Comparing fine motor performance among young children with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, and specific developmental disorder of motor function.

Objective: The acquisition of fine motor skills is considered to be a crucial developmental milestone throughout early childhood. This study aimed to investigate the fine motor performance of young children with different disability diagnoses. Methods: We enrolled a sample of 1,897 young children under the age of 6 years who were at risk of developmental delays and were identified by a transdisciplinary team. A series of standardized developmental assessments included the Bayley Scales of Infant Development-Third Edition, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, Peabody Developmental Motor Scale-Second Edition, and Movement Assessment Battery for Children-Second Edition were used. Retrospective chart reviews were conducted on all children to identify specific developmental disorders. The number of autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), comorbidity, motor dysfunction, and unspecified developmental delays (DD) were 363 (19.1%), 223 (11.8%), 234 (12.3%), 285 (15.0%), 128 (6.7%), and 590 (31.1%), respectively. Results: Young children with ID, comorbidity, and motor dysfunction demonstrated significant difficulty in performing manual dexterity and visual motor integration tasks and scored significantly lower in these areas than children with ASD, ADHD, and unspecified DD. In addition, fine motor performance was associated with cognitive ability in children with different disability diagnoses, indicating that young children showed better fine motor performance when they demonstrated better cognitive ability. Conclusion: Our findings support that differences in fine motor performance differ by disability type. Close links between fine motor performance and cognitive ability in children under the age of 6 years were seen in all disability types.

Mesomorphism Modulation of Perfluorinated Janus Triphenylenes by Inhomogeneous Chain Substitution Patterns.

Two isomeric series of compounds with "inverted" chains' substitution patterns, 7,10-dialkoxy-1,2,3,4-tetrafluoro-6,11-dimethoxytriphenylene and 6,11-dialkoxy-1,2,3,4-tetrafluoro-7,10-dimethoxytriphenylene, labelled respectively p-TPFn and m-TPFn, and two non-fluorinated homologous isomers, 3,6-dibutoxy-2,7-dimethoxytriphenylene and 2,7-dibutoxy-3,6-dimethoxytriphenylene, p-TP4 and m-TP4, respectively, were synthesized in three steps and obtained in good yields by the efficient transition-metal-free, fluoroarene nucleophilic substitution via the reaction of appropriate 2,2'-dilithium biphenylenes with either perfluorobenzene, C6 F6 , to yield p-TPFn and m-TPFn, or o-difluorobenzene, C6 H4 F2 , for p-TP4 and m-TP4, respectively. The single-crystal structures of p-TPF4, m-TPF4 and p-TP4, unequivocally confirmed that the cyclization reactions occurred at the expected positions, and that the fluorinated molecules stack up into columns with short separation, a propitious situation for the emergence of columnar mesophases. The mesomorphous properties were found to be greatly affected by both chains' length and positional isomerism: a Colhex phase is found for p-TPF4 and m-TPF4, but mesomorphism vanishes in p-TPF6, and changes for the isomeric homologs m-TPFn, with the induction for n≥6 of a lamello-columnar phase, LamColrec . As expected, both non-fluorinated compounds are deprived of mesomorphism. These compounds emit blue-violet colour in solution, independently of the chains' substitution pattern, and the absolute fluorescence quantum yields can reach up to 46 %. In thin films, fluorescence is slightly redshifted.

A boy with a progressive neurologic decline harboring two coexisting mutations in KMT2D and VPS13D.

INTRODUCTION: Kabuki syndrome (KS) and spinocerebellar ataxia (SCA) are both rare conditions with neurodevelopmental abnormalities. Approaching a patient with complex phenotypes and differentiating the role of mutations may be beneficial but challenging in predicting the disease prognosis. CASE PRESENTATION: A boy presented with progressive ataxia, developmental regression, and myoclonus since 4 years of age. Additional features included growth hormone deficiency, excessive body hair, dysmorphic facies, hypoparathyroidism, and bilateral sensorineural hearing impairment. Brain magnetic resonance imaging depicted T2-weighted hyperintensities over bilateral globus pallidus, thalamus, subcortical white matter, and brainstem. The results of tandem mass spectrometry, mitochondrial deletion, and mitochondrial DNA sequencing were inconclusive. Whole-exome sequencing (WES) on genomic DNA obtained from peripheral blood cells revealed a known pathogenic variant at KMT2D gene (c.5993A > G, p.Tyr1998Cys) related to KS and two compound heterozygous, likely pathogenic variants at VPS13D gene (c.908G > A, p.Arg303Gln and c.8561T > G, p.Leu2854Arg) related to autosomal recessive SCA type 4 (SCAR4). DISCUSSION: SCAR4 is mainly adult-onset, but a few pediatric cases have recently been reported with progressive gait instability and developmental delay. The VPS13D gene has been suggested to play a role in mitochondrial size, autophagy, and clearance, thus explaining the clinical and imaging phenotypes. CONCLUSION: Our case showed a rare co-existence of KS and SCAR4, highlighting the utility of WES in atypical cases that a single-gene disease cannot fully explain.

Multiple domestications of Asian rice.

The origin of domesticated Asian rice (Oryza sativa L.) has been controversial for more than half a century. The debates have focused on two leading hypotheses: a single domestication event in China or multiple domestication events in geographically separate areas. These two hypotheses differ in their predicted history of genes/alleles selected during domestication. Here we amassed a dataset of 1,578 resequenced genomes, including an expanded sample of wild rice from throughout its geographic range. We identified 993 selected genes that generated phylogenetic trees on which japonica and indica formed a monophyletic group, suggesting that the domestication alleles of these genes originated only once in either japonica or indica. Importantly, the domestication alleles of most selected genes (~80%) stemmed from wild rice in China, but the domestication alleles of a substantial minority of selected genes (~20%) originated from wild rice in South and Southeast Asia, demonstrating separate domestication events of Asian rice.

Enzyme replacement therapy for children with acid sphingomyelinase deficiency in the real world: A single center experience in Taiwan.

Background: Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease with multi-systemic involvement, with no disease-modifying treatment available. Olipudase alfa is an investigational enzyme product developed to replace the deficient acid sphingomyelinase in ASMD patients. Several clinical trials have reported promising safety and efficacy results in adult and pediatric patients. However, no data have been reported outside of the clinical trial setting yet. This study aimed to evaluate major outcomes in pediatric chronic ASMD patients receiving olipudase alfa in the real-world setting. Materials and methods: Two children with type A/B (chronic neuropathic) ASMD have received olipudase alfa treatment since May 2021. Clinical parameters, including height, weight, complete blood count, liver function tests, lipid profiles, biomarkers, abdominal ultrasonography with shear wave elastography, chest computed tomography, nerve conduction studies, neurodevelopmental evaluations, and six-minute walk tests, were checked at baseline and every three to six months in the first year of enzyme replacement therapy (ERT) to assess its efficacy and safety. Results: The two patients in our study started olipudase alfa treatment at the age of 5 years and 8 months and 2 years and 6 months. During the first year of treatment, both patients saw a reduction in their hepatic and splenic volumes as well as liver stiffness. Height z-score, weight z-score, lipid profiles, biomarker levels, interstitial lung disease scores, and bone mineral densities also improved over time. The six-minute walk test showed a gradual increase in walking distance in both patients. There were no obvious improvements or deterioration in neurocognitive function and peripheral nerve conduction velocities after treatment. No severe infusion-associated reactions were noted during the first year of treatment. One patient had two episodes of transient but significantly elevated liver enzymes during the dose-escalation phase. The patient was asymptomatic, and the impaired liver function resolved spontaneously within two weeks. Conclusion: Our results provide real-world experience that olipudase alfa is safe and effective in improving major systemic clinical outcomes for pediatric chronic ASMD patients. Monitoring of liver stiffness by shear wave elastography is a noninvasive procedure that can monitor treatment efficacy during ERT.

Chromium-Catalyzed Defluorinative Reductive Coupling of Aldehydes with gem-Difluoroalkenes.

Herein, a mild and convenient defluorinative reductive cross coupling of gem-difluoroalkenes with aliphatic aldehydes has been developed to afford diverse silyl-protected ß-fluorinated allylic alcohols. The reaction is operationally simple and shows good functional group tolerance with moderate to excellent yields. The utility of this method is demonstrated by converting the products into various bioactive fluorinated compounds, showing its potential applications in drug discovery and biochemistry.

Risk patterns associated with transient hearing impairment and permanent hearing loss in infants born very preterm: A retrospective study.

AIM: To determine the risk patterns associated with transient hearing impairment (THI) and permanent hearing loss (PHL) of infants born very preterm who failed hearing screenings. METHOD: We enrolled 646 infants (347 males, 299 females) born at no more than 30 weeks' gestation between 2006 and 2020 who received auditory brainstem response screening at term-equivalent age. Audiological examinations of infants who failed the screening revealed THI, when hearing normalized, or PHL, defined as a persistent unilateral or bilateral hearing threshold above 20 dB. Principal component analysis (PCA) was used to characterize risk patterns. RESULTS: Among the 646 infants, 584 (90.4%) had normal hearing, 42 (6.5%) had THI, and 20 (3.1%) had PHL. Compared with the group with normal hearing, the THI and PHL groups had significantly higher rates of neurodevelopmental impairment at 24 months corrected age. PCA of risk patterns showed the THI group and especially the PHL group had more severe haemodynamic and respiratory instability. Moreover, severe intraventricular haemorrhage (IVH) was also a risk for PHL. Propensity score matching revealed an association of haemodynamic and respiratory instability with PHL. INTERPRETATION: In infants born preterm, the severity and duration of haemodynamic and respiratory instability are risk patterns for both THI and PHL; severe IVH is an additional risk for PHL. WHAT THIS PAPER ADDS: Neurodevelopmental delay was more common in infants born preterm who failed hearing screening. Principal component analysis revealed the risk patterns associated with hearing impairment. Haemodynamic-respiratory instability was associated with transient and permanent hearing impairment outcomes. Severe haemodynamic-respiratory instability and intraventricular haemorrhage was associated with permanent hearing loss.

Anti-freezing dual-network hydrogels with high-strength, self-adhesive and strain-sensitive for flexible sensors.

Hydrogels as flexible sensor have attracted significant attention due to its conductivity, stretchability and flexibility. However, it is still a great challenge to prepare hydrogels that simultaneously possess high strength, anti-fatigue, self-adhesion, and anti-freezing. Herein, a multifunctional dual-network hydrogel was prepared by in situ polymerization of acrylic monomer in chitosan chains, and coordinated with aluminum chloride and glycerol. Based on chain entanglement, hydrogen bonding and coordination interactions, this dual-network hydrogel exhibited excellent mechanical properties, good fatigue resistance, and excellent adhesion performance. It can be used as a strain sensor for its stable conductivity and high sensitivity, which could monitor both large human motions and subtle motions. Due to the presence of glycerol, the hydrogel showed outstanding freezing resistance and still kept flexible and conductive even at low temperatures (-20 °C). This hydrogel can be applied as a flexible wearable sensor for monitoring human motion in extreme low-temperature condition.

Modular Synthesis of Enantioenriched α-Chiral Homoallylic Amidines Enabled by Relay Ir/Cu Catalysis.

The cascade of Ir-catalyzed enantioselective allylic amination and Cu-catalyzed alkyne-azide cycloaddition was designed for the asymmetric synthesis of homoallylic amidines. The nucleophilic addition of an in situ-generated enantioenriched tertiary allylamine to a ketenimine intermediate triggers a rapid and stereospecific zwitterionic aza-Claisen rearrangement in a 1,3-chiral transfer manner. The approach allows modular access to enantioenriched α-chiral homoallylic amidines in high yields with a high level of enantiomeric purity.

Postnatal Serum Total Thyroxine Level Associated with Short- and Long-Term Anthropometric Outcomes in Very Preterm Infants.

Thyroxine (T4) importantly regulates the growth of newborns. Compared to fetuses with equivalent gestational ages, very preterm infants (VPIs) often experience relatively low thyroxinemia, with a normal thyroid-stimulating hormone (TSH) concentration < 10 µIU/mL. However, there is continued debate regarding postnatal thyroxine supplementation for VPIs with normal TSH and transitionally low thyroxinemia. Little research has explored the role of the postnatal total T4 (TT4) serum concentration on the growth of VPIs. In this study, we aim to clarify whether the postnatal thyroxine concentration is associated with the short- and long-term growth outcomes of VPIs. A total of 334 surviving VPIs in our previously reported cohort, born in the period August 2007−July 2016, were enrolled. The exposure variable was the postnatal TT4 concentration at 1 month old. The primary outcomes were body weight increments over 28 days after the screening and anthropometric outcomes at the corrected age of 24 months old. Infants with any hormonal replacement, severe brain injury, congenital anomaly, or cerebral palsy were excluded. In total, 290 (86.8%) VPIs were included for analysis. In the 28 days after thyroid function screening, the TT4 concentration was found to have a significant association with positive increments in body weight (mean increment: 25.7 g per 1 µg/dL; p < 0.001) and a positive body weight z-score (mean increment: 0.039 per 1 µg/dL; p = 0.037), determined by generalized estimating equation analysis. At the corrected age of 24 months old, a higher postnatal TT4 concentration was associated with a lower body mass index (mean coefficient: −0.136; 95% CI: −0.231 to −0.041, p = 0.005) and lower body mass index z-score (mean coefficient: −0.097; 95% CI: −0.170 to −0.024, p = 0.009). Infants with a TT4 concentration > 6.4 ug/dL had significantly lower odds of overweight status (odds ratio: 0.365; 95% CI: 0.177 to 0.754, p = 0.006). We conclude that the postnatal TT4 concentration is associated with a positive increment in body weight in the short term. At the same time, the postnatal TT4 concentration is associated with lower odds of overweight status after long-term follow-up.

Early-life respiratory trajectories and neurodevelopmental outcomes in infants born very and extremely preterm: A retrospective study.

AIM: To determine whether early-life respiratory trajectories are associated with neurodevelopmental impairment (NDI) in infants born very and extremely preterm. METHOD: The daily type of respiratory supports in the first 8 weeks after birth were analysed in 546 infants (285 males, 261 females; median gestational age = 28.0 weeks, interquartile range = 3 weeks), comprising 301 infants born very preterm (gestation = 28-30 weeks) and 245 infants born extremely preterm (gestation <28 weeks), who survived to discharge from 2004 to 2018 and received follow-up assessment by Bayley Scales of Infant and Toddler Development at a corrected age of 24 months. NDI included cognition or motor impairment, moderate and severe cerebral palsy, or visual and hearing impairment. RESULTS: Clustering analysis identified three respiratory patterns with increasing severity: improving; slowly improving; and delayed improvement. These were significantly associated with increasing rates of NDI in infants born very and extremely preterm and smaller head circumference in infants born extremely preterm (both p < 0.001). By day 28, the proportion of infants who were under different categories of ventilation support significantly differed according to the three trajectory groups in infants born very and extremely preterm (both p < 0.05). Models that included adverse respiratory trajectories demonstrated more negative impacts on neurodevelopment than those without. INTERPRETATION: An adverse early-life respiratory trajectory was associated with NDI at follow-up, especially in infants born extremely preterm, suggesting a lung-brain axis of preterm birth. WHAT THIS PAPER ADDS: Clustering analysis identified three respiratory trajectories with increasing severity in infants born preterm. Increasing severity of respiratory trajectories was associated with increasing rates of neurodevelopmental impairment. Adverse respiratory trajectories had a significantly negative impact on neurodevelopmental outcomes.

OBJETIVO: Determinar se as trajetórias respiratórias no início da vida estão associadas ao comprometimento do neurodesenvolvimento (CND) em bebês nascidos muito e extremamente prematuros. MÉTODOS: O tipo diário de suporte respiratório nas primeiras 8 semanas após o nascimento foi analisado em 546 bebês (285 meninos, 261 meninas; idade gestacional mediana = 28,0 semanas, intervalo interquartil = 3 semanas), compreendendo 301 bebês nascidos muito prematuros (gestação = 28-30 semanas) e 245 bebês nascidos extremamente prematuros (gestação < 28 semanas), que sobreviveram à alta entre 2004 e 2018 e receberam avaliação de seguimento por meio da Bayley Scales of Infant and Toddler Development na idade corrigida de 24 meses. O CND incluiu deficiência cognitiva ou motora, paralisia cerebral moderada e grave ou deficiência visual e auditiva. RESULTADOS: A análise de agrupamento identificou três padrões respiratórios com gravidade crescente: melhorando; melhorando lentamente; e melhora tardia. Estes foram significativamente associados com taxas crescentes de CND em bebês nascidos muito e extremamente prematuros e menor perímetro cefálico em bebês nascidos extremamente prematuros (ambos p < 0,001). No dia 28, a proporção de bebês que estavam sob diferentes categorias de suporte ventilatório diferiu significativamente de acordo com os três grupos de trajetória em bebês nascidos muito prematuros e extremamente prematuros (ambos p < 0,05). Os modelos que incluíram trajetórias respiratórias adversas demonstraram mais impactos negativos no neurodesenvolvimento do que aqueles sem. INTERPRETAÇÃO: Uma trajetória respiratória adversa no início da vida foi associada ao CND no seguimento, especialmente em bebês nascidos extremamente prematuros, sugerindo um eixo pulmão-cérebro de nascimento prematuro.

Agreement Between Caregivers' Concerns of Children's Developmental Problems and Professional Identification in Taiwan.

Objective: Early detection of developmental delays relies on the accuracy of the caregivers' concerns of children's developmental problems. The aim of this study was to investigate the agreement between the caregivers' awareness of children's developmental problems and professional identification. Methods: Caregivers of 1,963 children (age range: 5-71 months; mean: 38.4 months) younger than 6 years old who were at risk of developmental delays and referred to the center for a comprehensive evaluation were enrolled in this study. Children were identified by a transdisciplinary team including a pediatric neurologist, a pediatric psychiatrist, two psychologists, two occupational therapists, two physical therapists, two speech therapists, a social worker, and a special instructor. A series of standardized developmental assessments were used to identify children with developmental delay. Retrospective chart reviews were conducted on all children to confirm specific developmental disorders. Results: The caregivers' initial concerns of cognitive, speech/language, emotional/behavioral, and motor and global development showed low agreement with the results of professional identification. The major disagreement was observed in the cognitive domain. Speech/language developmental concern was an important red-flag indicator of cognitive and emotional/behavioral developmental delays. The presence of intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder was high in this study. When having caregivers' concerns about speech/language and emotional/behavioral development, the odds of children with autism spectrum disorder was 2.37 and 2.17 times greater than those without autism spectrum disorder, respectively. The presence of attention deficit hyperactivity disorder was significantly associated with concerns about cognitive and emotional/behavioral developmental delays. Child's age and mothers' level of education were significant indicators for detecting the child's developmental problems. Conclusion: It is recommended that assessing the cognitive developmental status is essential for all children in the identification process. Practitioners should not overlook caregivers' concern about speech/language and emotional/behavioral development. Transdisciplinary practitioners provide educational guidance to caregivers, especially in the domains of cognitive, speech/language, and emotional/behavioral development.

Effect of first-month head-size growth trajectory on cognitive outcomes in preterm infants.

BACKGROUND: To examine whether the patterns of head-size growth trajectory in the first month after birth are associated with different susceptibility to cognitive impairment outcomes at age 24 months. METHODS: This retrospective cohort study included 590 infants of very-preterm survivors born between 2001 and 2016 receiving neurodevelopmental assessment at age 24 months. 403 children were enrolled for analysis after excluding infants with small-for-gestational age and severe brain injury. The head circumference (HC) growth evaluated weekly in the first month after birth compared to the at-birth HC was analyzed using group-based trajectory modeling. Neurocognition outcomes were determined as normal, borderline delay, or impaired using the Bayley Scales of Infant Development. RESULTS: The HC growth dynamics in the first month after birth showed three trajectory patterns: delayed catch-up (31.5%), slow catch-up (54.0%), and fast catch-up (14.5%), which significantly corresponded to different rates of impaired cognition at 19.5%, 6.0%, and 8.5%, respectively (p < 0.001). While 60% of the fast catch-up group had normal cognition, only one-third of the delayed catch-up group showed normal cognition. Three neonatal risk factors, gestational age (p = 0.006), respiratory distress syndrome requiring surfactant therapy (p = 0.012), and hemodynamically significant patent ductus arteriosus requiring intervention (p = 0.047) significantly affected HC growth trajectory patterning that led to cognitive impairment outcomes at follow-up. CONCLUSION: Preterm infants with delayed catch-up of head-size growth in the first month of age is susceptible to cognitive impairment outcome.

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability.

BACKGROUND AND OBJECTIVES: To investigate the pathogenicity of 2 novel KDM5C variations, report the clinical and neuroimaging findings, and review the available literature. METHODS: Physical examinations, structural neuroimaging studies, and exome sequence analysis were performed. KDM5C constructs were used to study the effect of the variations in transfected cells. RESULTS: We identified 2 novel variations c.2233C>G and c.3392_3393delAG in the KDM5C gene harboring from 2 Chinese families with X-linked intellectual disability (ID). The affected male patients exhibited severe ID, short stature, and facial dysmorphism. The 1 with c.3392_3393delAG additionally had epilepsy and autistic spectrum disorder (ASD). Transiently transfected mutant KDM5C constructs both reduced protein expression and stability and decreased histone demethylase activities in cells. Reviewing the available literature, we found that the associated ASD tended to occur in patients with variations near the C-terminus of KDM5C. DISCUSSION: We report the clinical, molecular genetic, and pathologic features in patients with novel variations of KDM5C. The variability of the clinical phenotype in addition to an ID may associate with altered particular parts of KDM5C.

Lactate Predicts Neurological Outcomes after Perinatal Asphyxia in Post-Hypothermia Era: A Prospective Cohort Study.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of mortality and neurological disability in infancy after perinatal asphyxia. Reliable biomarkers to predict neurological outcomes of neonates after perinatal asphyxia are still not accessible in clinical practice. METHODS: A prospective cohort study enrolled neonates with perinatal asphyxia. Biochemical blood tests and cerebral Doppler ultrasound were measured within 6 h of age and at the 4th day old. Neurological outcomes were assessed at 1 year old. RESULTS: Sixty-four neonates with perinatal asphyxia were enrolled. Fifty-eight (90%) had hypoxic-ischemic encephalopathy (HIE) including 20 (34%) Stage I, 21 (36%) Stage II, and 17 (29%) Stage III. In the asphyxiated infants without therapeutic hypothermia, HIE stage, PH, and base excess levels within 6 h of age were the predictors of adverse outcomes. In the asphyxiated infants receiving therapeutic hypothermia, HIE stage failed to predict outcomes. Instead, blood lactate levels and pulsatility index (PI) of medial cerebral arteries (MCA) either in 6 h of age or at the 4th day old independently predicted adverse outcomes. CONCLUSIONS: Blood lactate, which is a common accessible test at the hospital and MCA PI on cerebral ultrasound could predict adverse outcomes in asphyxiated infants receiving therapeutic hypothermia.

Global Transcriptional Repression of Diguanylate Cyclases by MucR1 Is Essential for Sinorhizobium-Soybean Symbiosis.

The ubiquitous bacterial second messenger c-di-GMP is intensively studied in pathogens but less so in mutualistic bacteria. Here, we report a genome-wide investigation of functional diguanylate cyclases (DGCs) synthesizing c-di-GMP from two molecules of GTP in Sinorhizobium fredii CCBAU45436, a facultative microsymbiont fixing nitrogen in nodules of diverse legumes, including soybean. Among 25 proteins harboring a putative GGDEF domain catalyzing the biosynthesis of c-di-GMP, eight functional DGCs were identified by heterogenous expression in Escherichia coli in a Congo red binding assay. This screening result was further verified by in vitro enzymatic assay with purified full proteins or the GGDEF domains from representative functional and nonfunctional DGCs. In the same in vitro assay, a functional EAL domain catalyzing the degradation of c-di-GMP into pGpG was identified in a protein that has an inactive GGDEF domain but with an active phosphodiesterase (PDE) function. The identified functional DGCs generally exhibited low transcription levels in soybean nodules compared to free-living cultures, as revealed in transcriptomes. An engineered upregulation of a functional DGC in nodules led to a significant increase of c-di-GMP level and symbiotic defects, which were not observed when a functional EAL domain was upregulated at the same level. Further transcriptional analysis and gel shift assay demonstrated that these functional DGCs were all transcriptionally repressed in nodules by a global pleiotropic regulator, MucR1, that is essential in Sinorhizobium-soybean symbiosis. These findings shed novel insights onto the systematic regulation of c-di-GMP biosynthesis in mutualistic symbiosis. IMPORTANCE The ubiquitous second messenger c-di-GMP is well-known for its role in biofilm formation and host adaptation of pathogens, whereas it is less investigated in mutualistic symbioses. Here, we reveal a cocktail of eight functional diguanylate cyclases (DGCs) catalyzing the biosynthesis of c-di-GMP in a broad-host-range Sinorhizobium that can establish nitrogen-fixing nodules on soybean and many other legumes. These functional DGCs are generally transcribed at low levels in soybean nodules compared to free-living conditions. The engineered nodule-specific upregulation of DGC can elevate the c-di-GMP level and cause symbiotic defects, while the upregulation of a phosphodiesterase that quenches c-di-GMP has no detectable symbiotic defects. Moreover, eight functional DGCs located on two different replicons are all directly repressed in nodules by a global silencer, MucR1, that is essential for Sinorhizobium-soybean symbiosis. These findings represent a novel mechanism of a strategic regulation of the c-di-GMP biosynthesis arsenal in prokaryote-eukaryote interactions.

Evaluation of Effects of Ractopamine on Cardiovascular, Respiratory, and Locomotory Physiology in Animal Model Zebrafish Larvae.

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect of RAC in aquatic animals. In this study, we aimed to explore the potential physiological response after acute RAC exposure in zebrafish by evaluating multiple endpoints like locomotor activity, oxygen consumption, and cardiovascular performance. Zebrafish larvae were subjected to waterborne RAC exposure at 0.1, 1, 2, 4, or 8 ppm for 24 h, and the corresponding cardiovascular, respiratory, and locomotion activities were monitored and quantified. In addition, we also performed in silico molecular docking for RAC with 10 zebrafish endogenous ß-adrenergic receptors to elucidate the potential acting mechanism of RAC. Results show RAC administration can significantly boost locomotor activity, cardiac performance, oxygen consumption, and blood flow rate, but without affecting the cardiac rhythm regularity in zebrafish embryos. Based on structure-based flexible molecular docking, RAC display similar binding affinity to all ten subtypes of endogenous ß-adrenergic receptors, from adra1aa to adra2db, which are equivalent to the human one. This result suggests RAC might act as high potency and broad spectrum ß-adrenergic receptors agonist on boosting the locomotor activity, cardiac performance, and oxygen consumption in zebrafish. To validate our results, we co-incubated a well-known ß-blocker of propranolol (PROP) with RAC. PROP exposure tends to minimize the locomotor hyperactivity, high oxygen consumption, and cardiac rate in zebrafish larvae. In silico structure-based molecular simulation and binding affinity tests show PROP has an overall lower binding affinity than RAC. Taken together, our studies provide solid in vivo evidence to support that RAC plays crucial roles on modulating cardiovascular, respiratory, and locomotory physiology in zebrafish for the first time. In addition, the versatile functions of RAC as ß-agonist possibly mediated via receptor competition with PROP as ß-antagonist.

Massive Gastric Hemorrhage after Indomethacin Therapy: A Rare Presentation and Critical Management in an Extremely Preterm Infant.

Indomethacin has been widely used in preterm infants with hemodynamically significant patent ductus arteriosus (PDA). Gastrointestinal complications of indomethacin have been reported in 5% of treated neonates. However, massive gastric mucosa hemorrhage is a rarely reported complication. To the best of our knowledge, the infant in this report is the smallest reported in the literature to have undergone successful surgery for such a complication. A male preterm infant weighing 566 g was born at 252/7 weeks of gestational age without a complicated maternal history. Soon after birth, he received nasal noninvasive respiratory support and minimal feeding. PDA was observed since the first day of life (DOL), treatments were initiated on the second DOL for the hemodynamical significance, and PDA was closed after two courses of indomethacin therapy (0.2 mg/kg). At midnight on the seventh DOL, generalized pallor, bloody gastric drainage, and a distended stomach were observed. Massive gastric bleeding was suspected. He suffered from intermittent hypotension, which was corrected with blood products and fluid resuscitation under monitoring with a radial arterial line. Gastric lavage with cooling saline was performed twice but in vain. Prior to surgical consultation, intravascular volume transfusion was given twice. An exploratory laparotomy was arranged after obtaining the parents' consent. Blood oozing from the gastric mucosa was observed through gastrostomy and was successfully stopped via epinephrine-soaked gauze compression. After the operation, his clinical course remained uneventful, and he was discharged without neurological anomaly at two-year follow-up. Physicians need to be cautious of indomethacin's effect on platelet dysfunction in preterm infants with multiple predisposing factors. The tendency for mucosal bleeding should be continuously monitored after indomethacin therapy.

Postnatal Serum Total Thyroxine of Very Preterm Infants and Long-Term Neurodevelopmental Outcome.

Primary congenital hypothyroidism is a disease associated with low serum thyroxine and elevated thyroid-stimulating hormone (TSH) levels. The processes of screening and treating congenital hypothyroidism, in order to prevent neurodevelopmental impairment (NDI) in newborns, have been well investigated. Unlike term infants, very preterm infants (VPIs) may experience low thyroxine with normal TSH levels (<10.0 µIU/mL) during long-stay hospitalization. In the current literature, thyroxine treatment has been evaluated only for TSH-elevated VPIs. However, the long-term impact of low thyroxine levels in certain VPIs with normal TSH levels deserves more research. Since July 2007, VPIs of this study unit received screenings at 1 month postnatal age (PNA) for serum TSH levels and total thyroxine (TT4), in addition to two national TSH screenings scheduled at 3-5 days PNA and at term equivalent age. This study aimed to establish the correlation between postnatal 1-month-old TT4 concentration and long-term NDI at 24 months corrected age among VPIs with serial normal TSH levels. VPIs born in August 2007-July 2016 were enrolled. Perinatal demography, hospitalization morbidities, and thyroid function profiles were analyzed, and we excluded those with congenital anomalies, brain injuries, elevated TSH levels, or a history of thyroxine treatments. In total, 334 VPIs were analyzed and 302 (90.4%) VPIs were followed-up. The postnatal TT4 concentration was not associated with NDI after multivariate adjustment (odd ratios 1.131, 95% confidence interval 0.969-1.32). To attribute the NDI of TSH-normal VPIs to a single postnatal TT4 concentration measurement may require more research.