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Background: Whilst single chemical exposures are suspected to be obesogenic, the combined role of chemical mixtures in paediatric obesity is not well understood., Objectives: We aimed to evaluate the potential associations between chemical mixtures and obesity in a population-based sample of Canadian children., Methods: We ascertained biomonitoring and health data for children aged 3-11 from the cross-sectional Canadian Health Measures Survey from 2007 to 2019. Several chemicals of interest were measured in blood or urine and paediatric obesity was defined based on measured anthropometrics. Using quantile-based G computational analysis, we quantified the effects of three chemical mixtures selected a priori. Models were adjusted for sociodemographic and environmental factors identified through a directed acyclic graph. Results are presented through adjusted relative risks (RR) with 95% confidence intervals (95% CI)., Results: We included 9147 children. Of these, 24.1% were overweight or obese. Exposure to the mixture of bisphenol A, acrylamide, glycidamide, metals, parabens and arsenic increased the risk of childhood overweight or obesity by 45% (95% CI 1.09, 1.93), obesity by 109% (95% CI 1.27, 3.42) and central obesity by 82% (95% CI 1.30, 2.56)., Conclusions: Our findings support the role of early childhood chemical exposures in paediatric obesity and the potential combined effects of chemicals., (© 2024 His Majesty the King in Right of Canada. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation. Reproduced with the permission of the Minister of Health Canada.)

After intracerebral hemorrhage (ICH) occurs, the overproduction of reactive oxygen species (ROS) and iron ion overload are the leading causes of secondary damage. Removing excess iron ions and ROS in the meningeal system can effectively alleviate the secondary damage after ICH. This study synthesized ginsenoside Rb1 carbon quantum dots (RBCQDs) using ginsenoside Rb1 and ethylenediamine via a hydrothermal method. RBCQDs exhibit potent capabilities in scavenging ABTS + free radicals and iron ions in solution. After intrathecal injection, the distribution of RBCQDs is predominantly localized in the subarachnoid space. RBCQDs can eliminate ROS and chelate iron ions within the meningeal system. Treatment with RBCQDs significantly improves blood flow in the meningeal system, effectively protecting dying neurons, improving neurological function, and providing a new therapeutic approach for the clinical treatment of ICH., (© 2024. The Author(s).)

The assessment of consciousness states, especially distinguishing minimally conscious states (MCS) from unresponsive wakefulness states (UWS), constitutes a pivotal role in clinical therapies. Despite that numerous neural signatures of consciousness have been proposed, the effectiveness and reliability of such signatures for clinical consciousness assessment still remains an intense debate. Through a comprehensive review of the literature, inconsistent findings are observed about the effectiveness of diverse neural signatures. Notably, the majority of existing studies have evaluated neural signatures on a limited number of subjects (usually below 30), which may result in uncertain conclusions due to small data bias. This study presents a systematic evaluation of neural signatures with large-scale clinical resting-state electroencephalography (EEG) signals containing 99 UWS, 129 MCS, 36 emergence from the minimally conscious state, and 32 healthy subjects (296 total) collected over 3 years. A total of 380 EEG-based metrics for consciousness detection, including spectrum features, nonlinear measures, functional connectivity, and graph-based measures, are summarized and evaluated. To further mitigate the effect of data bias, the evaluation is performed with bootstrap sampling so that reliable measures can be obtained. The results of this study suggest that relative power in alpha and delta serve as dependable indicators of consciousness. With the MCS group, there is a notable increase in the phase lag index-related connectivity measures and enhanced functional connectivity between brain regions in comparison to the UWS group. A combination of features enables the development of an automatic detector of conscious states., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Escherichia coli Septu system, an anti-phage defense system, comprises two components: PtuA and PtuB. PtuA contains an ATPase domain, while PtuB is predicted to function as a nuclease. Here we show that PtuA and PtuB form a stable complex with a 6:2 stoichiometry. Cryo-electron microscopy structure of PtuAB reveals a distinctive horseshoe-like configuration. PtuA adopts a hexameric arrangement, organized as an asymmetric trimer of dimers, contrasting the ring-like structure by other ATPases. Notably, the three pairs of PtuA dimers assume distinct conformations and fulfill unique roles in recruiting PtuB. Our functional assays have further illuminated the importance of the oligomeric assembly of PtuAB in anti-phage defense. Moreover, we have uncovered that ATP molecules can directly bind to PtuA and inhibit the activities of PtuAB. Together, the assembly and function of the Septu system shed light on understanding other ATPase-containing systems in bacterial immunity., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aim: Disruption of functional brain connectivity is thought to underlie disorders of consciousness (DOC) and recovery of impaired connectivity is suggested as an indicator of consciousness restoration. We recently found that rhythmic acoustic-electric trigeminal-nerve stimulation (i.e., musical stimulation synchronized to electrical stimulation of the trigeminal nerve) in the gamma band can improve consciousness in patients with DOC. Here, we investigated whether these beneficial stimulation effects are mediated by alterations in functional connectivity., Methods: Sixty-three patients with DOC underwent 5 days of gamma, beta, or sham acoustic-electric trigeminal-nerve stimulation. Resting-state electroencephalography was measured before and after the stimulation and functional connectivity was assessed using phase-lag index (PLI)., Results: We found that gamma stimulation induces an increase in gamma-band PLI. Further characterization revealed that the enhancing effect is (i) specific to the gamma band (as we observed no comparable change in beta-band PLI and no effect of beta-band acoustic-electric stimulation or sham stimulation), (ii) widely spread across the cortex, and (iii) accompanied by improvements in patients' auditory abilities., Conclusion: These findings show that gamma acoustic-electric trigeminal-nerve stimulation can improve resting-state functional connectivity in the gamma band, which in turn may be linked to auditory abilities and/or consciousness restoration in DOC patients., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

In response to the persistent exposure to phage infection, bacteria have evolved diverse antiviral defense mechanisms. In this study, we report a bacterial two-component defense system consisting of a Sir2 NADase and a HerA helicase. Cryo-electron microscopy reveals that Sir2 and HerA assemble into a ∼1 MDa supramolecular octadecamer. Unexpectedly, this complex exhibits various enzymatic activities, including ATPase, NADase, helicase, and nuclease, which work together in a sophisticated manner to fulfill the antiphage function. Therefore, we name this defense system "Nezha" after a divine warrior in Chinese mythology who employs multiple weapons to defeat enemies. Our findings demonstrate that Nezha could sense phage infections, self-activate to arrest cell growth, eliminate phage genomes, and subsequently deactivate to allow for cell recovery. Collectively, Nezha represents a paradigm of sophisticated and multifaceted strategies bacteria use to defend against viral infections., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Iron overload and oxidative stress are pivotal in the pathogenesis of brain injury secondary to intracerebral hemorrhage (ICH). There is a compelling need for agents that can chelate iron and scavenge free radicals, particularly those that demonstrate substantial brain penetration, to mitigate ICH-related damage. In this study, we have engineered an amine-functionalized aspirin-derived carbon quantum dot (NACQD) with a nominal diameter of 6-13 nm. The NACQD possesses robust iron-binding and antioxidative capacities. Through intrathecal administration, NACQD therapy substantially reduced iron deposition and oxidative stress in brain tissue, alleviated meningeal inflammatory responses, and improved the recovery of neurological function in a murine ICH model. As a proof of concept, the intrathecal injection of NACQD is a promising therapeutic strategy to ameliorate the ICH injury.

Doublecortin-like kinase 1 (DCLK1) is a prominent kinase involved in carcinogenesis, serving as a diagnostic marker for early cancer detection and prevention, as well as a target for cancer therapy. Extensive research efforts have been dedicated to understanding its role in cancer development and designing selective inhibitors. In our previous work, we successfully determined the crystal structure of DCLK1 while it was bound to its autoinhibitory domain (AID) at the active site. By analyzing this structure, we were able to uncover the intricate molecular mechanisms behind specific cancer-causing mutations in DCLK1. Utilizing molecular dynamics simulations, we discovered that these mutations disrupt the smooth assembly of the AID, particularly affecting the R2 helix, into the kinase domain (KD). This disruption leads to the exposure of the D533 residue of the DFG (Asp-Phe-Gly) motif in the KD, either through steric hindrance, the rearrangement of electrostatic interactions, or the disruption of local structures in the AID. With these molecular insights, we conducted a screening process to identify potential small-molecule inhibitors that could bind to DCLK1 through an alternative binding mode. To assess the binding affinity of these inhibitors to the KD of DCLK1, we performed calculations on their binding energy and conducted SPR experiments. We anticipate that our study will contribute novel perspectives to the field of drug screening and optimization, particularly in targeting DCLK1.

Exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) is suggested to interfere with endocrine function and may affect female pubertal development. However, the epidemiological evidence on age at menarche associated with PFAS exposure is still inconsistent. Our objective was to investigate association of serum PFAS concentrations with age at menarche among 12-19 years old girls. We used data on 432 girls from National Health and Nutrition Examination Survey (NHANES) 2007-2012 cycles. NHANES reported serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) as quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Age at menarche was self-reported by girls or their guardians. Multivariable linear regression models were applied to estimate the association of individual PFAS exposure with age at menarche. The combined effects of PFAS mixture exposures on age at menarche were assessed using three statistical methods, including Bayesian kernel machine regression (BKMR), weighted quantile sum regression (WQS), and elastic net regression (ENR). In the single-chemical model, girls in the middle tertile of serum PFOA concentration had a lower age at menarche [regression coefficient (β) = -0.73 years, 95% confidence interval (CI): -1.44, -0.01; P = 0.047], compared with those in the lower tertile. Girls in the higher tertile of PFNA exposure were associated with older age at menarche (β = 0.36 years, 95% CI: 0.03, 0.80; P = 0.027), compared with those in the lower tertile. In the multiple-chemical models using BKMR and ENR approaches, higher PFNA exposure was significantly associated with older age at menarche among girls, after adjusting for other PFAS. We found suggestive evidence that higher PFAS mixture exposures may be related to an increase in age at menarche using the BKMR model. In conclusion, exposure to PFNA was associated with the later timing of menarche among girls., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the spacer acquisition stage of CRISPR-Cas immunity, spacer orientation and protospacer adjacent motif (PAM) removal are two prerequisites for functional spacer integration. Cas4 has been implicated in both processing the prespacer and determining the spacer orientation. In Cas4-lacking systems, host 3'-5' DnaQ family exonucleases were recently reported to play a Cas4-like role. However, the molecular details of DnaQ functions remain elusive. Here, we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system, in which a DnaQ domain naturally fuses with Cas2. We presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation module. Our biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different efficiencies. Based on these results, we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

To create a functional neural circuit, neurons develop a molecular identity to discriminate self from non-self. The invertebrate Dscam family and vertebrate Pcdh family are implicated in determining synaptic specificity. Recently identified in Chelicerata, a shortened Dscam (sDscam) has been shown to resemble the isoform-generating characters of both Dscam and Pcdh and represent an evolutionary transition. Here we presented the molecular details of sDscam self-recognition via both trans and cis interactions using X-ray crystallographic data and functional assays. Based on our results, we proposed a molecular zipper model for the assemblies of sDscam to mediate cell-cell recognition. In this model, sDscam utilized FNIII domain to form side-by-side interactions with neighboring molecules in the same cell while established hand-in-hand interactions via Ig1 domain with molecules from another cell around. Together, our study provided a framework for understanding the assembly, recognition, and evolution of sDscam., (© 2023. The Author(s).)

Wuhan Tianhe International Airport (WUH) was suspended to contain the spread of COVID-19, while Shanghai Hongqiao International Airport (SHA) saw a tremendous flight reduction. Closure of a major international airport is extremely rare and thus represents a unique opportunity to straightforwardly observe the impact of airport emissions on local air quality. In this study, a series of statistical tools were applied to analyze the variations in air pollutant levels in the vicinity of WUH and SHA. The results of bivariate polar plots show that airport SHA and WUH are a major source of nitrogen oxides. NO x , NO 2 and NO diminished by 55.8%, 44.1%, 76.9%, and 40.4%, 33.3% and 59.4% during the COVID-19 lockdown compared to those in the same period of 2018 and 2019, under a reduction in aircraft activities by 58.6% and 61.4%. The concentration of NO 2 , SO 2 and PM 2.5 decreased by 77.3%, 8.2%, 29.5%, right after the closure of airport WUH on 23 January 2020. The average concentrations of NO, NO 2 and NO x scatter plots at downwind of SHA after the lockdown were 78.0%, 47.9%, 57.4% and 62.3%, 34.8%, 41.8% lower than those during the same period in 2018 and 2019. However, a significant increase in O 3 levels by 50.0% and 25.9% at WUH and SHA was observed, respectively. These results evidently show decreased nitrogen oxides concentrations in the airport vicinity due to reduced aircraft activities, while amplified O 3 pollution due to a lower titration by NO under strong reduction in NO x emissions., (Copyright © 2022. Published by Elsevier B.V.)

White matter disruption plays an important role in disorders of consciousness (DOC). The aim of this study was to analyze the connectometry between DOC patients and healthy controls and to explore the relationship between diffusion connectometry and levels of consciousness. Fourteen patients with DOC and 13 sex- and age-matched controls were included in this study. The participants underwent diffusion magnetic resonance imaging (MRI) and T1-weighted structural MRI at 7 Tesla. Diffusion MRI connectometry was performed to investigate the differences between groups, and to subsequently study the correlation between Coma Recovery Scale-Revised (CRS-R) indexes and white matter integrity. In DOC patients, the quantitative anisotropy (QA) was significantly reduced in deep white matter tracts, whereas significantly higher QA values were found in the bilateral cerebellum compared with healthy controls. Moreover, the QA values in many tracts within the right hemisphere were higher in patients in a minimally conscious state compared to those in vegetative state/unresponsive wakefulness syndrome, which was reflected by the correlation between diffusion connectometry and CRS-R indexes. These results indicate that the cerebellum may play an important role in DOC, and the lateralization of the cerebral hemisphere in affected patients may suggest neural compensation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Good diet quality during pregnancy provides adequate nutrition to support both the mothers and the fetus. The objective of this study is to describe the distribution of diet quality during pregnancy and to study the association between social factors and diet quality during pregnancy in a Canadian population. This study was based on 1535 pregnant women who provided dietary information in the 3D Cohort Study in Quebec, Canada. A 3-day food record was used to collect dietary intake in the second trimester of pregnancy. A Canadian adaption of the Healthy Eating Index (HEI-C) 2010 was used to quantify diet quality. Univariate and multiple linear regression models were used to calculate unadjusted and adjusted effect estimates and confidence intervals for the association between social factors and HEI-C. The mean HEI-C 2010 score in this study was 62.9 (SD: 11.2). Only 4.5% and 8.3% of the pregnant women consumed the recommended amounts of whole grains and 'greens and beans', respectively. Diet quality was lower in some subgroups of pregnant women. After multivariable adjustment, lower diet quality was observed in participants who were less educated, younger, overweight or obese before pregnancy, or parous. There was an interaction between ethnicity and immigration status on diet quality in pregnancy. These findings could be useful for health practitioners and policymakers in developing strategies to improve the diet quality of pregnant women., (© 2022 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Electric vehicles (EVs) have been promoted acceleratively to reduce greenhouse gas (GHG) emissions, however, the GHG emission reduction potential of different powertrain EVs has not been investigated thoroughly. In this study, we firstly quantified and compared the GHG emissions of different powertrain vehicles in a life cycle perspective with particular focus on energy and climate consequences, for current and future integrated scenarios, to facilitate carbon reduction assessment for Shanghai. Four major types of EVs were considered. The results show that life cycle total energy consumption and GHG emissions of all EVs are lower than that of gasoline internal combustion engine vehicles (GICEVs), among which battery-powered electric vehicles (BEVs) is the lowest. Compared with GICEVs, the total energy use and GHG emissions of BEVs decrease by 34.2% and 41.7% respectively. As the electrification of vehicle powertrain system innovates, the life cycle emissions of GHG are gradually concentrated to the upstream stage. The sensitivity analysis demonstrates that life cycle GHG emissions of vehicles are most sensitive to the proportion of thermal power than other three parameters (utilization rate of recycled steel, vehicle lifetime and curb weight). The scenario analysis indicates that BEVs present the more favorable carbon emission decline performance over other EVs from a long-term perspective. It is estimated that up to 12.5 million tons of GHG emissions could be reduced under the optimistic scenario in 2050 in Shanghai. In the process of energy conversion from oil to electricity in transport in Shanghai, BEVs should be constantly promoted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-β-carboline (PAC), a tubulin inhibitor, promotes selective degradation of αβ-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation. The degradation is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and βGlu198, which is identified as a low-barrier hydrogen bond (LBHB). In contrast, another two tubulin inhibitors that only form normal hydrogen bonds with βGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. We then screened for compounds capable of forming an LBHB with βGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimer degradation through the LBHB. Our study provided a unique example of LBHB function and identified a novel approach to obtain tubulin degraders.

The intestinal microbiota regulate the brain function of the host through the production of a myriad of metabolites and are associated with various neurological diseases. Understanding the intestinal microbiome of patients with prolonged disorders of consciousness (DoC) is important for the evaluation and treatment of the disease. To investigate the differences in the intestinal microbiome and short-chain fatty acids (SCFAs) among patients in a vegetative state (VS), a minimally conscious state (MCS), and emerged from MCS (EMCS), as well as the influence of antibiotics on these patients, 16S ribosomal RNA (16S rRNA) sequencing and targeted lipidomics were performed on fecal samples from patients; in addition, analysis of the electroencephalogram (EEG) signals was performed to evaluate the brain function of these patients. The results showed that the intestinal microbiome of the three groups differed greatly, and some microbial communities showed a reduced production of SCFAs in VS patients compared to the other two groups. Moreover, reduced microbial communities and five major SCFAs, along with attenuated brain functional connectivity, were observed in MCS patients who were treated with antibiotics compared to those who did not receive antibiotic treatment, but not in the other pairwise comparisons. Finally, three genus-level microbiota- Faecailbacterium, Enterococcus , and Methanobrevibacter -were considered as potential biomarkers to distinguish MCS from VS patients, with high accuracy both in the discovery and validation cohorts. Together, our findings improved the understanding of patients with prolonged DoC from the intestinal microbiome perspective and provided a new reference for the exploration of therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Cheng, He, Meng, Yu, Xu, Wen, Hong, Gao, Li, Pan, Li and Luo.)

The neurophysiological basis of the association between interhemispheric connectivity and speech comprehension processing remains unclear. This prospective study examined regional cerebral blood flow (CBF), homotopic functional connectivity, and neurovascular coupling, and their effects on comprehension performance in post-stroke aphasia. Multimodal imaging data (including data from functional magnetic resonance imaging and arterial spin labeling imaging) of 19 patients with post-stroke aphasia and 22 healthy volunteers were collected. CBF, voxel-mirrored homotopic connectivity (VMHC), CBF-VMHC correlation, and CBF/VMHC ratio maps were calculated. Between-group comparisons were performed to identify neurovascular changes, and correlation analyses were conducted to examine their relationship with the comprehension domain. The correlation between CBF and VMHC of the global gray matter decreased in patients with post-stroke aphasia. The total speech comprehension score was significantly associated with VMHC in the peri-Wernicke area [posterior superior temporal sulcus (pSTS): r = 0.748, p = 0.001; rostroventral area 39: r = 0.641, p = 0.008]. The decreased CBF/VMHC ratio was also mainly associated with the peri-Wernicke temporoparietal areas. Additionally, a negative relationship between the mean CBF/VMHC ratio of the cingulate gyrus subregion and sentence-level comprehension was observed ( r = -0.658, p = 0.006). These findings indicate the contribution of peri-Wernicke homotopic functional connectivity to speech comprehension and reveal that abnormal neurovascular coupling of the cingulate gyrus subregion may underly comprehension deficits in patients with post-stroke aphasia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Shang, Ye, Ling, Zhong, Zhang, Zhang, Zhang, Yu, He, Ye and Luo.)

Lignin is a renewable bioresource that can be used for a variety of value-added applications. However, the effective separation of lignin from lignocellulosic biomass remains an ongoing challenge. In this study, lignin was extracted from waste palm fiber and successfully converted into a dehumidifying material. The following four process parameters of lignin extraction from palm fiber were optimized systematically and comprehensively using the response surface methodology: reaction time, extraction temperature, ethanol concentration and solid/liquid ratio. The results revealed that under the optimum processing conditions (111 min of extraction at 174 °C using 73% ethanol at 1/16 g/mL solid/liquid ratio), the extraction yield of lignin was 56.2%. The recovery of ethanol solvent was as high as 91.8%. Further, the lignin could be directly used without purification to produce lignin-based activated carbon fibers (LACFs) with specific surface area and total pore volume of 1375 m 2 /g and 0.881 cm 3 /g, respectively. Compared with the commercial pitch-based activated carbon fiber, the LACF has a higher specific area and superior pore structure parameters. This work provides a feasible route for extracting lignin from natural palm fiber and demonstrates its use in the preparation of activated carbon fiber with a remarkable performance as a solid dehumidification agent., (© 2022. The Author(s).)

Large scale genomic aberrations including duplication, deletion, translocation, and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of cancer. The current prime editor, PE2, consisting of Cas9-nickase and reverse transcriptase enables efficient editing of genomic deletion and insertion, however, at small scale. Here, we designed a novel prime editor by fusing reverse transcriptase (RT) to nuclease wild-type Cas9 (WT-PE) to edit large genomic fragment. WT-PE system simultaneously introduced a double strand break (DSB) and a single 3' extended flap in the target site. Coupled with paired prime editing guide RNAs (pegRNAs) that have complementary sequences in their 3' terminus while target different genomic regions, WT-PE produced bi-directional prime editing, which enabled efficient and versatile large-scale genome editing, including large fragment deletion up to 16.8 megabase (Mb) pairs and chromosomal translocation. Therefore, our WT-PE system has great potential to model or treat diseases related to large-fragment aberrations., (© 2022. The Author(s).)

Background: Obesity is a priority public health concern in Canada and other parts of the world. The study primarily aims at assessing the role of  self-perceived work and life stress on obesity among working adults in Canada., Methods: The study was conducted based on a total of 104,636 Canadian adults aged 18 and above, extracted from the 2017-2018 Canadian Community Health Survey (CCHS) data. We used a mixed-effect logistic regression model to determine the possible association between two stress variables and obesity, controlling for other variables in the model. The random effect term accounts for the correlation among the observations from the same health region., Results: A total of 63,815 adult respondents (aged 18 and above) who were working during the 12 months prior to the survey were studied. Of those, 18.7% were obese based on their self-reported BMI > =30.0 kg/m 2 . More than two-thirds of the respondents reported that their stress level is a bit stressful to extremely stressful. The results of multivariable mixed-effect logistic regression showed that the odds of obesity were 1.432 times (95% CI: 1.248-1.644) among those who reported extremely work-related stress, compared to those who had no work-related stress. Perceived life stress was not significantly associated with obesity risk among working adult population, after adjusting other factors., Conclusion: The study concluded that obesity among Canadian adults is 18.7% of the working adult population being obese. Given the reported high prevalence of stress and its effect on obesity, the findings suggested improving social support systems, individual/group counseling, and health education focusing on work environments to prevent and manage stressors and drivers to make significant program impacts., (© 2022. The Author(s).)

Naming is a commonly impaired language domain in various types of aphasia. Emerging evidence supports the cortico-subcortical circuitry subserving naming processing, although neurovascular regulation of the non-dominant thalamic and basal ganglia subregions underlying post-stroke naming difficulty remains unclear. Data from 25 subacute stroke patients and 26 age-, sex-, and education-matched healthy volunteers were analyzed. Region-of-interest-wise functional connectivity (FC) was calculated to measure the strength of cortico-subcortical connections. Cerebral blood flow (CBF) was determined to reflect perfusion levels. Correlation and mediation analyses were performed to identify the relationship between cortico-subcortical connectivity, regional cerebral perfusion, and naming performance. We observed increased right-hemispheric subcortical connectivity in patients. FC between the right posterior superior temporal sulcus (pSTS) and lateral/medial prefrontal thalamus (lPFtha/mPFtha) exhibited significantly negative correlations with total naming score. Trend-level increased CBF in subcortical nuclei, including that in the right lPFtha, and significant negative correlations between naming and regional perfusion of the right lPFtha were observed. The relationship between CBF in the right lPFtha and naming was fully mediated by the lPFtha-pSTS connectivity in the non-dominant hemisphere. Our findings suggest that perfusion changes in the right thalamic subregions affect naming performance through thalamo-cortical circuits in post-stroke aphasia. This study highlights the neurovascular pathophysiology of the non-dominant hemisphere and demonstrates thalamic involvement in naming after stroke., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To assess relationships between breast-feeding, rapid growth in the first year of life and overweight/obesity status at the age of 2 years., Design: As part of an observational, longitudinal study beginning in early pregnancy, multivariable logistic regressions were used to assess associations between breast-feeding duration (total and exclusive) and rapid weight gain (RWG) between birth and 1 year of age, and to determine predictors of overweight/obesity status at the age of 2 years., Setting: Nine hospitals located in the province of Quebec, Canada., Participants: A sample of 1599 term infants who participated in the 3D Cohort Study., Results: Children having RWG in the first year and those having excess weight at the age of 2 years accounted for 28 % and < 10 %, respectively. In multivariable models, children breastfed < 6 months and from 6 months to < 1 year were, respectively, 2·5 times (OR 2·45; 95 % CI 1·76, 3·41) and 1·8 times (OR 1·78; 95 % CI 1·29, 2·45) more likely to show RWG up to 1 year of age compared to children breastfed ≥ 1 year. Children exclusively breastfed < 3 months had significantly greater odds of RWG in the first year (OR 1·94; 95 % CI 1·25, 3·04) compared to children exclusively breastfed for ≥ 6 months. Associations between breast-feeding duration (total or exclusive) and excess weight at the age of 2 years were not detected. RWG in the first year was found to be the main predictor of excess weight at the age of 2 years (OR 6·98; 95 % CI 4·35, 11·47)., Conclusions: The potential beneficial effects of breast-feeding on rate of growth in the first year of life suggest that interventions promoting breast-feeding are relevant for obesity prevention early in life.

Caffeic acid O-methyltransferase from Ligusticum chuanxiong (LcCOMT) showed strict regiospecificity despite a relative degree of preference. Compared with caffeic acid, methyl caffeate was the preferential substrate by its low Km and high Kcat. In this study, we obtained the SAM binary (1.80 Å) and SAH binary (1.95 Å) complex LcCOMT crystal structures, and established the ternary complex structure with methyl caffeate by molecular docking. The active site of LcCOMT included phenolic substrate pocket, SAM/SAH ligand pocket and conserved catalytic residues as well. The regiospecificity of LcCOMT that permitted only 3-hydroxyl group to be methylated arise from the interactions between the active site and the phenyl ring. However, the propanoid tail governed the relative preference of LcCOMT. The ester group in methyl caffeate stabilized the anionic intermediate caused by His268-Asp269 pair, whereas caffeic acid was unable to stabilize the anionic intermediate due to the adjacent carboxylate anion in the propanoid tail. Ser183 residue formed an additional hydrogen bond with SAH and its role was identified by S183A mutation. Ile318 residue might be a potential site for determination of substrate preference, and its mutation led to the change of tertiary conformation. The results supported the selective mechanism of LcCOMT., (Copyright © 2021. Published by Elsevier B.V.)

Accumulating evidence shows that consciousness is linked to neural oscillations in the thalamocortical system, suggesting that deficits in these oscillations may underlie disorders of consciousness (DOC). However, patient-friendly non-invasive treatments targeting this functional anomaly are still missing and the therapeutic value of oscillation restoration has remained unclear. We propose a novel approach that aims to restore DOC patients' thalamocortical oscillations by combining rhythmic trigeminal-nerve stimulation with comodulated musical stimulation ("musical-electrical TNS"). In a double-blind, placebo-controlled, parallel-group study, we recruited 63 patients with DOC and randomly assigned them to groups receiving gamma, beta, or sham musical-electrical TNS. The stimulation was applied for 40 min on five consecutive days. We measured patients' consciousness before and after the stimulation using behavioral indicators and neural responses to rhythmic auditory speech. We further assessed their outcomes one year later. We found that musical-electrical TNS reliably lead to improvements in consciousness and oscillatory brain activity at the stimulation frequency: 43.5 % of patients in the gamma group and 25 % of patients in the beta group showed an improvement of their diagnosis after being treated with the stimulation. This group of benefitting patients still showed more positive outcomes one year later. Moreover, patients with stronger behavioral benefits showed stronger improvements in oscillatory brain activity. These findings suggest that brain oscillations contribute to consciousness and that musical-electrical TNS may serve as a promising approach to improve consciousness and predict long-term outcomes in patients with DOC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Thalamus and thalamocortical connectivity are crucial for consciousness; however, their microstructural changes in patients with a disorder of consciousness (DOC) have not yet been thoroughly characterized. In the present study, we applied the novel fixel-based analysis to comprehensively investigate the thalamus-related microstructural abnormalities in 10 patients with DOC using 7-T diffusion-weighted imaging data. We found that compared to healthy controls, patients with DOC showed reduced fiber density (FD) and fiber density and cross-section (FDC) in the mediodorsal, anterior, and ventral anterior thalamic nuclei, while fiber-bundle cross-section (FC) was not significantly altered in the thalamus. Impaired thalamocortical connectivity in the DOC cohort was mainly connected to the middle frontal gyrus, anterior cingulate gyrus, fusiform gyrus, and sensorimotor cortices, including the precentral gyrus and postcentral gyrus, with predominant microstructural abnormalities in FD and FDC. Correlation analysis showed that FC of the right mediodorsal thalamus was negatively correlated with the level of consciousness. Our results suggest that microstructural abnormalities of thalamus and thalamocortical connectivity in DOC were mainly attributed to axonal injury. In particular, the microstructural integrity of the thalamus is a vital factor in consciousness generation., (© 2021 Wiley Periodicals LLC.)

Doublecortin-like kinase 1 (DCLK1) is upregulated in many tumors and is a marker for tumor stem cells. Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy. However, the regulation of DCLK1 kinase activity is poorly understood, particularly the function of its autoinhibitory domain (AID), and, moreover, no physiological activators of DCLK1 have presently been reported. Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1. The C-terminal AID functions to block the ATP-binding site and is competitive with ATP. HPCAL1 binds directly to the AID in a Ca 2+ -dependent manner, which releases the autoinhibition. We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation. Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

C1q tumor necrosis factor-related proteins (CTRPs), which are members of the adipokine superfamily, have gained significant interest in the recent years. CTRPs are homologs of adiponectin with numerous functions and are closely associated with metabolic diseases, such as abnormal glucose and lipid metabolism and diabetes. Previous studies have demonstrated that CTRPs are highly involved in the regulation of numerous physiological and pathological processes, including glycolipid metabolism, protein kinase pathways, cell proliferation, cell apoptosis and inflammation. CTRPs also play important roles in the development and progression of numerous types of tumor, including liver, colon and lung cancers. This observation can be attributed to the fact that diabetes, obesity and insulin resistance are independent risk factors for tumorigenesis. Numerous CTRPs, including CTRP3, CTRP4, CTRP6 and CTRP8, have been reported to be associated with tumor progression by activating multiple signal pathways. CTRPs could therefore be considered as diagnostic markers and therapeutic targets in some cancers. However, the underlying mechanisms of CTRPs in tumorigenesis remain unknown. The present review aimed to determine the roles and underlying mechanisms of CTRPs in tumorigenesis, which may help the development of novel cancer treatments in the future., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kong et al.)

While converging evidence suggests linguistic roles of white matter tracts, detailed associations between white matter alterations of dual pathways and language abilities remain unknown in aphasic patients. We aimed to verify language functions of dual-pathway tracts from specific domains and investigate the influence of moderators. PubMed, Web of Science, Embase, and CENTRAL were searched for studies published between January 1, 1985 and March 17, 2019. A meta-analysis of 46 studies including 1353 aphasic patients was performed by pooling correlation coefficients between linguistic domains and diffusion metrics of dual-pathway tracts. Among these tracts, the fractional anisotropy (FA) value of the left inferior fronto-occipital fasciculus predominated across most linguistic aspects, showing the strongest correlations with global severity, comprehension, naming and reading ability. The left uncinate fasciculus and inferior longitudinal fasciculus also showed significant FA - comprehension correlations. For syntactic processing, FA values of the left superior longitudinal fasciculus and arcuate fasciculus showed significant positive correlations. Meta-regression revealed no influence of etiology on FA - language correlations, while sex had a moderating effect on the FA - comprehension correlation of the arcuate fasciculus, and age influenced the FA - naming correlation in the superior longitudinal fasciculus. In conclusion, multifunctional characteristics of tracts were revealed in aphasic patients, including broad linguistic associations of the inferior fronto-occipital fasciculus, and repetition and syntactic involvement of the arcuate fasciculus. Language associations of the inferior longitudinal fasciculus and uncinate fasciculus were clarified regarding comprehension subdomains. The insignificant moderating effect of the etiology indicates damage of dual pathways is the common neural mechanism, while sex and age influence the correlation with comprehension and naming ability, respectively, in specific tracts., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Although the resting-state networks of patients with disorders of consciousness (DOC) have been widely investigated, the underlying neural mechanisms remain unclear. Here we aimed to explore the static and dynamic alterations in the regional brain activity in patients with DOC and detect the diagnostic ability of each index. Nineteen patients in the vegetative state, 19 in the minimally conscious state (MCS), and 41 healthy controls were recruited for this study. The fractional amplitudes of the low-frequency fluctuation (fALFF) and dynamic fALFF (dfALFF) values were computed, and intergroup differences were detected by analysis of variance. Sub-frequency analysis (slow-4 band and slow-5 band) of fALFF was also performed. Machine learning classifiers were established based on these measures to explore the classification accuracies between patients and controls. The fALFF and dfALFF analyses showed significant intergroup differences in the medial prefrontal gyrus, precuneus, left angular gyrus, and right middle cingulate cortex (MCC), whereas only the dfALFF analysis revealed aberrations in the right inferior frontal gyrus (IFG), right angular gyrus, left supramarginal gyrus (SMG), and left middle occipital gyrus (MOG). Sub-frequency analysis suggested a potential frequency dependent alteration in the default mode network (DMN). The fALFF model exhibited a higher classification accuracy (ACC) (90.50%) than the dfALFF model (86.29%). The combination of fALFF and dfALFF did not improve classification performance. The strength and stability of regional brain activities were disrupted in patients with DOC. Our findings demonstrate that dynamic analysis may reveal more pathological regions and provide a better understanding of the pathophysiologic mechanisms of DOC., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objectives: Although laboratory parameters have long been recognized as indicators of outcome of traumatic brain injury (TBI), it remains a challenge to predict the recovery of disorder of consciousness (DOC) in severe brain injury including TBI. Recent advances have shown an association between alterations in brain connectivity and recovery from DOC. In the present study, we developed a prognostic model of DOC recovery via a combination of laboratory parameters and resting-state functional magnetic resonance imaging (fMRI)., Methods: Fifty-one patients with DOC (age = 52.3 ± 15.2 y, male/female = 31/20) were recruited from Hangzhou Hospital of Zhejiang CAPR and were sub-grouped into conscious (n = 34) and unconscious (n = 17) groups based upon their Glasgow Outcome Scale-Extended (GOS-E) scores at 12-month follow-ups after injury. Resting-state functional connectivity, network nodal measures (centrality), and laboratory parameters were obtained from each patient and served as features for support vector machine (SVM) classifications., Results: We found that functional connectivity was the most accurate single-domain model (ACC: 70.1% ± 4.5%, P = 0.038, 1000 permutations), followed by degree centrality, betweenness centrality, and laboratory parameters. The stacked multi-domain prognostic model (ACC: 73.4% ± 3.1%, P = 0.005, 1000 permutations) combining all single-domain models yielded a significantly higher accuracy compared to that of the best-performing single-domain model (P = 0.002)., Conclusion: Our results suggest that laboratory parameters only contribute to the outcome prediction of DOC patients, whereas combining information from neuroimaging and clinical parameters may represent a strategy to achieve a more accurate prognostic model, which may further provide better guidance for clinical management of DOC patients., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Epidemiological evidence regarding the link between cancer and atrial fibrillation (AF) are limited and outcomes of metastatic cancer comorbid with AF need to be elucidated., Objective: This study aims to evaluate the prevalence, temporal trends, and outcomes of AF in hospitalized metastatic cancer patients., Methods: The National Inpatient Sample (NIS) database was used to identify adult patients with metastatic tumors from 2003 to 2014. We analyzed the trends in AF prevalence, in-hospital mortality, total cost, length of stay (LOS), and comorbidities pertaining to metastatic cancer. Multivariable-adjusted models were used to evaluate the association of AF with clinical factors, in-hospital mortality, total cost, and LOS., Results: Among 2,478,598 patients with metastatic cancer, 8.74% (216,737) were diagnosed with AF. The proportion of comorbid AF increased from 8.28% in 2003 to 10.06% in 2014 (p < 0.0001). Older age, white race, male, Medicare, higher income, larger hospital bed size, and urban teaching hospital were associated with higher AF occurrence. Among primary tumor sites, lung cancer experienced the highest odds of AF compared to other cancers. Patients with metastasis to lymph node and respiratory organ had higher odds of AF. In metastatic cancer, AF was associated with higher in-hospital mortality (odds ratio: 1.48; 95% confidence interval: 1.43-1.54), 18% longer LOS, and 19% higher cost., Conclusions: AF prevalence in metastatic cancer continues to increase from 2003 to 2014. AF is linked to poorer prognosis and higher healthcare resource utilization. As the population ages, optimal preventive and treatment management strategies are needed for metastatic cancer comorbid with AF., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In the adaptation stage of CRISPR-Cas systems, the Cas1-Cas2 integrase captures and integrates new invader-derived spacers into the CRISPR locus, serving as a molecular memory of prior infection. As of yet, the structural information of Cas1-Cas2 complex is available only for two species. Here we present the crystal structure of Cas1-Cas2 complex of Pyrococcus furiosus, which showed a distinct architecture from the known Cas1-Cas2 complexes. The shorter C-terminal tail of Pfu Cas2 directs the Cas1 dimers go in the opposite direction, resulting in a different prespacer binding mode. Based on our structural and mutagenesis results, we modeled a prespacer with a shorter duplex and longer 3' overhangs to bind Pfu Cas1-Cas2 complex. The prespacer preference was confirmed by EMSA, fluorescence polarization, and in vitro integration assays. This model provides a potential explanation for the longer spacer acquisition observed in P. furiosus when deleting both cas4 genes. Our study highlights the diversity of the CRISPR adaptation module., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Microtubules, composed of αβ-tubulin heterodimers, have remained popular anticancer targets for decades. Six known binding sites on tubulin dimers have been identified thus far, with five sites on β-tubulin and only one site on α-tubulin, hinting that compounds binding to α-tubulin are less well characterized. Cevipabulin, a microtubule-active antitumor clinical candidate, is widely accepted as a microtubule-stabilizing agent by binding to the vinblastine site. Our x-ray crystallography study reveals that, in addition to binding to the vinblastine site, cevipabulin also binds to a new site on α-tubulin. We find that cevipabulin at this site pushes the αT5 loop outward, making the nonexchangeable GTP exchangeable, which reduces the stability of tubulin, leading to its destabilization and degradation. Our results confirm the existence of a new agent binding site on α-tubulin and shed light on the development of tubulin degraders as a new generation of antimicrotubule drugs targeting this novel site., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The thalamus plays crucial roles in consciousness generation and information processing. Previous evidence suggests that disorder of consciousness (DOC) caused by severe brain injury, is potentially related to thalamic abnormalities. However, how the morphology and microstructure change in thalamic subfields and thalamocortical fiber pathways in patients with DOC, and the relationships between these changes and the consciousness status remain unclear. Here, we generated the individual-specific thalamic parcellation in 10 DOC patients and 10 healthy controls (HC) via a novel thalamic segmentation framework based on the fiber orientation distribution (FOD) derived from 7-Tesla diffusion MRI, and investigated the shape deformation of thalamic nuclei as well as the microstructural changes associated with thalamic nuclei and thalamocortical pathways in patients with DOC. Enlargement of dorsal posterior nucleus and atrophy of anterior nucleus in the right thalamus were observed in DOC cohort relative to the HCs, and the former was closely linked to the consciousness level of the patients. We also found significant reductions of fiber density, but not fiber bundle cross-section, within several thalamic nuclei and most of the thalamocortical fiber pathways, suggesting that loss of axons might take primary responsibility for the impaired thalamocortical connections in patients with DOC rather than the change in fiber-bundle morphology. Furthermore, the individual-specific thalamic parcellation achieved 80% accuracy in classifying patients at the minimally conscious state from the vegetative state, compared with ~60% accuracy based on group-level parcellations. Our findings provide the first evidence for the shape deformation of thalamic nuclei in DOC patients and the microstructural basis of the disrupted thalamocortical connections., (© The Author(s) 2021. Published by Oxford University Press.)

Introduction: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk., Methods and Analysis: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study., Ethics and Dissemination: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation., Trial Registration Number: ChiCTR1800017773., Protocol Version: November 11, 2020 (Version #5)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The vegetative state (VS) and minimally conscious state (MCS) are two major types of chronic disorders of consciousness (DoC). The assessment of these two consciousness states generally relies on the Coma Recovery Scale-Revised (CRS-R) score, but a high misdiagnosis rate limits the generalized use of this score. To identify metabolites in human plasma that can accurately distinguish VS from MCS patients, comprehensive plasma metabolic profiles were obtained with targeted metabolomics analysis and untargeted and targeted lipidomics analysis. Univariate and multivariate analyses were used to assess the significance of differences. Compared with healthy controls (HCs), the DoC groups, Emerged from Minimally Conscious State (EMCS) group and Alzheimer's disease (AD) group had significantly different metabolic profiles. Purine metabolism pathway differed the most between the DoC (MCS and VS) and HC groups. In this pathway, adenosine, ADP, and AMP, which are the derived products of ATP degradation, were decreased in the MCS and VS groups compared to healthy controls. More importantly, we identified certain lipids for which the levels were enriched in the VS or MCS groups. Specifically, phosphatidylcholine, (38:5)-H (PC(38:5)-H), and arachidonic acid (AA) differed substantially between the VS and MCS groups and may be used to distinguish these two groups of patients. Together, our findings suggest that metabolic profiling is significantly altered in patients with chronic DoC., Competing Interests: Conflict of Interest There are no potential conflicts of interest relevant to this manuscript., (copyright: © 2021 Yu et al.)

CRISPR-Cas immune systems process and integrate short fragments of DNA from new invaders as spacers into the host CRISPR locus to establish molecular memory of prior infection, which is also known as adaptation in the field. Some CRISPR-Cas systems rely on Cas1 and Cas2 to complete the adaptation process, which has been characterized in a few systems. In contrast, many other CRISPR-Cas systems require an additional factor of Cas4 for efficient adaptation, the mechanism of which remains less understood. Here we present biochemical reconstitution of the Synechocystis sp. PCC6803 type I-D adaptation system, X-ray crystal structures of Cas1-Cas2-prespacer complexes, and negative stained electron microscopy structure of the Cas4-Cas1 complex. Cas4 and Cas2 compete with each other to interact with Cas1. In the absence of prespacer, Cas4 but not Cas2 assembles with Cas1 into a very stable complex for processing the prespacer. Strikingly, the Cas1-prespacer complex develops a higher binding affinity toward Cas2 to form the Cas1-Cas2-prespacer ternary complex for integration. Together, we show a two-step sequential assembly mechanism for the type I-D adaptation module of Synechocystis, in which Cas4-Cas1 and Cas1-Cas2 function as two exclusive complexes for prespacer processing, capture, and integration., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Coastal ecosystem is vulnerable to heavy metal contamination. The northern Hangzhou Bay is under intensifying impact of anthropogenic activities. To reveal the heavy metal pollution status in the coastal environment of the Hangzhou Bay, a long-term investigation into the heavy metal contamination during 2011 to 2016 was initiated. Seawater and sediment samples of 25 locations depending on the sewage outlet locations in the northern Hangzhou Bay were collected to analyze the concentrations and temporal and spatial distribution of Cu, Pb, Zn, Cd, Hg, and As. Pollution condition, ecological risk, and potential sources were additionally analyzed. Results show that the annual mean concentrations of Cu, Pb, Zn, Cd, Hg, and As were 2.13-4.59, 0.212-1.480, 7.81-20.34, 0.054-0.279, 0.026-0.090, and 1.08-2.57 μg/L in the seawater, and were 16.34-28.35, 16.25-26.33, 67.32-97.61, 0.084-0.185, 0.029-0.061, and 6.09-14.08 μg/L in the sediments. A decreasing trend in Cu, Pb, Zn, Cd, and Hg concentrations and an increasing trend in As of the seawater were observed. However, in the sediment, the heavy metals demonstrated a rising trend, except for Hg. The single-factor pollution index showed an increasing trend in Cd and As in the seawater, depicting an enhanced pollution of Cd and As, while in the sediments, Cu, Pb, and As were in pollution-free level (average Geo-accumulation index (I geo ) values below 0) in general, and only occasional slight pollution occurred in individual years, e.g., As with 0.403 in 2016. The mean I geo values of Cd ranged from - 0.865 to 0.274 during 2011 to 2016, indicating that the pollution level of Cd was slight, but is likely to increase in the forthcoming years. The level of heavy metal contamination in sediments was low in 2011 (5.853) and 2012 (5.172), and moderate during 2013 to 2016 (in the range of 6.107 to 7.598), while the degree of potential ecological risk was low in the study period, except moderate in 2013 (125.107). The highest contamination degree and potential ecological risk appeared in 2013 (Cd = 7.598; RI = 125.107), while Cd and Hg contributed over 75% of the ecological risk. Overall, the results show low pollution level and low potential ecological risk in the northern Hangzhou Bay; however, more attention should be paid to the potential ecological risk due to Hg and Cd. Graphical abstract Spatial distribution of the heavy metal levels in the sediment of the coastal environment of the northern Hangzhou Bay on a long-term basis.

Background: Knowledge translation (KT) theories, frameworks, and models (TFMs) can help guide and explain KT processes, and facilitate the evaluation of implementation outcomes. They play a critical role in conducting KT research and practice. Currently, little is known about the usage of TFMs in KT in Chinese healthcare settings. The aim of this scoping review is to identify which TFMs had been used for KT in healthcare settings in China, and how these TFMs were used., Methods: The protocol for this scoping review is in accordance with the Arksey and O'Malley framework and further enhanced by the recommendations suggested by Levac et al. We will search 8 databases (4 Chinese and 4 English) to identify relevant studies. Four reviewers (2 for Chinese, 2 for English) will independently screen studies based on the eligibility criteria. The basic characteristic of studies and the TFMs utilization (i.e., what, why, and how) will be extracted. Methodological quality and reporting quality will be assessed using the Mixed Method Appraisal Tool (MMAT) and the Standards for Reporting Implementation Studies (StaRI) (or Standards for Quality Improvement Reporting Excellence, SQUIRE 2.0 for quality improvement studies), respectively. All the retrieved TFMs will be categorized into Nilsen's classifications of TFMs for KT research. We will employ the qualitative content analysis approach to summarize how these TFMs have been used, and the rationale. A consultation will be conducted through a 1-h interactive virtual meeting with an expert panel of knowledge users., Discussion: By conducting this scoping review, we expect to gain a comprehensive and in-depth understanding of why and how TFMs have been used in KT research and practice in China, and to identify gaps and provide recommendations for more efficient and meaningful use of TFMs in the future., Systematic Review Registration: This review has been registered with the Open Science Framework (10.17605/OSF.IO/8NXAM).

Background: The complex crossing-fiber characteristics in the dual-stream system have been ignored by traditional diffusion tensor models regarding disconnections in post-stroke aphasia. It is valuable to identify microstructural damage of crossing-fiber pathways and reveal accurate fiber-specific language mapping in patients with aphasia., Methods: This cross-sectional study collected magnetic resonance imaging data from 29 participants with post-stroke aphasia in the subacute stage and from 33 age- and sex-matched healthy controls. Fixel-based analysis was performed to examine microstructural fiber density (FD) and bundle cross-section alterations of specific fiber populations in crossing-fiber regions. Group comparisons were performed, and relationships with language scores were assessed., Results: The aphasic group exhibited significant fixel-wise FD reductions in the dual-stream tracts, including the left inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus, and superior longitudinal fasciculus (SLF) III (family-wise-error-corrected p < 0.05). Voxel- and fixel-wise comparisons revealed mismatched distributions in regions with crossing-fiber nexuses. Fixel-wise correlation analyses revealed significant associations between comprehension impairment and reduced FD in the temporal and frontal segments of the left IFOF, and also mapped naming ability to the IFOF. Average features along the whole course of dominant tracts assessed with tract-wise analyses attributed word-level comprehension to the IFOF (r = 0.723, p < 0.001) and revealed a trend-level correlation between sentence-level comprehension and FD of the SLF III (r = 0.451, p = 0.021). The mean FD of the uncinate fasciculus (UF) and IFOF correlated with total and picture naming scores, and the IFOF also correlated with responsive naming subdomains (Bonferroni corrected p < 0.05)., Conclusions: FD reductions of dual streams suggest that intra-axonal volume reduction constitutes the microstructural damage of white matter integrity in post-stroke aphasia. Fixel-based analysis provides a complementary method of language mapping that identifies fiber-specific tracts in the left hemisphere language network with greater specificity than voxel-based analysis. It precisely locates the precise segments of the IFOF for comprehension, yields fiber-specific evidence for the debated UF-naming association, and reveals dissociative subdomain associations with distinct tracts., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The association between isolated maternal hypothyroxinemia (IMH) during pregnancy and preterm birth (PTB), especially for subtypes of PTB, is unclear. This study aimed at determining the association between IMH diagnosed in early pregnancy and PTB, with further investigation into various subtypes of PTB. Methods: This study included 41,911 pregnant women (963 with IMH and 40,948 euthyroid women) who underwent first-trimester prenatal screening at the International Peace Maternity and Child Health Hospital (IPMCH) in Shanghai, China between January 2013 and December 2016. PTB was defined as birth before 37 weeks of gestation. PTB was further classified into three clinically relevant groups to investigate the clinical heterogeneity of PTB: (a) preterm birth with premature rupture of membranes (PROM-PTB); (b) spontaneous preterm birth with intact membranes (S-PTB); and (c) medically-induced preterm birth (MI-PTB). The overall and sex-specific effect of IMH on PTB and various subtypes of PTB were estimated by using logistic regression in crude and adjusted models. Results: Pregnant women with IMH had an increased risk of PTB (odds ratio [OR]: 1.32 [95% confidence interval; CI: 1.02-1.70], p  = 0.03) compared with women with euthyroid function. The increased risk of PTB is mainly driven by S-PTB (OR: 1.57 [CI: 1.11-2.24], p  = 0.01), while women with early pregnancy IMH had no statistically significant increased risk of PROM-PTB and MI-PTB. The effect of IMH on PTB was modified by fetal sex ( p -values for interaction = 0.04). More prominent effects were observed in women carrying a female fetus, while no statistically significant effects were found in women carrying a male fetus. Conclusions: This study revealed that pregnant women with IMH in early pregnancy have a higher risk of PTB compared with euthyroid women. The effect of IMH on PTB is mainly driven by S-PTB and is modified by fetal sex.

Background: There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it., Methods: Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool., Results: Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins., Conclusions: The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution., (© 2020 Wiley Periodicals LLC.)

At the end of 2019, a novel coronavirus, designated as SARS-CoV-2, emerged in Wuhan, China and was identified as the causal pathogen of COVID-19. The epidemic scale of COVID-19 has increased dramatically, with confirmed cases increasing across China and globally. Understanding the potential affecting factors involved in COVID-19 transmission will be of great significance in containing the spread of the epidemic. Environmental and meteorological factors might impact the occurrence of COVID-19, as these have been linked to various diseases, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), whose causative pathogens belong to the same virus family as SARS-CoV-2. We collected daily data of COVID-19 confirmed cases, air quality and meteorological variables of 33 locations in China for the outbreak period of 29 January 2020 to 15 February 2020. The association between air quality index (AQI) and confirmed cases was estimated through a Poisson regression model, and the effects of temperature and humidity on the AQI-confirmed cases association were analyzed. The results show that the effect of AQI on confirmed cases associated with an increase in each unit of AQI was statistically significant in several cities. The lag effect of AQI on the confirmed cases was statistically significant on lag day 1 (relative risk (RR) = 1.0009, 95% confidence interval (CI): 1.0004, 1.0013), day 2 (RR = 1.0007, 95% CI: 1.0003, 1.0012) and day 3 (RR = 1.0008, 95% CI: 1.0003, 1.0012). The AQI effect on the confirmed cases might be stronger in the temperature range of 10 °C ≤ T < 20 °C than in other temperature ranges, while the RR of COVID-19 transmission associated with AQI was higher in the relative humidity (RH) range of 10% ≤ RH < 20%. Results may suggest an enhanced impact of AQI on the COVID-19 spread under low RH., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Human dihydroorotate dehydrogenase ( h DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3- d ][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against h DHODH. Further optimization led to compounds 11k and 11l , which inhibited h DHODH activity with IC 50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with h DHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with h DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.

Aircraft engine emissions during landing and take-off cycle are commonly estimated on the basis of the International Civil Aviation Organization (ICAO) promulgated calculation model and emission parameters; however, the ICAO certified parameters are generally not applicable for an individual airport. In this study, the operation times, fuel and emission parameters of 8 aircraft models during taxi phase at Shanghai Hongqiao International Airport (SHA) are analyzed with the Aircraft Communication Addressing and Reporting System (ACARS) data, and compared with corresponding values referenced by the ICAO. The results show perceptible discrepancies between the SHA-specific and ICAO certified values. The taxi-out times at SHA are considerably overestimated (up to 35.3%) by ICAO for all the analyzed aircraft models, whereas the taxi-in durations are highly close to the ICAO referenced value with a variation within -6.3% to 9.7%. In the majority of cases, the localized fuel flows and emission indices (EIs) are overvalued by ICAO, and the extent of overestimation can be as large as 21.6% and 28.3%, respectively. Variabilities in operation times, fuel and emission parameters are also characterized depending on aircraft types. Additionally, as a novel attempt, the effect of engine aging on EIs is explored and no significant correlation has been detected, indicating that other factors may affect the EIs dominantly over engine age. The resulting SHA-specific emission parameters are significant towards a precise emission quantification and modeling of impacts on air quality and health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)