Immediate and longer-term changes in mental health of children with parent-child separation experiences during the COVID-19 pandemic.

BACKGROUND: The psychological impact of the COVID-19 pandemic has been understudied among vulnerable populations. This study aimed to examine the immediate and longer-term changes in the mental health of children with parent-child separation experiences during the COVID-19 pandemic, and identify potential buffering opportunities for mental health. METHODS: This longitudinal cohort study used data from 723 rural Chinese children who provided data before (Oct. 2019) the COVID-19 pandemic and during the following 2 years. Changes in the probability of depressive symptoms, anxiety symptoms, non-suicide self-injurious (NSSI), suicidal ideation, suicide plan, and suicide attempt were tested across four waves using generalized estimating models (GEE). RESULTS: Compared with children who never experienced parent-child separation, children persistently separated from parents since birth experienced greater deterioration in all mental health in the 2-year follow-up (average change: depressive symptoms: ß = 0.59, 95% CI [0.26, 0.93]; anxiety symptoms: ß = 0.45, 95% CI [0.10, 0.81]; NSSI: ß = 0.66, 95% CI [0.31, 1.01]; suicide ideation: ß = 0.67, 95% CI [0.38, 0.96]; suicide plan: ß = 0.77, 95% CI [0.38, 1.15]; suicide attempt: ß = 1.12, 95% CI [0.63, 1.62]). However, children with childhood separation from their parents but reunited with them during the transition to adolescence showed similar even lower changes to counterparts who never experienced parent-child separation (all ps > 0.05). CONCLUSION: These results indicating improvements in supportiveness of the caregiving environment during the transition to adolescence may provide the opportunity to buffer the adverse impact of COVID-19 on mental health. Translating such knowledge to inform intervention and prevention strategies for youths exposed to adversity is a critical goal for the field.

Compression Property of TPEE-3D Fibrous Material and Its Application in Mattress Structural Layer.

Thermoplastic poly(ether/ester) elastomer (TPEE) has great potential as a mattress material due to its high resilience, breathability, and light weight. This study aimed to evaluate the feasibility of TPEE-3D fibrous material (T3DF), a three-dimensional block material made of TPEE fibers randomly aligned and loop-connected, for mattress application. After testing the compression properties of T3DF, the effects of T3DF structural layers on mattress firmness were investigated. The results showed that T3DF had good energy absorption capacity, broad indentation hardness range (126.94-333.82 N), and high compression deflection coefficient (2.79-4.39). The thickness and density of T3DF were the main factors influencing mattress firmness, and the impact of thickness was more significant (p < 0.05). Owing to the hard and soft segments contained in TPEE, T3DF could be used for both the padding and core layers of the mattress. The hardness value and Dsurface of the mattress with a T3DF padding layer increased with T3DF density but decreased with T3DF thickness. Moreover, the hardness value and Dsurface of the mattress with a T3DF core layer increased with T3DF density, while with T3DF thickness, its Dsurface increased and Dbottom decreased. Therefore, the thick and low-density T3DF padding layer could improve the comfort of the mattress surface, a thin T3DF core layer could satisfy both the softer surface and the firmer bottom of the mattress.

MIB-derived odor management based upon hydraulic regulation in small drinking water reservoirs: Principle and application.

The musty odorant (2-methylisoborneol, MIB) is prevalent in source water reservoirs and has become one of the major challenges for drinking water quality. This study proposes an approach to control the growth of MIB-producing cyanobacteria in a small reservoir based on hydraulic regulation, according to the results of long-term field investigations, laboratory culture experiments, model construction, and field application. Field investigations found that longer hydraulic retention time (HRT) is a factor that triggers MIB episodes. The culture study revealed that the maximum cell density, growth rate of MIB-producing Planktothricoides raciborskii, and MIB concentration are determined by the HRT (R2= 0.94, p-value < 0.001) and can be minimized by decreasing the HRT to less than 10 d. On this basis, an HRT regulation model was constructed and validated by field investigation, and critical HRT values were evaluated for 14 cyanobacteria genera. By decreasing the HRT to 5.4 ± 0.8 d, which is lower than the critical value of 7.5 ∼ 15.0 d, an MIB episode was successfully terminated in ZXD Reservoir in 2021. The results suggest that the proposed principle can provide a scientific basis for HRT regulation, which has been proved to be effective and feasible. This approach avoids negative impacts on water quality, does not require extra investment in engineering infrastructure, and in some cases may be applied readily by changing existing operational procedures. Therefore, HRT-based regulation is a promising strategy targeting MIB control and possibly for other cyanobacterial-derived water quality problems in small reservoirs.

Identification of urine biomarkers associated with early puberty in children: An untargeted metabolomics analysis.

A trend toward earlier pubertal maturation in both sexes has been shown in many countries. Early puberty affects an increasing proportion of children for reasons that remain obscure. Novel candidate biomarkers are strongly needed. We sought to apply untargeted metabolomic profiling to identify triggering mechanisms and candidate biomarkers in children with early puberty. Participants aged 7 - 12 years old were recruited directly from two elementary schools of Bengbu, Anhui Province, China, from Feb 2021 to May 2021. Early puberty was determined by breast and testicular development at baseline (May 2021) and 6-month later. Ultra-high-performance liquid chromatography-based untargeted metabolomic profiling was performed on urine samples of children with early puberty and control subjects. Metabolomic profiling for early puberty in a sex dependent manner. For boys, we identified several perturbed pathways, including histidine metabolism, glycine, serine and threonine metabolism, and selenoamino acid metabolism, associated with early puberty. In contrast, there were differences in pyruvate metabolism, one carbon pool by folate, and D-glutamine and D-glutamate metabolism pathways in girls with early puberty compared with controls. In addition, 4-hydroxyhippuric acid and 5-methoxytryptophol were shown as potential independent diagnostic biomarker for early puberty in boys, 3-hydroxybenzoic acid and glutaminylproline were shown as early biomarker for early puberty in girls, achieving area under the ROC curve of 0.71 and 0.72 in discriminating early puberty boys, and 0.70 and 0.74 in discriminating early puberty girls from controls. Through metabolomic analysis, we have identified metabolic perturbations and potential biomarkers of early puberty.

Identification and Characterization of a New Regulator, TagR, for Environmental Stress Resistance Based on the DNA Methylome of Streptomyces roseosporus.

DNA methylation is a defense that microorganisms use against extreme environmental stress, and improving resistance against environmental stress is essential for industrial actinomycetes. However, research on strain optimization utilizing DNA methylation for breakthroughs is rare. Based on DNA methylome analysis and KEGG pathway assignment in Streptomyces roseosporus, we discovered an environmental stress resistance regulator, TagR. A series of in vivo and in vitro experiments identified TagR as a negative regulator, and it is the first reported regulator of the wall teichoic acid (WTA) ABC transport system. Further study showed that TagR had a positive self-regulatory loop and m4C methylation in the promoter improved its expression. The ΔtagR mutant exhibited better hyperosmotic resistance and higher decanoic acid tolerance than the wild type, which led to a 100% increase in the yield of daptomycin. Moreover, enhancing the expression of the WTA transporter resulted in better osmotic stress resistance in Streptomyces lividans TK24, indicating the potential for wide application of the TagR-WTA transporter regulatory pathway. This research confirmed the feasibility and effectiveness of mining regulators of environmental stress resistance based on the DNA methylome, characterized the mechanism of TagR, and improved the resistance and daptomycin yield of strains. Furthermore, this research provides a new perspective on the optimization of industrial actinomycetes. IMPORTANCE This study established a novel strategy for screening regulators of environmental stress resistance based on the DNA methylome and discovered a new regulator, TagR. The TagR-WTA transporter regulatory pathway improved the resistance and antibiotic yield of strains and has the potential for wide application. Our research provides a new perspective on the optimization and reconstruction of industrial actinomycetes.

Association between early life adversity and allostatic load in girls with precocious puberty.

CONTEXT: The mechanisms underlying the elevated long-term health risk in girls with precocious puberty remain unclear, but might result from physiological wear and tear associated with greater exposure to early life adversity. OBJECTIVE: This study aims to explore early life adversity in girls with precocious puberty and its association with allostatic load. METHODS: Early life adversity and hair cortisol concentration were measured among 213 girls with precocious puberty (8.21 ± 1.07). Allostatic load score is constructed by using 13 physiological biomarkers representing four systems and hair cortisol concentration. Multivariate linear regression models have estimated the associations between cumulative early life adversity exposure with total and system-specific allostatic load scores. Associations between cumulative early life adversity and the risk of high allostatic load (3 + high-risk biomarkers) were tested using binary logistics regression. RESULTS: More than two-thirds (67.6%) of girls with central precocious puberty reported two or more early life adversity exposure. Compared to those with no early life adversity exposure, girls who reported early life adversity score ≥ 2 had significantly higher total allostatic load score (ß: 1.20-1.64, P < 0.001). Metabolic system was more sensitive to cumulative early life adversity exposure, each form of early life adversity exposure was associated with 0.48-unit increases in metabolic allostatic load score (95%CI: 0.06, 0.90, P = 0.026). Girls reported early life adversity score ≥ 3 were three times more likely to have a high allostatic load compared with those without early life adversity exposure in both unadjusted and adjusted models (ORadjusted=3.83, 95%CI: 1.17, 12.55, P = 0.001). CONCLUSION: Multisystem physiological dysregulation is observed in girls with central precocious puberty, which might result from cumulative wear-and-tear associated with early life adversity.

Jin-Zhen oral liquid for pediatric coronavirus disease (COVID-19): A randomly controlled, open-label, and non-inferiority trial at multiple clinical centers.

Background: As the coronavirus disease 2019 (COVID-19) pandemic progressed, especially with the emergence of the Omicron variant, the proportion of infected children and adolescents increased significantly. Some treatment such as Chinese herbal medicine has been administered for COVID-19 as a therapeutic option. Jin-Zhen Oral Liquid is widely used for pediatric acute bronchitis, while the efficacy and safety in the treatment of pediatric COVID-19 are unclear. Methods: We conducted a randomized controlled, open-label, multicenter, non-inferiority clinical study involving hospitalized children with mild to moderate COVID-19. Children eligible for enrollment were randomly assigned in a 1:1 ratio to Jin-Zhen Oral Liquid (the treatment group) and Jinhua Qinggan Granules (the positive control group) and received the respective agent for 14 days, followed by a 14-day follow-up after discontinuation of the treatment. The primary efficacy endpoint was the time to first negative viral testing. The secondary endpoints were the time and rate of major symptoms disappearance, duration of hospitalization, and the proportion of symptoms changed from asymptomatic or mild to moderate or severe/critical illness. In addition, the safety end points of any adverse events were observed. Results: A total of 240 child patients were assigned randomly into the Jin-Zhen Oral Liquid (117 patients) and Jinhua Qinggan Granules (123 patients) groups. There was no significant difference of the baselines in terms of the clinical characteristics and initial symptoms between the two groups. After 14-day administration, the time to first negative viral testing in the Jin-Zhen group (median 6.0 days, 95% CI 5.0-6.0) was significantly shorter compared with the positive control Jinhua Qinggan Granules group (median 7.0 days, 95% CI 7.0-8.0). The time and rate of major clinical symptoms disappearance were comparable to the positive control. The symptom disappearance time of pharyngalgia and hospitalization duration were significantly shortened in the Jin-zhen Oral Liquid group. No participants in either group experienced post-treatment exacerbation to severe or critical illness. No adverse events were observed in the Jin-Zhen Oral Liquid treatment group (0.0%) while 1 patient with adverse events occurred in the positive control Jinhua Qinggan granules group (0.8%). No serious adverse events were observed during the study period in both groups. Conclusion: Jin-Zhen Oral Liquid is safe and effective in the treatment of mild to medium COVID-19 in children. It is non-inferior to Jinhua Qinggan granules in shortening the time to first negative viral testing, the time and rate of major clinical symptoms disappearance, and the hospitalization duration. The results suggest that Jin-Zhen Oral Liquid can be a recommended drug for treatment of pediatric COVID-19 patients.

Early warning of MIB episode based on gene abundance and expression in drinking water reservoirs.

Cellular 2-methylisoborneol (MIB) yield of cyanobacteria varies under different conditions according to culture studies and field investigations, the causal mechanism remains unclear and results in ineffective MIB prediction. Through an intensive field survey during an MIB episode produced by Pseudanabaena cinerea in QCS reservoir, we demonstrated that MIB synthesis (mic) gene abundance (DNA) and expression (RNA) might be useful as parameters for early warning of MIB production. It was found that the abundance of mic DNA and RNA peaked ahead of MIB concentrations by 10 and 7 days, respectively. In addition, the RNA abundance (R2 = 0.45, p < 0.01) showed a slightly higher correlation with MIB compared to DNA abundance (R2 = 0.37, p < 0.01), suggesting that the conditions for the growth of Pseudanabaena cinerea might be slightly different from those for mic gene expression, which was verified by a culture experiment. The highest cell growth was obtained under 36 µmol photons m-2 s-1, while the highest cellular MIB yield and mic gene expression level were obtained under 85 µmol photons m-2 s-1. Our results clearly supported that light intensity was the virtual regulator governing the mic gene expression within the controlled culture experiment and the actual MIB episode in the reservoir. Besides these results, we developed an early warning model using mic gene abundance as an indicator of MIB episodes, which was verified in two other reservoirs. Our findings highlight the effect of light intensity on mic gene expression and MIB synthesis and provide an early warning tool targeting MIB episode prediction, which therefore should be of importance for source water authorities.

Biosynthesis of 2-methylisoborneol is regulated by chromatic acclimation of Pseudanabaena.

Cyanobacteria can sense different light color by adjusting the components of photosynthetic pigments including chlorophyll a (Chl a), phycoerythrin (PE), and phycocyanin (PC), etc. Filamentous cyanobacteria are the main producer of 2-methylisoborneol (MIB) and many can increase their PE levels so that they are more competitive in subsurface layer where green light is more abundant, and have caused extensive odor problems in drinking water reservoirs. Here, we identified the potential correlation between MIB biosynthesis and ambient light color induced chromatic acclimation (CA) of a MIB-producing Pseudanabaena strain. The results suggest Pseudanabaena regulates the pigment proportion through Type III CA (CA3), by increasing PE abundance and decreasing PC in green light. The biosynthesis of MIB and Chl a share the common precursor, and are positively correlated with statistical significance regardless of light color (R2=0.68; p<0.001). Besides, the PE abundance is also positively correlated with Chl a in green light (R2=0.57; p=0.019) since PE is the antenna that can only transfer the energy to PC and Chl a. In addition, significantly higher MIB production was observed in green light since more Chl a was synthesized.

miR-34a regulates silent synapse and synaptic plasticity in mature hippocampus.

AMPAR-lacking silent synapses are prevailed and essential for synaptic refinement and synaptic plasticity in developing brains. In mature brain, they are sparse but could be induced under several pathological conditions. How they are regulated molecularly is far from clear. miR-34a is a highly conserved and brain-enriched microRNA with age-dependent upregulated expression profile. Its neuronal function in mature brain remains to be revealed. Here by analyzing synaptic properties of the heterozygous miR-34a knock out mice (34a_ht), we have discovered that mature but not juvenile 34a_ht mice have more silent synapses in the hippocampus accompanied with enhanced synaptic NMDAR but not AMPAR function and increased spine density. As a result, 34a_ht mice display enhanced long-term potentiation (LTP) in the Schaffer collateral synapses and better spatial learning and memory. We further found that Creb1 is a direct target of miR-34a, whose upregulation and activation may mediate the silent synapse increment in 34a_ht mice. Hence, we reveal a novel physiological role of miR-34a in mature brains and provide a molecular mechanism underlying silent synapse regulation.

Analysis of sagittal spinal alignment at the adolescent age: for furniture design.

Knowledge of the parameters of the human spine is essential in designing ergonomic furniture. The purpose of this study was to evaluate spinal alignment in adolescents of various ages. The lengths, curvatures, and concave-convex spacings of the spine were investigated in 268 participants aged 9-18 years. Ten ages were classified, and the rate of increase of parameters was calculated for each age and age group. The results showed that spinal parameters, except for cervical lordosis, increased with age. Adolescents were classified as 9-10, 11-12, 13-15, and 16-18 years old. A rapid increment of lengths and concave-convex spacings occurred at ages 13-15, while that of curvatures occurred at ages 16-18. Spinal parameters differed significantly among the age groups (p < 0.05). Concave-convex spacings reflected differences in the spine more clearly than the other parameters. This study suggests the necessity of designing spine-related furniture based on spinal parameters, thus providing adaptive support for the adolescent spine, particularly the lumbar spine. Practitioner summary: This study examined spinal lengths, curvatures, and concave-convex spacings in adolescents aged 9-8 years and then divided them into four age groups. Concave-convex spacings effectively reflected spinal differences between age groups, particularly the lumbar spine. These results can inform the ergonomic design of spine-related furniture.HIGHLIGHTSSpinal parameters increased progressively between 9 and 18 years. Regression analysis showed good linear correlations between TK, LL, SK, TS, and LS with age.Age classification of adolescents was Group I (9-10 years), Group II (11-12 years), Group III (13-15 years), and Group IV (16-18 years). The rapid increment of lengths and concave-convex spacings were in Group III while that of curvatures were in Group IV.Concave-convex spacings were vital parameters to evaluate the global balance of the spine.The lumbar spine is an essential segment for characterizing spinal alignment.

Oriented bio-feeding control of the anaerobic biodegradation of ethinyl estradiol.

Up to 95% of hormones are excreted into domestic wastewater with urine or feces, but their macromolecules are difficult to biodegrade. This project studies the treatment of Ethinyl Estradiol (EE2) in swine wastewater in an Upstream Solids Reactor (USR), and explores a new method for oriented bio-feeding to regulate the anaerobic biodegradation process. It was found that the metabolism of lactic acid and propionic acid was accompanied by changes in EE2 content, but lactic acid molecules were not readily bioavailable, so adding propionic acid was more suitable. However, controlling the pH to lower (4.73) and higher (8.73) values inhibited further fermentation of acetic acid and propionic acid, which was not favorable for the removal of EE2. This is simply due to the fact that propionic acid as a carbon source changes the preference of the microbes for consuming EE2. The order of the effect of addition of propionic acid on the removal of EE2 was as follows: P400>P800>P0>P200 (addition of propionic acid). The P400 removal efficiency increased from 60% to 85%. In the metabolism of EE2, after oxidation, hydrolysis, ketosis, hydroxylation and enzymatic action, dienoic acid and oleic acid were generated, and there was no secondary pollution from EE2 metabolites. In conclusion, feeding microorganisms with propionic acid can enhance the anaerobic biodegradation of EE2, providing a new strategy for the anaerobic biodegradation and bioremediation of refractory pollutants.

Circadian time- and sleep-dependent modulation of cortical parvalbumin-positive inhibitory neurons.

Parvalbumin-positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time- and sleep-dependent manner throughout the 24-h day. We first show that PV-evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus-evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.

[Characteristics and Dfferences of Dissolved Oxygen Stratification in Different Tributaries of Three Gorges Reservoir During Impoundment Period].

Taking the Xiaojiang and Xiangxi Rivers, two typical tributaries of the Three Gorges Reservoir, as examples, this study analyzed and compared the hydrodynamic, thermal stratification, and temporal and spatial differences in dissolved oxygen (DO) and their responses to the water storage process in the two tributaries through field monitoring at different stages of the 2020 impoundment period. The results showed that:① at the initial stage of water storage, the DO in the surface layer of the Xiaojiang River was higher (7.00-13.00 mg·L-1) due to atmospheric reoxygenation and phytoplankton photosynthesis, and the oxycline appeared in the water depth of 3-5 m. A large area of anoxia (DO<2.00 mg·L-1) or even an anaerobic sublayer occurred in the water below 5 m. The DO in the Xiangxi River could be divided into three layers vertically:oxygen-rich surface water (8.00-12.00 mg·L-1), middle water (6.00-8.00 mg·L-1), and low-oxygen bottom water (4.00-6.00 mg·L-1). ② Thermal stratification provided a stable physical environment, whereas the upstream inflow and vegetation decomposition in the water-level fluctuation zone increased the content of organic matter, which likely increased the oxygen consumption which was conducive to the formation of an anaerobic bottom layer. In the Xiangxi River, the risk of hypoxia in the bottom water body was low because of the oxygen replenishment from the long-term downslope-bottom density current.③ Continuous monitoring also showed that the storage of the reservoir played a significant role in the replenishment of DO in tributaries, which effectively and rapidly improved the anaerobic phenomenon in the Xiaojiang River. In the Three Gorges Reservoir, it is feasible to ameliorate the water ecological problems such as anoxia and anaerobic conditions in the tributaries via reservoir operation. This study aids understanding of the characteristics and differences of DO stratification in different tributaries of the Three Gorges Reservoir, which can provide theoretical and technical support for reservoir ecological operation.

m4C DNA methylation regulates biosynthesis of daptomycin in Streptomyces roseosporus L30.

Despite numerous studies on transcriptional level regulation by single genes in drug producing Actinomyces, the global regulation based on epigenetic modification is not well explored. N4-methylcytosine (m4C), an abundant epigenetic marker in Actinomycetes' genome, but its regulatory mechanism remains unclear. In this study, we identify a m4C methyltransferase (SroLm3) in Streptomyces roseosporus L30 and multi-omics studies were performed and revealed SroLm3 as a global regulator of secondary metabolism. Notably, three BGCs in ΔsroLm3 strain exhibited decreased expression compared to wild type. In-frame deletion of sroLm3 in S.roseosporus L30 further revealed its role in enhancing daptomycin production. In summary, we characterized a m4C methyltransferase, revealed the function of m4C in secondary metabolism regulation and biosynthesis of red pigment, and mapped a series of novel regulators for daptomycin biosynthesis dominated by m4C methylation. Our research further indicated that m4C DNA methylation may contribute to a metabolic switch from primary to secondary metabolism in Actinomyces.

Driving forces for the growth of MIB-producing Planktothricoides raciborskii in a low-latitude reservoir.

In comparison with the middle- and high-latitude regions, the low-latitude regions are less associated with the occurrence of 2-methylisoborneol (MIB) episodes, since most of the previously identified MIB producers favor moderate/low light/temperature conditions. Here, we report a serious MIB outbreak over the period from Jul. 2018 to Jun. 2019 in a low-latitude reservoir with a mean annual water temperature of 25.6 °C. The MIB episode lasted for a long period, from Jul. 2018 to Jan. 2019, and Planktothricoides raciborskii was confirmed to be the main MIB producer. The growth characteristics of P. raciborskii were explored through both laboratory culturing and on-site verification experiments. The results indicated that this strain was not nutrient-sensitive at TN > 800 µg L-1 and TP > 10 µg L-1, but favored moderate light intensity (54 µmol photon m-2·s-1) and high temperature (30 °C). The two bloom-forming genera, Limnothrix and Aphanizomenon, favoring lower temperature and similar or relatively higher light intensity, showed much greater proliferation, about 13 folds (Limnothrix) and 58 folds (Aphanizomenon), from Dec. to Jun.; by contrast, the high water temperature (29.9 ± 2.8 °C) and light intensity (189.1 ± 87.6 µmol photon m-2·s-1) from Jul. to Nov. were not favorable to Limnothrix or Aphanizomenon, which might have created an opportunity for the growth of MIB-producing P. raciborskii. In addition, we also found that high temperature could promote the release of MIB from P. raciborskii cells, therefore exerting increased pressure on drinking water treatment processes.

Improving the Yield and Quality of Daptomycin in Streptomyces roseosporus by Multilevel Metabolic Engineering.

Daptomycin is a cyclic lipopeptide antibiotic with a significant antibacterial action against antibiotic-resistant Gram-positive bacteria. Despite numerous attempts to enhance daptomycin yield throughout the years, the production remains unsatisfactory. This study reports the application of multilevel metabolic engineering strategies in Streptomyces roseosporus to reconstruct high-quality daptomycin overproducing strain L2797-VHb, including precursor engineering (i.e., refactoring kynurenine pathway), regulatory pathway reconstruction (i.e., knocking out negative regulatory genes arpA and phaR), byproduct engineering (i.e., removing pigment), multicopy biosynthetic gene cluster (BGC), and fermentation process engineering (i.e., enhancing O2 supply). The daptomycin titer of L2797-VHb arrived at 113 mg/l with 565% higher comparing the starting strain L2790 (17 mg/l) in shake flasks and was further increased to 786 mg/l in 15 L fermenter. This multilevel metabolic engineering method not only effectively increases daptomycin production, but can also be applied to enhance antibiotic production in other industrial strains.

Casual Associations and Shape Between Prepuberty Body Mass Index and Early Onset of Puberty: A Mendelian Randomization and Dose-Response Relationship Analysis.

Background: There is an ongoing controversial issue regarding whether onset of puberty is related to childhood BMI. Objectives: This study aims at investigating the causal association and its shape between prepuberty BMI and early puberty onset. Methods: Breast development and testicular volume were assessed annually from a population-based prospective cohort of 997 children for consecutive years by professional endocrinologists. Seventeen puberty- and BMI-related SNPs were selected to calculate the polygenic risk score. The two-stage least square method was used to assess and confirm causal effects. A dose-response association between prepuberty BMI and early puberty onset was conducted by using restricted cubic spline Cox regression. Results: After adjusting for covariates, prepuberty BMI was positively associated with early thelarche among girls (coefficients = 0.18, 95% CI: 0.01, 0.29). A non-linear model suggested an inverted U-shaped relationship between prepuberty BMI and risk for early thelarche (χ2 = 276.3, p < 0.001). The risk for early thelarche increased rapidly from prepuberty BMI at 15.70 kg/m2 (P25) to 20.75 kg/m2 (P85) and gradually decreased afterward. Compared with the P25 of prepuberty BMI, the HRs (95% CI) for early thelarche were 5.08 (1.15, 8.55), 4.48 (1.02, 7.74), 10.15 (3.93, 17.50), and 8.43 (1.91, 13.71) for percentiles P25-P50, P50-P75, P75-P85, and ≥P85 of BMI categories, respectively. In boys, compared with the P25 of prepuberty BMI, boys with BMI between P25 and P50 showed an increased risk of early puberty (HR: 3.94, 95% CI: 1.44, 6.80). Conclusions: Prepuberty BMI may serve the purpose of identifying the girls at higher risk of early thelarche, which could assist in the adaptation of prevention and intervention strategies targeting childhood obesity. The findings emphasize a non-linear correlation between prepuberty BMI and early puberty onset.

A novel strategy of gene screen based on multi-omics in Streptomyces roseosporus.

Daptomycin is a new lipopeptide antibiotic for treatment of severe infection caused by multi-drug-resistant bacteria, but its production cost remains high currently. Thus, it is very important to improve the fermentation ability of the daptomycin producer Streptomyces roseosporus. Here, we found that the deletion of proteasome in S. roseosporus would result in the loss of ability to produce daptomycin. Therefore, transcriptome and 4D label-free proteome analyses of the proteasome mutant (Δprc) and wild type were carried out, showing 457 differential genes. Further, five genes were screened by integrated crotonylation omics analysis. Among them, two genes (orf04750/orf05959) could significantly promote the daptomycin synthesis by overexpression, and the fermentation yield in shake flask increased by 54% and 76.7%, respectively. By enhancing the crotonylation modification via lysine site mutation (K-Q), the daptomycin production in shake flask was finally increased by 98.8% and 206.3%, respectively. This result proved that the crotonylation modification of appropriate proteins could effectively modulate daptomycin biosynthesis. In summary, we established a novel strategy of gene screen for antibiotic biosynthesis process, which is more convenient than the previous screening method based on pathway-specific regulators. KEY POINTS: • Δprc strain has lost the ability of daptomycin production • Five genes were screened by multi-omics analysis • Two genes (orf04750/orf05959) could promote the daptomycin synthesis by overexpression.

Sleep duration trajectory during the transition to adolescence and subsequent risk of non-suicidal self-harm.

Non-suicidal self-harm (NSSH) and chronic insufficient sleep are both major health problems during the transition from childhood to adolescence. We examined to identify sleep duration trajectories from childhood to adolescence and their associations with subsequent risk of NSSH. A cohort of children around the period of pubertal onset (7-9 years old) were followed from 2013 over 6 years. Group-based trajectory modeling was recruited to identify sleep duration trajectories derived from 5 repeated measures. Association between sleep duration trajectories with the risk of NSSH was examined using multivariate logistic regression model. Nonlinear dose-response associations between sleep duration and NSSH risk were also assessed using restricted cubic spline models. Of the 1973 participants included in the study (mean ± SD, 8.1 ± 0.9 years age at baseline, 41.1% female). Three sleep duration trajectories were identified: persistent sleeping ≥ 8 h/day (27.7%), moderately decreasing (60.8%) and rapidly decreasing (11.5%) sleep duration groups. After multivariable adjustment for covariates, compared with the persistent sleeping ≥ 8 h/day group, the odds ratio of NSSH was 2.58 (95% CI 1.92, 3.45) for the moderately decreasing group, and 4.16 (2.86, 6.04) for rapidly decreasing group. In dose-response analysis, sleep duration was associated with NSSH risk in a non-linear fashion (χ2 = 25.16, Pnonlinearity < 0.001). When compared with the reference (sleep duration = 8 h), the ORs (95% CI) for NSSH risks were 3.20 (1.93, 5.29), 2.37 (1.64, 3.41), 1.75 (1.39, 2.20) and 1.30 (1.18, 1.44) for sleep duration at 4 to 7 h, respectively. Also, we found sleep duration at 9 h [0.82 (0.75, 0.89)] and at 10 h [0.72 (0.57, 0.91)] significantly associated with decreased risk of NSSH. Longitudinal sleep duration patterns may assist in identification of adolescents at greatest risk of NSSH in the future, which could lead to improved targeting of prevention and intervention strategies. The findings also highlight a non-linear relationship between sleep duration and NSSH during the transition to adolescence.