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Purpose The purpose of this paper is to demonstrate the impact of the welding sequence on the substrate plate distortion during the wire and arc additive manufacturing (WAAM) process. This paper also aims to show the capability of finite element simulations in the prediction of those thermally induced distortions. Design/methodology/approach An experiment was conducted in which solid aluminum blocks were manufactured using two different welding sequences. The distortion of the substrates was measured at predefined positions and converted into bending and torsion values. Subsequently, a weakly coupled thermo-mechanical finite element model was created using the Abaqus simulation software. The model was calibrated and validated with data gathered from the experiments. Findings The results of this paper showed that the welding sequence of a part significantly affects the formation of thermally induced distortions of the final part. The calibrated simulation model was able to capture the different distortion behavior attributed to the welding sequences. Originality/value Within this work, a simulation model was developed capable of predicting the distortion of WAAM parts in advance. The findings of this paper can be used to improve the design of WAAM welding sequences while avoiding high experimental efforts.

In eukaryotes, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are essential for maintaining cellular proteostasis and associated with cancer progression. Our previous studies have demonstrated that phosphatase and tensin homolog (PTEN), one of the most frequently mutated genes in human cancers, limits proteasome abundance and determines chemosensitivity to proteasome inhibitors in cholangiocarcinoma (CCA). However, whether PTEN regulates the lysosome pathway remains unclear.We tested the effects of PTEN on lysosome biogenesis and exosome secretion using loss- and gain-of-function strategies in CCA cell lines. Using in vitro dephosphorylation assays, we explored the regulatory mechanism between PTEN and the key regulator of lysosome biogenesis, transcription factor EB (TFEB). Using the migration assays, invasion assays, and trans-splenic liver metastasis mouse models, we evaluated the function of PTEN deficiency, TFEB-mediated lysosome biogenesis, and exosome secretion on tumor metastasis. Moreover, we investigated the clinical significance of PTEN expression and exosome secretion by retrospective analysis.PTEN facilitated lysosome biogenesis and acidification through its protein phosphatase activity to dephosphorylate TFEB at Ser211. Notably, PTEN deficiency increased exosome secretion by reducing lysosome-mediated degradation of multi-vesicular bodies (MVBs), which further facilitated the proliferation and invasion of CCA. TFEB agonist curcumin analog C1 restrained the metastatic phenotype caused by PTEN deficiency in mouse models, and we highlighted the correlation between PTEN deficiency and exosome secretion in clinical cohorts.In CCA, PTEN deficiency impairs lysosome biogenesis to facilitate exosome secretion and cancer metastasis in a TFEB phosphorylation-dependent manner.

Synchrotron radiation based dynamic micro-computed tomography (micro-CT) is a powerful technique available at synchrotron light sources for investigating evolving microstructures. Wet granulation is the most widely used method of producing pharmaceutical granules, precursors to products like capsules and tablets. Granule microstructures are known to influence product performance, so this is an area for potential application of dynamic CT. Here, lactose monohydrate (LMH) was used as a representative powder to demonstrate dynamic CT capabilities. Wet granulation of LMH has been observed to occur on the order of several seconds, which is too fast for lab-based CT scanners to capture the changing internal structures. The superior X-ray photon flux from synchrotron light sources makes sub-second data acquisition possible and well suited for analysis of the wet-granulation process. Moreover, synchrotron radiation based imaging is non-destructive, does not require altering the sample in any way, and can enhance image contrast with phase-retrieval algorithms. Dynamic CT can bring insights to wet granulation, an area of research previously only studied via 2D and/or ex situ techniques. Through efficient data-processing strategies, dynamic CT can provide quantitative analysis of how the internal microstructure of an LMH granule evolves during the earliest moments of wet granulation. Here, the results revealed granule consolidation, the evolving porosity, and the influence of aggregates on granule porosity.

Visualization of low-density tissue scaffolds made from hydrogels is important yet challenging in tissue engineering and regenerative medicine (TERM). For this, synchrotron radiation propagation-based imaging computed tomography (SR-PBI-CT) has great potential, but is limited due to the ring artifacts commonly observed in SR-PBI-CT images. To address this issue, this study focuses on the integration of SR-PBI-CT and helical acquisition mode (i.e. SR-PBI-HCT) to visualize hydrogel scaffolds. The influence of key imaging parameters on the image quality of hydrogel scaffolds was investigated, including the helical pitch (p), photon energy (E) and the number of acquisition projections per rotation/revolution (N p), and, on this basis, those parameters were optimized to improve image quality and to reduce noise level and artifacts. The results illustrate that SR-PBI-HCT imaging shows impressive advantages in avoiding ring artifacts with p = 1.5, E = 30 keV and N p = 500 for the visualization of hydrogel scaffolds in vitro. Furthermore, the results also demonstrate that hydrogel scaffolds can be visualized using SR-PBI-HCT with good contrast while at a low radiation dose, i.e. 342 mGy (voxel size of 26 µm, suitable for in vivo imaging). This paper presents a systematic study on hydrogel scaffold imaging using SR-PBI-HCT and the results reveal that SR-PBI-HCT is a powerful tool for visualizing and characterizing low-density scaffolds with a high image quality in vitro. This work represents a significant advance toward the non-invasive in vivo visualization and characterization of hydrogel scaffolds at a suitable radiation dose.

OBJECTIVE: To explore the value of vascular architecture detected by micro vascular imaging (MVI) in preoperative diagnosis of focal liver lesions (FLLs). METHODS: In this retrospective study, patients with surgery and histopathologically proved or radiologically confirmed FLLs were included. Vascular architecture of FLLs were acquired by color Doppler flow imaging (CDFI) and MVI on LOGIQ™ E20 ultrasound machine (C1–6 convex array probes). Alder semiquantitative analysis (grade 0–3) and morphologic features of blood vessels (pattern a–f) were used to assess the blood flow within the FLLs. Interobserver agreement for evaluating blood flow of FLLs was analyzed. Using Adler’s grading or morphologic patterns as diagnostic criteria for malignant FLLs, the diagnostic efficiency was analyzed and compared. RESULTS: From October 2021 and February 2022, 50 patients diagnosed with 40 malignant FLLs and 10 benign FLLs were finally included. The Kappa value within two observers for evaluating the blood flow of FLLs was 0.78 for MVI and 0.55 for CDFI. According to Alder semiquantitative analysis, more high-level blood flow signals (grade 2–3) were detected by MVI than CDFI (P < 0.05). Based on high-level blood flow signals (grade 2–3) and hypervascular supply patterns (pattern e and f), the diagnostic accuracy for malignant FLLs were 76% and 68% for MVI, 56% and 38% for CDFI, respectively. CONCLUSION: MVI is superior to CDFI in evaluating vascular architecture of FLLs. The high-level flow signals and hypervascular pattern detected by MVI have a useful and complementary value in preoperative non-invasive identification of malignant FLLs.

Family conflict is a risk factor for suicidal behaviors among adolescents. However, few longitudinal studies have investigated this association and explored the mediation effect of behavioral and emotional problems. This study aimed to examine the longitudinal association between family conflict, internalizing and externalizing problems, and suicidal behaviors in a large sample of Chinese adolescents.This longitudinal study of 7,072 adolescents was based on the Shandong Adolescent BehaviorHealth Cohort (SABHC). Participants completed a self-administrated questionnaire to assess family conflict, internalizing and externalizing problems, suicidal behaviors, and family demographics at baseline. Excluding adolescents with any suicidal behavior at baseline (N = 839), others (N = 6,233) were allowed to report their internalizing and externalizing problems and suicidal behaviors one-year later. Path analyses were conducted to examine the mediation relationship of internalizing and externalizing problems between family conflict and suicidal behaviors.Of 6,233 participants, mean age was 14.52 at baseline and 51.2% were males. Adolescents with subsequent suicidal behaviors reported higher scores in family conflict, internalizing and externalizing problems (Ps 0.01). Path analyses showed that internalizing and externalizing problems played a significant mediating role in the associations of family conflict with suicidal behaviors after adjusting for covariates.Family conflict is associated with suicidal behaviors in adolescents, which is partially mediated by internalizing and externalizing problems. Internalizing problems is the major mediator between family conflict and suicidal thought or suicide plan; however, internalizing and externalizing problems play similar mediating roles in the family conflict-suicide attempt link.

Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs.We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues.A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

High-performance flexible perovskite solar cells based on a citric acid modified transparent conductive substrate of silver nanowires semi-embedded in colorless polyimide.

Voltage losses are one of the main obstacles for further improvement in the power conversion efficiency of organic solar cells. In this work, we investigate the effect of thermal stress on voltage losses in various material systems by multiple spectroscopic measurements on both devices and thin films. The energetics of nonfullerene small molecules are more readily altered under thermal stress compared to all-polymer and fullerene-based systems, thereby strongly affecting open-circuit voltage. These energetics variations correlate with the glass transition of respective materials. While nonfullerene small molecular acceptor systems exhibit both dynamic and static disorders which can be restrained in annealed films, all-polymeric systems exhibit dominated static disorders, which are also stable against thermal stress. The much higher voltage losses in fullerene-based systems compared to the other two counterparts are mainly due to the losses from device band gap to charge transfer states and the high nonradiative recombination.

HIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the “Shock and Kill” strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4+ T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3′-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4+ T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs., GRAPHICAL ABSTRACT

BackgroundVariants inPPP2R5D, affecting the regulatory B56δ subunit of protein phosphatase 2A (PP2A), have been identified in individuals with neurodevelopmental abnormalities. However, the molecular and clinical spectra remain incompletely understood.MethodsIndividuals withPPP2R5Dvariants were enrolled through Simons Variation in Individuals Project/Simons Searchlight. Data were collected from medical history interviews, medical record review, online validated instruments and neuroimaging review. Genetic variants were biochemically characterised.ResultsWe studied 76 individuals withPPP2R5Dvariants, including 68 with pathogenic de novo variants, four with a variant of uncertain significance (VUS) and four siblings with a novel dominantly inherited pathogenic variant. Among 13 pathogenic variants, eight were novel and two (p.Glu198Lys and p.Glu200Lys) were highly recurrent. Functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding or both—with the most severe phenotypes associated with variants that completely retained one of these binding characteristics and lost the other—further supporting a dominant-negative disease mechanism. p.Glu198Lys showed the highest C-binding defect and a more severe clinical phenotype. The inherited p.Glu197Gly variant had a mild substrate binding defect, and three of four VUS had no biochemical impact. Common clinical phenotypes were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%). The mean composite Vineland score was 59.8, and most participants were in the ‘moderate to low’ and ‘low’ adaptive levels in all domains.ConclusionOur study delineates the most common features ofPPP2R5D-related neurodevelopmental disorders, expands the clinical and molecular spectrum and identifies genotype–phenotype correlations.

Prolonged mobile phone use has been demonstrated to be associated with mental health problems and suicidal behavior in adolescents. This study examined the mediating role of depressive symptoms in the association between duration of mobile phone use (DMPU) and suicidal behavior in adolescents.A total of 6,923 participants from the Shandong Adolescent BehaviorHealth Cohort (SABHC) were included in the analysis. Participants completed a self-administered questionnaire to assess DMPU on weekdays and weekends, mental disorders, insomnia symptoms, depressive symptoms, suicidal behavior (thought, plan, or attempt), and family demographics in November-December 2015. One year later, a follow-up survey was conducted to ask participants to report their depressive symptoms and suicidal behavior. Path analyses with logistic regressions were performed to examine the mediating role of depressive symptoms in the DMPU-suicidal behavior link.Of the sample, mean age was 14.58 (SD = 1.45) and 3,455 (49.9 %) were female at baseline. 12.12 % of participants reported having ever suicidal behavior during the past 12 months at baseline, and 10.63 % reported having ever suicidal behavior during 1-year follow-up. Path analyses showed that the depressive symptoms played a partial mediating role in the association of DMPU on weekdays and weekends with subsequent suicidal behavior. After controlling for covariates, depressive symptoms accounted for 33.6 % and 58.6 % of the total effect of DMPU on weekdays and weekends on suicidal behavior, respectively.All variables were measured based on self-report.The link between DMPU and suicidal behavior was partially mediated by depressive symptoms. Prolonged mobile phone use and depressive symptoms should be assessed and intervened to prevent suicidal behavior in adolescents.

Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation. As an essential trace element, iron is vital for many biological processes. Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation. Ferroptosis, a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs), is a promising therapeutic target for therapy-resistant cancers. Previous studies have reported that long noncoding RNA (lncRNA) is a group of critical regulators involved in modulating cell metabolism, proliferation, apoptosis, and ferroptosis. In this review, we summarize the associations among iron metabolism, ferroptosis, and ferroptosis-related lncRNA in tumorigenesis. This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.

When the N- and O-donor ligands are combined as coligands, two noncentrosymmetric (NCS) complexes of [Ni(p-bdc)(tipa)(H

Wurfbainia villosa is a well-known medicinal and edible plant that is widely cultivated in the Lingnan region of China. Its dried fruits (called Fructus Amomi) are broadly used in traditional Chinese medicine for curing gastrointestinal diseases and are rich in volatile terpenoids. Here, we report a high-quality chromosome-level genome assembly of W. villosa with a total size of approximately 2.80 Gb, 42 588 protein-coding genes, and a very high percentage of repetitive sequences (87.23%). Genome analysis showed that W. villosa likely experienced a recent whole-genome duplication event prior to the W. villosa-Zingiber officinale divergence (approximately 11 million years ago), and a recent burst of long terminal repeat insertions afterward. The W. villosa genome enabled the identification of 17 genes involved in the terpenoid skeleton biosynthesis pathway and 66 terpene synthase (TPS) genes. We found that tandem duplication events have an important contribution to the expansion of WvTPSs, which likely drove the production of volatile terpenoids. In addition, functional characterization of 18 WvTPSs, focusing on the TPS-a and TPS-b subfamilies, showed that most of these WvTPSs are multi-product TPS and are predominantly expressed in seeds. The present study provides insights into the genome evolution and the molecular basis of the volatile terpenoids diversity in W. villosa. The genome sequence also represents valuable resources for the functional gene research and molecular breeding of W. villosa.

Wire arc additive manufacturing (WAAM) is an additive manufacturing process based on gas metal arc welding. It allows the fabrication of large-volume metal components by the controlled deposition and stacking of weld beads. Next to the near-net-shape manufacturing of metal components, WAAM is also applied in the local reinforcement of structural parts, such as shell geometries. However, this procedure can lead to undesired thermally induced distortions. In this work, the distortion caused by the WAAM reinforcement of half-cylinder shell geometries was investigated through experiments and transient thermo-mechanical finite element simulations. In the experiments, the weld beads were applied to the specimen, while its thermal history was measured using thermocouples. The developing distortions were registered using displacement transducers. The experimental data were used to calibrate and validate the simulation. Using the validated model, the temperature field and the distortions of the specimens could be predicted. Subsequently, the simulation was used to assess different deposition patterns and shell thicknesses with regard to the resulting part distortions. The investigations revealed a non-linear relation between shell thickness and distortion. Moreover, the orientation and the sequence of the weld beads had a significant impact on the formation of distortion. However, those effects diminished with an increasing shell thickness.

AIM: To evaluate the effect of 0.05% atropine on the control of myopia for 2y (phase I) and on spherical equivalent refraction (SER) progression for 1y (phase II) after its withdrawal in Chinese myopic children. METHODS: Totally 142 children with myopia were randomly assigned to the 0.05% atropine group or to the placebo group. In phase I, children received 1 treatment for each eye daily. In phase II, the patients received no treatment. Axial length (AL), SER, intraocular pressure (IOP) and atropine-related side effects were assessed at 6 months' intervals. RESULTS: During phase I, the mean change of SER was -0.46±0.30 D in the atropine group, compared to -1.72±1.12 D in the placebo group (P0.05). Furthermore, the change in SER from the atropine group was 0.50±0.41 D, which was significantly lower than 0.72±0.60 D from placebo group, (P0.05). CONCLUSION: The use of 0.05% atropine for two consecutive years may effectively control elongation of AL and thus progression of myopia, without significant SER progression 1y after atropine withdrawal. Therefore, treatment with 0.05% atropine daily for 2y is effective and safe.

Xiao Fan,1 Qi Li,2 Tingsong Li,3 Xiaoyan He,4 Chuan Feng,1 Bin Qin,1 Ye Xu,1 Ling He1 1Department of Radiology, the Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People’s Republic of China; 2Department of Radiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Neurology, the Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People’s Republic of China; 4Center for Clinical Molecular Medicine, the Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People’s Republic of ChinaCorrespondence: Ling He, Department of Radiology, the Children’s Hospital of Chongqing Medical University, No. 136 Zhongshan Er Road, Yuzhong District, Chongqing, People’s Republic of China, Tel +86 13983399138, Email doctorheling@yeah.netBackground: Studies suggested that myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are an isolated group of diseases that are different from multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). The proportion of individuals with MOGAD is higher among children. However, limited data are available on autoimmune antibodies and neuroimaging features in children with MOGAD.Methods: This study retrospectively reviewed 42 children with MOGAD. The clinical, neuroradiological, and cerebrospinal fluid data were compared according to courses and radiological results.Results: Of the 42 patients, 28 suffered a monophasic course and 14 had a relapsing course. During the follow-up magnetic resonance imaging (MRI), 21 patients had a well-resolved brain condition and another 21 patients showed slight improvement with marked residuals. Most patients with relapse had cortical lesions and a leukodystrophy-like MRI pattern (all p < 0.05). Children with poor radiological outcomes have confluent and hazy lesions that involve both cortexes, white matter lesion of > 2 cm, and a leukodystrophy-like pattern, as well as cerebral lesions with T1 hypointensity or enhancement and spinal lesions (all p < 0.05). The multivariable logistic regression analysis used the aforementioned differential features and showed cerebral enhancement and a leukodystrophy-like pattern as the most effective variations associated with poor radiological outcomes of MOGAD with an area under the curve of 0.875.Conclusion: MOGAD in children have some radiological features suggestive of clinical courses and radiological outcomes. A good understanding of these differential features can help to give early warnings of disease recurrence or poor radiological improvement and develop subsequent therapeutic strategies.Keywords: myelin oligodendrocyte glycoprotein, encephalomyelitis, magnetic resonance imaging, demyelination, central nervous system

Pathogenic variants in the CACNA1A gene have been associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia 6. With increasing use of clinical genetic testing, associations have expanded to include developmental delay, epilepsy, paroxysmal dystonia, and neuropsychiatric disorders. We report 47 individuals with 33 unique likely pathogenic or pathogenic CACNA1A variants. A machine learning method, funNCion, was used to predict loss-of-function (LoF)/gain-of-function (GoF) impact of genetic variants, and a heuristic severity score was designed to analyze genotype/phenotype correlations. Commonly reported phenotypes include developmental delay/intellectual disability (96%), hemiplegic migraines (36%), episodic ataxia type 2 (32%), epilepsy (55%), autism spectrum disorder (23%), and paroxysmal tonic upward gaze (36%). Severity score was significantly higher for predicted GoF variants, variants in the S5/S6 helices, and the recurrent p.Val1392Met variant. Seizures/status epilepticus were correlated with GoF and were more frequent in those with the p.Val1392Met variant. Our findings demonstrate a breadth of disease severity in CACNA1A-related disease and suggest that the clinical phenotypic heterogeneity likely reflects diverse molecular phenotypes. A better understanding of the natural history of CACNA1A-related disease and genotype/phenotype correlations will help inform prognosis and prepare for future clinical trials.