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Genetic mutations of fused in sarcoma (FUS) causing amyotrophic lateral sclerosis (ALS) may disrupt mRNA splicing events. For example, the FUS c.1394-2delA variant was reported in two western ALS patients, but its molecular mechanism is unclear. In this study, we aim to investigate FUS splice site mutations in Chinese ALS patients.
Methods:
Sanger sequencing was used to identify FUS splicing mutations in Chinese ALS patients. We combined a deep learning tool (SpliceAI), RNA sequencing, and RT-PCR/RT-qPCR to analyze the effect of FUS c.1394-2delA mutation on RNA splicing and expression. AlphaFold was used to predict the protein structure of mutant FUS. In transfected cell lines, we used immunofluorescence to assess cytoplasmic mislocalization of mutant FUS protein.
Results:
We identified a de novo FUS splice acceptor site mutation (c.1394-2delA, p. Gly466Valfs*14) in one Chinese sporadic ALS patient, which is linked to exon 14 skipping, and upregulated total FUS mRNA expression. The FUS splice site mutation was predicted to be translated into a truncated protein product at C-terminal. In vitro studies revealed that the FUS mutation increased cytoplasmic mislocalization in both HEK293T and SH-SY5Y cells.
Conclusions:
We identified a de novo FUS splicing mutation (c.1394-2delA, p. Gly466Valfs*14) in 1 out of 233 Chinese ALS patients. It caused abnormal RNA splicing, upregulated gene expression, truncated FUS translation, and cytosolic mislocalization. Our findings suggested that FUS splice site mutation is rare in Chinese ALS patients and extended our knowledge of molecular mechanisms of the FUS c.1394-2delA mutation.
Well-resolved direct numerical simulations of turbulent open channel flows (OCFs) are performed for friction Reynolds numbers up to $Re_\tau =2000$. Various turbulent statistics are documented and compared with the closed channel flows (CCFs). As expected, the mean velocity profiles of the OCFs match well with the CCFs in the near-wall region but diverge notably in the outer region. Interestingly, a logarithmic layer with Kárman constant $\kappa =0.363$ occurs for OCF at $Re_\tau =2000$, distinctly different from CCF. Except for a very thin layer near the free surface, most of the velocity and vorticity variances match between OCFs and CCFs. The one-dimensional energy spectra reveal that the very-large-scale motions (VLSMs) with streamwise wavelength $\lambda _x>3 h$ or spanwise wavelength $\lambda _z>0.5 h$ contribute the most to turbulence intensity and Reynolds shear stress in the overlap and outer layers (where h is the water depth). Furthermore, the VLSMs in OCFs are stronger than those in CCFs, resulting in a slightly higher streamwise velocity variance in the former. Due to the footprint effect, these structures also have significant contributions to the mean wall shear stress, and the difference between OCF and CCF enlarges with increasing $Re_\tau$. In summary, the free surface in OCFs plays an essential role in various flow phenomena, including the formation of stronger VLSMs and turbulent kinetic energy redistribution.
We examined whether and how the degree of meaning overlap between morphologically related words influences sentence plausibility judgment in children. In two separate studies with kindergarten and second-graders, English-speaking and French-speaking children judged the plausibility of sentences that included two paired target words. Some of these word pairs were morphologically related, across three conditions with differing levels of meaning overlap: low (wait-waiter), moderate (fold-folder) and high (farm-farmer). In another two conditions, word pairs were related only by phonology (rock-rocket) or semantics (car-automobile). Children in both ages and languages demonstrated higher plausibility scores as meaning overlap increased between morphologically related words. Further, kindergarten children rated sentences that included word pairs with phonological overlap as more plausible than second-grade children, while second-grade children rated those with high meaning overlap as more plausible than kindergarten children. We interpret these findings in light of current models of morphological development.
In this study, we report the first complete mitochondrial genome of the tapeworm Nippotaenia mogurndae in the order Nippotaeniidea Yamaguti, 1939. This mitogenome, which is 14,307 base pairs (bp) long with an A + T content of 72.2%, consists of 12 protein-coding genes, 22 transfer RNA (tRNA) genes, two rRNA genes, and two non-coding regions. Most tRNAs have a conventional cloverleaf structure, but trnS1 and trnR lack dihydrouridine arms of tRNA. The two largest non-coding regions, NCR1 (220 bp) and NCR2 (817 bp), are located between trnY and trnS2 and between nad5 and trnG, respectively. Phylogenetic analyses of mitogenomic data indicate that N. mogurndae is closely related to tapeworms in the order Cyclophyllidea.
Compared to the streamwise instability, the cross-flow instability in high-enthalpy flows has received relatively less attention, but the latter is of vital importance in the flow transition for practical configurations. This work aims to investigate the cross-flow primary and secondary instabilities in hypersonic and high-enthalpy boundary layers, considering thermochemical non-equilibrium (TCNE) effects. The numerical tools adopted include a high-order shock-fitting solver, nonlinear parabolized stability equations and secondary instability theory (SIT). The flow over a swept parabola is calculated at a free-stream Mach number of 16. It is found that TCNE has a destabilizing effect on the cross-flow mode with a non-catalytic wall. Two important non-dimensional parameters are summarized to explain this effect. One is the ratio between the wall and boundary-layer edge temperatures, and the other is the cross-flow Mach number. Due to nonlinear effects, the stationary cross-flow vortices evolve and exhibit the classic rollover structures as in lower-speed flows. Two different disturbance energy norms are used in the energy budget analysis to classify the secondary cross-flow instability modes. The results from SIT highlight the importance of type-IV modes in TCNE flows at the downwash region of the vortex. The type-IV modes arise with the combined contribution from the wall-normal (on top and trough of the vortex) and spanwise (in the downwash region) production terms. The type-I mode is dominant in the calorically perfect gas case with an adiabatic wall, whereas the type-IV mode has the largest growth rate in the TCNE cases irrespective of wall temperature variation.
We aimed to examine the association between the quantity and quality of dietary fat in early pregnancy and gestational diabetes mellitus (GDM) risk. In total, 1477 singleton pregnant women were included from Sichuan Provincial Hospital for Women and Children, Southwest China. Dietary information was collected by a 3-d 24-h dietary recall. GDM was diagnosed based on the results of a 75-g, 2-h oral glucose tolerance test at 24–28 gestational weeks. Log-binomial models were used to estimate relative risks (RR) and 95% CI. The results showed that total fat intake was positively associated with GDM risk (Q4 v. Q1: RR = 1·40; 95 % CI 1·11, 1·76; Ptrend = 0·001). This association was also observed for the intakes of animal fat and vegetable fat. After stratified by total fat intake (< 30 %E v. ≥ 30 %E), the higher animal fat intake was associated with higher GDM risk in the high-fat group, but the moderate animal fat intake was associated with reduced risk of GDM (T2 v. T1: RR = 0·65; 95 % CI 0·45, 0·96) in the normal-fat group. Vegetable fat intake was positively associated with GDM risk in the high-fat group but not in the normal-fat group. No association between fatty acids intakes and GDM risk was found. In conclusion, total fat, animal and vegetable fat intakes were positively associated with GDM risk, respectively. Whereas when total fat intake was not excessive, higher intakes of animal and vegetable fat were likely irrelevant with increased GDM risk, even the moderate animal fat intake could be linked to lower GDM risk.
Maternal gestational weight gain (GWG) is an important determinant of infant birth weight, and having adequate total GWG has been widely recommended. However, the association of timing of GWG with birth weight remains controversial. We aimed to evaluate this association, especially among women with adequate total GWG. In a prospective cohort study, pregnant women’s weight was routinely measured during pregnancy, and their GWG was calculated for the ten intervals: the first 13, 14–18, 19–23, 24–28, 29–30, 31–32, 33–34, 35–36, 37–38 and 39–40 weeks. Birth weight was measured, and small-for-gestational-age (SGA) and large-for-gestational-age were assessed. Generalized linear and Poisson models were used to evaluate the associations of GWG with birth weight and its outcomes after multivariate adjustment, respectively. Of the 5049 women, increased GWG in the first 30 weeks was associated with increased birth weight for male infants, and increased GWG in the first 28 weeks was associated with increased birth weight for females. Among 1713 women with adequate total GWG, increased GWG percent between 14 and 23 weeks was associated with increased birth weight. Moreover, inadequate GWG between 14 and 23 weeks, compared with the adequate GWG, was associated with an increased risk of SGA (43 (13·7 %) v. 42 (7·2 %); relative risk 1·83, 95 % CI 1·21, 2·76). Timing of GWG may influence infant birth weight differentially, and women with inadequate GWG between 14 and 23 weeks may be at higher risk of delivering SGA infants, despite having adequate total GWG.
Hyperhomocysteinaemia (HHcy) is associated with all-cause mortality in some disease states. However, the correlation between HHcy and the risk of mortality in the general population has rarely been researched. We aimed to evaluate the association between HHcy and all-cause and cause-specific mortality among adults in the USA. This study analysed data from the National Health and Nutrition Examination Survey database (1999–2002 survey cycle). A multivariable Cox regression model was built to evaluate the correlation between HHcy and all-cause and cause-specific mortality. Smooth curve fitting was used to analyse their dose-dependent relationship. A total of 8442 adults aged 18–70 years were included in this study. After a median follow-up period of 14·7 years, 1007 (11·9 %) deaths occurred including 197 CVD-related deaths, 255 cancer-related deaths and fifty-eight respiratory disease deaths. The participants with HHcy had a 93 % increased risk of all-cause mortality (hazard ratio (HR) 1·93; 95 % CI (1·48, 2·51)), 160 % increased risk of CVD mortality (HR 2·60; 95 % CI (1·52, 4·45)) and 82 % increased risk of cancer mortality (HR 1·82; 95 % CI (1·03, 3·21)) compared with those without HHcy. For unmeasured confounding, E-value analysis proved to be robust. In conclusion, HHcy was associated with high risk of all-cause and cause-specific (CVD, cancer) mortality among adults aged below 70 years.
We prove that if X is a complex projective K3 surface and
$g>0$
, then there exist infinitely many families of curves of geometric genus g on X with maximal, i.e., g-dimensional, variation in moduli. In particular, every K3 surface contains a curve of geometric genus 1 which moves in a nonisotrivial family. This implies a conjecture of Huybrechts on constant cycle curves and gives an algebro-geometric proof of a theorem of Kobayashi that a K3 surface has no global symmetric differential forms.
Widely distributed Mid-Neoproterozoic mafic rocks of the Qilian – Qaidam – East Kunlun region record the tectonic evolution of the northeastern Tibetan Plateau. This study presents whole-rock geochemistry, zircon U–Pb geochronology and Hf isotopes for the Xialanuoer gabbros of the central South Qilian Belt (SQB). Zircon laser ablation – inductively coupled plasma – mass spectrometry (LA-ICP-MS) U–Pb dating indicates that the gabbros were emplaced at ca. 738 Ma, indicating they are contemporaneous with mafic magmatism elsewhere in the northeastern Tibetan Plateau. The gabbros have low SiO2, Cr and Ni contents and Mg# values, are relatively enriched in light rare-earth elements (LREEs) and depleted in high-field-strength elements (HFSEs; e.g. Nb and Ta), have no positive Zr or Hf anomalies and have relatively high Nb/Ta but low Nb/La ratios. These data indicate that the Xialanuoer gabbros formed from calc-alkaline basaltic magmas that were originally generated by the partial melting of an enriched mantle of type-I (EMI-type) enriched region of the lithospheric mantle, underwent little to no crustal contamination prior to their emplacement, and have within-plate basalt geochemical affinities. Combining these data with the presence of widespread contemporaneous continental rift-related magmatism and sedimentation in the North Qilian, Central Qilian, South Qilian, Quanji, North Qaidam and East Kunlun regions suggests that the northeastern Tibetan Plateau underwent Mid-Neoproterozoic continental rifting, which also affected other Rodinian blocks (e.g. Tarim, South China, Australia, North America and Southern Africa).
Two new eurypterids, a pterygotid Erettopterus qujingensis n. sp., and a slimoniid, Slimonia sp., are described from the upper Silurian (Pridolian) Yulongsi Formation of Yunnan Province, China. Erettopterus qujingensis n. sp. is characterized by several inversely curved ramus denticles and a metastoma with a deep notch in the center. The discovery not only extends the geographic extent of the genus Erettopterus and Slimonia from Euramerica to southwest China, but also gives insight into the similarity of ecosystem structures across the Silurian world.
This study is performed to figure out how the presence of diabetes affects the infection, progression and prognosis of 2019 novel coronavirus disease (COVID-19), and the effective therapy that can treat the diabetes-complicated patients with COVID-19. A multicentre study was performed in four hospitals. COVID-19 patients with diabetes mellitus (DM) or hyperglycaemia were compared with those without these conditions and matched by propensity score matching for their clinical progress and outcome. Totally, 2444 confirmed COVID-19 patients were recruited, from whom 336 had DM. Compared to 1344 non-DM patients with age and sex matched, DM-COVID-19 patients had significantly higher rates of intensive care unit entrance (12.43% vs. 6.58%, P = 0.014), kidney failure (9.20% vs. 4.05%, P = 0.027) and mortality (25.00% vs. 18.15%, P < 0.001). Age and sex-stratified comparison revealed increased susceptibility to COVID-19 only from females with DM. For either non-DM or DM group, hyperglycaemia was associated with adverse outcomes, featured by higher rates of severe pneumonia and mortality, in comparison with non-hyperglycaemia. This was accompanied by significantly altered laboratory indicators including lymphocyte and neutrophil percentage, C-reactive protein and urea nitrogen level, all with correlation coefficients >0.35. Both diabetes and hyperglycaemia were independently associated with adverse prognosis of COVID-19, with hazard ratios of 10.41 and 3.58, respectively.
First-generation refugee children often experience pre- and post-migration adversity and display high levels of mental health/wellbeing difficulties, but to date, research has not examined the impact of such factors on refugee children's L2 acquisition. Accordingly, this study examined the influence of externalizing and internalizing problem behaviours (wellbeing), time in refugee camps and low socioeconomic status (SES) (adversity) on the English-L2 abilities of 117 Syrian refugee children (7–14 years) in their third year of residency in Canada. Wellbeing difficulties and adversity factors accounted for variance on L2 vocabulary, morphosyntax, listening comprehension and narrative production tasks, beyond the variance accounted for by age of L2 acquisition and length of L2 exposure. Specifically, externalizing problem behaviours, time in refugee camp, maternal education and maternal employment predicted variance in L2 abilities. It is concluded that refugee children could have influences on their L2 acquisition that are different from those of bilinguals with other backgrounds.
Greek yogurt is one of the fastest growing products in the dairy industry. It is also known as strained yogurt, which is obtained after draining the whey. As a result of the draining process, Greek yogurt has higher total solids and lower lactose than regular yogurt. Since it is a concentrated yogurt, its sensory characteristics are different from regular yogurt. However, there is little information about factors influencing the quality of Greek yogurt and sensory evaluation techniques applied to Greek yogurt. This review aims to describe the effects of ingredients, starter cultures, processing techniques and other parameters on quality characteristics and sensory properties of Greek yogurt. In addition, advantages and limitations of novel sensory evaluation techniques applied to Greek yogurt products are discussed. In particular, we take a look at advanced techniques such as the electronic nose and electronic tongue and the benefits of these techniques with regard to Greek yogurt. This review should help the Greek yogurt industry to improve its current products and develop innovative products based on appropriate food evaluation techniques.
This longitudinal study investigated how lexical restructuring can stimulate emerging bilingual children’s phonological awareness in their first (L1) and second (L2) languages. Sixty-two English (L1) – French (L2) bilingual children (Mage = 75.7 months, SD = 3.2) were taught new English and French word pairs differing minimally in phonological contrast. The results indicated that increasing lexical specificity in English mediated the relationship between English vocabulary and English phonological awareness both concurrently and longitudinally at the end of Grade 1. A longitudinal relationship was established among French vocabulary, French lexical specificity, and French phonological awareness at the end of Grade 1. Notably, cross-language transfer from English lexical specificity was a better predictor of development in French phonological awareness, especially for words that contained phonological contrasts that occurred in both languages. The results from this study highlight the phonological foundations of early literacy and extend the lexical restructuring hypothesis to emerging bilingual children.
For individual cultures, findings on regulating embryo density by changing the microdrop volume are contradictory. The aim of this study was to investigate the relationship between embryo density and the developmental outcome of day 3 embryos after adjusting covariates. In total, 1196 embryos from 206 couples who had undergone in vitro fertilization treatment were analyzed retrospectively. Three embryo densities were used routinely, i.e. one embryo in a drop (30 μl/embryo), two embryos in a drop (15 μl/embryo) and three embryos in a drop (10 μl/embryo). Embryo quality on day 3 was evaluated, both the cell number of day 3 embryos and the proportion of successful implantations served as endpoints. Maternal age, paternal age, antral follicles and level of anti-Müllerian hormone, type of infertility, controlled ovarian stimulation protocol, length of stimulation, number of retrieved oocytes, number of zygotes (two pronuclei) and insemination type were covariates and adjusted. After adjusting fully for all covariates, the cell number of day 3 embryos was significantly increased by 0.40 (95% CI 0.00, 0.79; P = 0.048) and 0.78 (95% CI 0.02, 1.54; P = 0.044) in the 15 μl/embryo and 10 μl/embryo group separately, compared with the 30 μl/embryo group. The proportions of implanted embryos were 42.1%, 48.7% and 0.0% in the 30 μl/embryo, 15 μl/embryo and 10 μl/embryo groups respectively. There was no statistical significance (P = 0.22) between the 30 μl/embryo group and the 15 μl/embryo group. After adjusting for confounders that were significant in univariate analysis, embryo density was still not associated with day 3 embryo implantation potential (P > 0.05). In a 30-μl microdrop, culturing embryos with an embryo density of both 15 and 10 μl/embryo increased the cell number of day 3 embryos, which did not benefit embryo implanting potential, compared with individual culture of 30 μl/embryo.
The COVID-19 pandemic caused significant psychological consequences among the public, especially for people in the epicenter. This study examined the ‘bull's eye’ model by comparing the level of psychological distress and the effect of different stressors in Wuhan (the original epicenter) with that in the surrounding areas in Hubei Province during the pandemic. Data were obtained from a cross-national survey of 10 478 respondents between the ages of 18 and 80 years in Hubei Province during the peak of the pandemic. Results of the ordinary least squares regression models showed that Wuhan residents experienced more psychological distress than those in the surrounding areas. Social and economic problems caused by the pandemic, risk exposure, perceived discrimination, and information-seeking behaviors were positively associated with distress. Social assistance was negatively associated with distress. Findings were consistent with the bull's eye model by revealing both a higher level of psychological distress and a stronger effect of stressors among the Wuhan residents than with those in low-risk areas. Thus, policymakers and psychological workers should provide adequate psychological services in high-risk areas. Lowering risk exposure, reducing discrimination against people in the epicenter, and improving information quality are essential to alleviate their psychological distress.
Boundary layer transition over a lifting body of 1.6 m length at $2^\circ$ angle of attack has been simulated at Mach 6 and a unit Reynolds number $1.0 \times 10^7$ m$^{-1}$. The model geometry is the same as the Hypersonic Transition Research Vehicle designed by the China Aerodynamics Research and Development Center. Four distinct transitional regions are identified, i.e. windward vortex region, shoulder vortex region, windward cross-flow region and shoulder cross-flow region. Multi-dimensional linear stability analyses by solving the two-dimensional eigenvalue problem (spatial BiGlobal approach) and the plane-marching parabolized stability equations (PSE3D approach) are further carried out to uncover the dominant instabilities in the last three regions as well as the shoulder attachment-line region. The shoulder vortex is conducive to both inner and outer modes of shear-layer instability, of which the latter most likely trigger the vortex breakdown. A novel method is presented to substantially reduce the computational cost of BiGlobal and PSE3D in resolving the cross-flow instabilities in cross-flow regions. The peak frequencies of cross-flow modes lie between 15 and 45 kHz. Whereas oblique second Mack modes are marginally unstable in the windward cross-flow region, they could be strong enough to compete with the cross-flow modes in the shoulder cross-flow region. In the shoulder attachment-line region, there exists only one unstable mode of Mack instability, differing from previous studies that show a hierarchy of modes in the context of symmetrical attachment-line flows. Results of the numerical simulation and multi-dimensional stability analyses are compared when possible, showing a fair agreement between the two approaches and highlighting the necessity of considering non-parallel effects.
The wheat aphid Sitobion miscanthi (CWA) is an important harmful pest in wheat fields. Insecticide application is the main method to effectively control wheat aphids. However, CWA has developed resistance to some insecticides due to its extensive application, and understanding resistance mechanisms is crucial for the management of CWA. In our study, a new P450 gene, CYP4CJ6, was identified from CWA and showed a positive response to imidacloprid and thiamethoxam. Transcription of CYP4CJ6 was significantly induced by both imidacloprid and thiamethoxam, and overexpression of CYP4CJ6 in the imidacloprid-resistant strain was also observed. The sensitivity of CWA to these two insecticides was increased after the knockdown of CYP4CJ6. These results indicated that CYP4CJ6 could be associated with CWA resistance to imidacloprid and thiamethoxam. Subsequently, the posttranscriptional regulatory mechanism was assessed, and miR-316 was confirmed to participate in the posttranscriptional regulation of CYP4CJ6. These results are crucial for clarifying the roles of P450 in the resistance of CWA to insecticides.