Cx43) had higher permeability, whereas Cx30 showed little permeability to miRNAs. In the tested connexin cell lines, the permeability to miRNAs demonstrated: Cx43 \u3e Cx26/30 \u3e Cx26 \u3e Cx31 \u3e Cx30 = Cx-null. However, consistent with a uniform structure of miRNAs, there was no significant difference in permeability to different miRNAs. The passage is efficient; the miRNA level in the recipient cells could be up to 30% of the donor level. Moreover, the transferred miRNA is functional and could regulate gene expression in neighboring cells. Connexin mutation and gap junctional blockers could eliminate this miRNA intercellular transfer and gene regulation. These data reveal a novel mechanism for intercellular genetic communication. Given that connexin expression is cell-specific, this connexin-dependent, miRNA intercellular genetic communication may play an important role in synchronizing and coordinating proliferation and differentiation of specific cell types during multicellular organ development

Progressive Age-Dependence and Frequency Difference in the Effect of Gap Junctions on Active Cochlear Amplification and Hearing

Mutations of Connexin 26 (Cx26, GJB2), which is a predominant gap junction isoform in the cochlea, can induce high incidence of nonsyndromic hearing loss. We previously found that targeted-deletion of Cx26 in supporting Deiters cells and outer pillar cells in the cochlea can influence outer hair cell (OHC) electromotility and reduce active cochlear amplification leading to hearing loss, even though there are no gap junction connexin expressions in the auditory sensory hair cells. Here, we further report that hearing loss and the reduction of active amplification in the Cx26 targeted-deletion mice are progressive and different at high and low frequency regions, first occurring in the high frequency region and then progressively extending to the middle and low frequency regions with mouse age increased. The speed of hearing loss extending was fast in the basal high frequency region and slow in the apical low frequency region, showing a logarithmic function with mouse age. Before postnatal day 25, there were no significant hearing loss and the reduction of active cochlear amplification in the low frequency region. Hearing loss and the reduction of active cochlear amplification also had frequency difference, severe and large in the high frequency regions. These new data indicate that the effect of gap junction on active cochlear amplification is progressive, but, consistent with our previous report, exists in both high and low frequency regions in adulthood. These new data also suggest that cochlear gap junctions may have an important role in age-related hearing loss

Knockout of Pannexin-1 Induces Hearing Loss

Mutations of gap junction connexin genes induce a high incidence of nonsyndromic hearing loss. Pannexin genes also encode gap junctional proteins in vertebrates. Recent studies demonstrated that Pannexin-1 (Panx1) deficiency in mice and mutation in humans are also associated with hearing loss. So far, several Panx1 knockout (KO) mouse lines were established. In general, these Panx1 KO mouse lines demonstrate consistent phenotypes in most aspects, including hearing loss. However, a recent study reported that a Panx1 KO mouse line, which was created by Genentech Inc., had no hearing loss as measured by the auditory brainstem response (ABR) threshold at low-frequency range (\u3c 24 kHz). Here, we used multiple auditory function tests and re-examined hearing function in the Genentech Panx1 (Gen-Panx1) KO mouse. We found that ABR thresholds in the Gen-Panx1 KO mouse were significantly increased, in particular, in the high-frequency region. Moreover, consistent with the increase in ABR threshold, distortion product otoacoustic emission (DPOAE) and cochlear microphonics (CM), which reflect active cochlear amplification and auditory receptor current, respectively, were significantly reduced. These data demonstrated that the Gen-Panx1 KO mouse has hearing loss and further confirmed that Panx1 deficiency can cause deafness

A Deafness Mechanism of Digenic Cx26 (\u3cem\u3eGJB2\u3c/em\u3e) and Cx30 (\u3cem\u3eGJB6\u3c/em\u3e) Mutations: Reduction of Endocochlear Potential by Impairment of Heterogeneous Gap Junctional Function in the Cochlear Lateral Wall

Digenic Connexin26 (Cx26, GJB2) and Cx30 (GJB6) heterozygous mutations are the second most frequent cause of recessive deafness in humans. However, the underlying deafness mechanism remains unclear. In this study, we created different double Cx26 and Cx30 heterozygous (Cx26+/−/Cx30+/−) mouse models to investigate the underlying pathological changes and deafness mechanism. We found that double Cx26+/−/Cx30+/− heterozygous mice had hearing loss. Endocochlear potential (EP), which is a driving force for hair cells producing auditory receptor current, was reduced. However, unlike Cx26 homozygous knockout (Cx26−/−) mice, the cochlea in Cx26+/−/Cx30+/− mice displayed normal development and had no apparent hair cell degeneration. Gap junctions (GJs) in the cochlea form two independent networks: the epithelial cell GJ network in the organ of Corti and the connective tissue GJ network in the cochlear lateral wall. We further found that double heterozygous deletion of Cx26 and Cx30 in the epithelial cells did not reduce EP and had normal hearing, suggesting that Cx26+/−/Cx30+/− may mainly impair gap junctional functions in the cochlear lateral wall and lead to EP reduction and hearing loss. Most of Cx26 and Cx30 in the cochlear lateral wall co-expressed in the same gap junctional plaques. Moreover, sole Cx26+/− or Cx30+/− heterozygous mice had no hearing loss. These data further suggest that digenic Cx26 and Cx30 mutations may impair heterozygous coupling of Cx26 and Cx30 in the cochlear lateral wall to reduce EP, thereby leading to hearing loss

Taiji Data Challenge for Exploring Gravitational Wave Universe

The direct observation of gravitational waves (GWs) opens a new window for exploring new physics from quanta to cosmos and provides a new tool for probing the evolution of universe. GWs detection in space covers a broad spectrum ranging over more than four orders of magnitude and enables us to study rich physical and astronomical phenomena. Taiji is a proposed space-based GW detection mission that will be launched in the 2030s. Taiji will be exposed to numerous overlapping and persistent GW signals buried in the foreground and background, posing various data analysis challenges. In order to empower potential scientific discoveries, the Mock LISA Data Challenge and the LISA Data Challenge (LDC) were developed. While LDC provides a baseline framework, the first LDC needs to be updated with more realistic simulations and adjusted detector responses for Taiji's constellation. In this paper, we review the scientific objectives and the roadmap for Taiji, as well as the technical difficulties in data analysis and the data generation strategy, and present the associated data challenges. In contrast to LDC, we utilize second-order Keplerian orbit and second-generation time delay interferometry techniques. Additionally, we employ a new model for the extreme-mass-ratio inspiral waveform and stochastic GW background spectrum, which enables us to test general relativity and measure the non-Gaussianity of curvature perturbations. Furthermore, we present a comprehensive showcase of parameter estimation using a toy dataset. This showcase not only demonstrates the scientific potential of the Taiji Data Challenge but also serves to validate the effectiveness of the pipeline. As the first data challenge for Taiji, we aim to build an open ground for data analysis related to Taiji sources and sciences. More details can be found on the official website at http://taiji-tdc.ictp-ap.org.Comment: 15 pages, 3 figure

Global prevalence of WHO infant feeding practices in 57 LMICs in 2010-2018 and time trends since 2000 for 44 LMICs

BackgroundThe World Health Assembly set a global target of increasing exclusive breastfeeding for infants under 6 months to at least 50% by year 2025. However, little is known about the current status of breastfeeding practice, as well as the trends in breastfeeding practices during recent years. We examined global prevalence of the World Health Organization (WHO) feeding practices in 57 low- and middle-income countries (LMICs) and time trends since 2000 for 44 selected countries.MethodsWe included 57 eligible LMICs that had completed data on breastfeeding and complementary feeding in 2010–2018 from the Demographic and Health Surveys (DHS) for examining current feeding status. We further selected 44 LMICs that had two standard DHS surveys between 2000 and 2009 and 2010–2018 to examine time trends of feeding status. We calculated global, regional, and national weighted prevalence estimates and 95% confidence intervals (CIs) for five breastfeeding indicators and two complementary feeding indicators.FindingsIn 57 LMICs during 2010–2018, global weighted prevalence was 51.9% for early initiation of breastfeeding, 45.7% for exclusive breastfeeding under 6 months, 32.0% for exclusive breastfeeding at 4–5 months, 83.1% for continued breastfeeding at 1 year, 56.2% for continued breastfeeding at 2 years, 14.9% for introduction of solid, semi-solid or soft foods under 6 months, and 63.1% for introduction of solid, semi-solid or soft foods at 6–8 months. Eastern Mediterranean (34.5%) and European regions (43.7%) (vs. South-East Asia/Western Pacific (55.2%)), and upper middle-income countries (38.4%) (vs. lower middle-income countries (47.4%)) had poorer performance of exclusive breastfeeding under 6 months. South-East Asia/Western Pacific regions (51.0%) (vs. other regions (68.3%-84.1%)) and low-income (66.4%) or lower middle-income countries (58.2%) (vs. upper middle-income countries (81.7%)) had lower prevalence of introduction of solid, semi-solid or soft foods at 6–8 months. In 44 selected LMICs from 2000 to 2009 to 2010–2018, total weighted prevalence presented an increase of 10.1% for exclusive breastfeeding under 6 months, but a 1.7% decrease for continued breastfeeding at 1 year. Over this period, the Eastern Mediterranean region had a 5.3% decrease of exclusive breastfeeding under 6 months, and the European region had a 2.0% increase for introduction of solid, semi-solid or soft foods under 6 months. The prevalence of introduction of solid, semi-solid or soft foods at 6–8 months decreased in South-East Asia/Western Pacific region by 15.2%, and in lower middle-income countries by 24.4%.InterpretationBreastfeeding practices in LMICs have continued to improve in the past decade globally, but practices still lag behind the WHO feeding recommendations. Breastfeeding practices differed greatly across WHO regions, with the Eastern Mediterranean and European regions, and upper middle-income countries facing the greatest challenges in meeting targets. Continued efforts are needed to achieve the 2025 global breastfeeding target.</p

Probing for dynamics of dark energy and curvature of universe with latest cosmological observations

We use the newly released 182 Type Ia supernova data combined with the third-year Wilkinson Microwave Anisotropic Probe data (WMAP3) and large scale structure (LSS) information including SDSS and 2dFGRS to constrain the dark energy equation of state (EoS) as well as the curvature of universe $\Omega_K$. Using the full dataset of Cosmic Microwave Background (CMB) and LSS rather than the shift parameter and linear growth factor, we make a Markov Chain Monte Carlo (MCMC) global fit, while paying particular attention to the dark energy perturbation. Parameterizing the EoS as $w_{DE}(a) = w_{0} + w_{1}(1-a)$, we find the best fit of ($w_0,w_1$) is ($-1.053,0.944$) and for $w_{DE}(a) = w_{0} + w_{1}\sin({3/2}\pi \ln(a))$, the best fit for ($w_0,w_1$) is ($-1.614,-1.046$). We find that a flat universe is a good approximation, namely, $|\Omega_K|>0.06$ has been excluded by 2$\sigma$ yet the inclusion of $\Omega_K$ can affect the measurement of DE parameters owing to their correlation and the present systematic effects of SNIa measurements.Comment: The wrongly-generated last page of pdf file is remove

Mutation of SLC35D3 causes metabolic syndrome by impairing dopamine signaling in striatal D1 neurons

We thank Dr. Ya-Qin Feng from Shanxi Medical University, Dr. Tian-Yun Gao from Nanjing University and Dr. Yan-Hong Xue from Institute of Biophysics (CAS) for technical assistance in this study. We are very thankful to Drs. Richard T. Swank and Xiao-Jiang Li for their critical reading of this manuscript and invaluable advice. Funding: This work was partially supported by grants from National Basic Research Program of China (2013CB530605; 2014CB942803), from National Natural Science Foundation of China 1230046; 31071252; 81101182) and from Chinese Academy of Sciences (KSCX2-EW-R-05, KJZD-EW-L08). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Maternal Pre-pregnancy Body Mass Index Categories and Infant Birth Outcomes: A Population-Based Study of 9 Million Mother-Infant Pairs

Background and aims: Infant adverse birth outcomes have been suggested to contribute to neonatal morbidity and mortality and may cause long-term health consequences. Although evidence suggests maternal prepregnancy body mass index (BMI) categories associate with some birth outcomes, there is no consensus on these associations. We aimed to examine the associations of maternal prepregnancy BMI categories with a wide range of adverse birth outcomes.Methods: Data were from a population-based retrospective cohort study of 9,282,486 eligible mother-infant pairs in the U.S. between 2016 and 2018. Maternal prepregnancy BMI was classified as: underweight (2); normal weight (18.5-24.9 kg/m2); overweight (25.0-29.9 kg/m2); obesity grade 1 (30-34.9 kg/m2); obesity grade 2 (35.0-39.9 kg/m2); and obesity grade 3 (≥40 kg/m2). A total of six birth outcomes of the newborn included preterm birth, low birthweight, macrosomia, small for gestational age (SGA), large for gestational age (LGA), and low Apgar score (5-min score Results: Maternal prepregnancy overweight and obesity increased the likelihood of infant preterm birth, with odds ratios (ORs) (95% CIs) of 1.04 (1.04-1.05) for overweight, 1.18 (1.17-1.19) for obesity grade 1, 1.31 (1.29-1.32) for obesity grade 2, and 1.47 (1.45-1.48) for obesity grade 3, and also for prepregnancy underweight (OR = 1.32, 95% CI = 1.30-1.34) after adjusting for all potential covariates. Prepregnancy overweight and obesity were associated with higher odds of macrosomia, with ORs (95% CIs) of 1.53 (1.52-1.54) for overweight, 1.92 (1.90-1.93) for obesity grade 1, 2.33 (2.31-2.35) for obesity grade 2, and 2.87 (2.84-2.90) for obesity grade 3. Prepregnancy overweight and obesity was associated with higher odds of LGA, with ORs (95% CIs) of 1.58 (1.57-1.59) for overweight, 2.05 (2.03-2.06) for obesity grade 1, 2.54 (2.52-2.56) for obesity grade 2, and 3.17 (3.14-3.21) for obesity grade 3. Prepregnancy overweight and obesity were also associated with higher odds of low Apgar score, with ORs (95% CIs) of 1.12 (1.11-1.14) for overweight, 1.21 (1.19-1.23) for obesity grade 1, 1.34 (1.31-1.36) for obesity grade 2, and 1.55 (1.51-1.58) for obesity grade 3.Conclusion: Our findings suggest maintaining or obtaining a healthy body weight for prepregnancy women could substantially reduce the likelihood of important infant adverse birth outcomes.</p