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Abstract Suppressor of Mek1 (Smek1) is a regulatory subunit of protein phosphatase 4. Genome‐wide association studies have shown the protective effect of SMEK1 in Alzheimer's disease (AD). However, the physiological and pathological roles of Smek1 in AD and other tauopathies are largely unclear. Here, the role of Smek1 in preventing neurodegeneration is investigated in tauopathy. Smek1 is downregulated in the aged human brain. Through single‐cell sequencing, a novel neuronal cluster is identified that possesses neurodegenerative characteristics in Smek1−/− mice. Smek1 deficiency caused markedly more severe motor and cognitive impairments in mice, as well as neuronal loss, gliosis, and tau hyperphosphorylation at major glycogen synthase kinase 3β (Gsk3β) sites. Protein‐protein interaction analysis revealed that the Ran‐binding domain (RanBD) in the N‐terminus of Smek1 facilitated binding with kinesin family member 2A (Kif2a). Depletion of Smek1 resulted in cytoplasmic aggregation of Kif2a, axon outgrowth defects, and impaired mitochondrial axonal trafficking. Downregulation of Kif2a markedly attenuated tau hyperphosphorylation and axon outgrowth defects in shSmek1 cells. For the first time, this study demonstrates that Smek1 deficiency progressively induces neurodegeneration by exacerbating tau pathology and mitochondrial dysfunction in an age‐dependent manner.

Abstract Clinical, laboratory, and microbiological features, clinical outcomes, and pyogenic liver abscess (PLA) prognosis evaluation in non‐liver cancer (Non‐LC) and liver cancer patients treated with transarterial chemoembolization (TACE, LC‐TACE). Clinical data of 48 consecutive PLA patients from January 2016 to December 2020 were retrospectively analyzed. Mortality between two PLA patient groups were compared, and mortality risk factors were evaluated. A total of 48 PLA patients (31 males and 17 females) from January 2016 to December 2020 met the study's inclusion criteria. There were 32 and 16 patients in the Non‐LC and LC‐TACE groups, respectively. Positive pus culture rate in the Non‐LC group was 87.5% and positive pus culture rate in LC‐TACE group was 81.3%. In the Non‐LC group, 28 patients improved after treatment, 1 patient did not improve, and 3 patients died during hospitalization, with a 9.4% mortality rate. In the LC‐TACE group, nine patients improved after treatment, three patients did not improve, and four patients died during hospitalization, with a 25% mortality rate. The Non‐LC group cure time was 37.4 ± 23.1 days, while the LC‐TACE group was 91.5 ± 49.7 days. PLA of the Non‐LC group and the LC‐TACE group were different in terms of pathogenic bacteria and cure time, and so on. A more comprehensive treatment should be considered for PLA after TACE.

AIM: To evaluate the efficacy and safety of HLX04-O, an investigational ophthalmic formulation of HLX04 (bevacizumab biosimilar) for intravitreal injection, as a treatment for wet age-related macular degeneration (wAMD) in a phase 1/2 clinical trial (NCT04993352). METHODS: Eligible patients with wAMD were enrolled to receive HLX04-O intravitreal injections at a dose of 1.25 mg/0.05 mL every four weeks. Efficacy and adverse events were evaluated every month during study visits. RESULTS: A 76-year-old male with wAMD in his left eye participated in the trial and completed six cycles of HLX04-O intravitreal injections. Changes were observed in macular center point thickness (baseline vs last study visit, 437 vs 255 μm) and best-corrected visual acuity letter score (baseline vs last study visit, 36 vs 77) of the affected eye, which indicated an improvement in wAMD over treatment. No adverse events were reported by the data cutoff date. CONCLUSION: HLX04-O at 1.25 mg/0.05 mL every four weeks is well tolerated in this patient, demonstrating promising safety and efficacy in wAMD treatment. Large-scale studies are required to confirm the outcomes.

Abstract Paleogeographic reconstruction of Precambrian terranes reworked by Phanerozoic orogens (e.g., the Tibetan Plateau) results in complex lithotectonic relations due to intracrustal reworking by tectonothermal events. Detrital zircon rare earth element (REE) databases at global (global major river sands) and regional (the Gangdese Mountains, southern Tibet) scales reveal trends in LREEN‾/HREEN‾ and Eu/Eu* that effectively record the crustal evolution of the source, including crustal thickness and redox state of the magma that generated the zircons. Regional comparisons of these chemical markers provide a new approach for paleogeographic reconstructions that we apply to study the origin of the Lhasa terrane, southern Tibet. Using Precambrian to early Paleozoic sedimentary and igneous rocks in the Lhasa terrane and compiling detrital zircon analyses from the northern margin of Gondwana, we show that the Lhasa terrane had an African affinity in the Rodinia–Gondwana supercontinent cycles (ca. 1.4–0.4 Ga).

Abstract Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.

IntroductionDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of Parkinson's disease (PD). Moreover, remote programming is widely used in Mainland China. This necessitates evaluating the ability of remote programming to achieve the ideal postoperative effect. Therefore, we aimed to retrospectively evaluate the effects of different programming modes on the effectiveness of STN-DBS 12 months postoperatively in patients with PD.MethodsClinical data were collected retrospectively, before and 12 months after surgery, in 83 patients with PD. Based on the programming modes voluntarily selected by the patients during 12 months postoperatively, they were divided into three groups, namely remote programming alone, hospital programming alone, and hospital + remote programming. We compared the programming data and the effects of different programming methods on STN-DBS-related improvements 12 months postoperatively among these groups. Furthermore, we analyzed STN-DBS-related improvements at 12 months postoperatively in 76 patients.ResultsThe effectiveness of STN-DBS was not influenced by the three programming modes. The postoperative Movement Disorder Society Unified Parkinson's Disease Rating Scale scores did not reveal statistically significant differences between the remote alone and hospital alone programming groups, except for motor examination. The postoperative decline in the levodopa equivalent daily dose was most apparent in the hospital programming alone group. The programming frequency of the hospital + remote programming group was considerably higher than that of the remaining groups. Seventy-six patients with PD displayed good STN-DBS surgical efficacy.ConclusionProgramming modes do not influence the short-term efficacy of STN-DBS, and remote programming can yield a satisfactory surgical effect.

Abstract Background Recently, the relationship between thyroid hormones (THs) across the euthyroid ranges and metabolic syndrome (MetS) has been widely discussed. This study aimed to present specific cutoff values of THs to assess the association between THs and MetS in a euthyroid cohort. Methods Data of 2694 subjects, aged 18–80 years, who attended health examination in Xi’an Electric Power Central Hospital from April 2011 to December 2015 were collected and analyzed. The first cohort enrolled 929 participants (followed up by 2221 person-years totally) to assess correlations between serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) levels and MetS. The second cohort included 698 participants (followed up by 1709 person-years totally) to evaluate relationships between serum free triiodothyronine (FT3), free thyroxine (FT4) levels and MetS. MetS was defined according to the criteria of the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) scientific statements of 2009. Euthyroidism was defined as serum TSH, FT3 and FT4 levels within the reference ranges without taking any thyroid medication. Results The cutoff values for TSH, T3, T4, FT3 and FT4 were 2.0mIU/L, 1.9 nmol/L, 117 nmol/L, 4.3 pmol/L and 16 pmol/L, respectively. Participants were categorized into two groups according to cutoff values: the lower-THs group and the higher-THs group. There was no significant difference in the risk of MetS between two groups in TSH, T3, T4 and FT3. The incidence of MetS was significantly higher in lower-FT4 group than higher-FT4 group (1.00 vs 0.622 (0.458, 0.846), P = 0.002). The lower-FT4/higher-TSH group had the highest hazard ratios of MetS. (2.131vs 1.0 (1.380,3.291), P = 0.006). Conclusions Lower normal FT4 (FT4 ≤ 16.0 pmol/L) is an independent risk factor for MetS, and lower normal thyroid function (TSH > 2.0 mIU/L and FT4 ≤ 16.0 pmol/L) is associated with a higher risk of developing MetS.

The begomovirus–betasatellite complex constantly threatens crops in Asia. However, the quantitative relationship between begomoviruses and betasatellites remains largely unknown. The quantities of tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) and their ratio varied significantly in initial infection, and thereafter, the ratio tended to become constant. The TbCSB/TbCSV ratio in agrobacteria inoculum significantly affected that in plants in the initial infection but not thereafter. Null-mutation of βC1 that encodes a multifunctional protein important for pathogenesis in TbCSB significantly reduced the TbCSB/TbCSV ratio in plants. Viral inoculum plants with higher TbCSB/TbCSV ratios promoted whitefly transmission of the virus. The expression of AV1 encoded by TbCSV, βC1 encoded by TbCSB and the βC1/AV1 ratio varied significantly in the initial infection and thereafter the ratio tended to become constant. Additionally, the temporal dynamics of the ratio between another begomovirus and its betasatellite was similar to that of TbCSV and was positively regulated by βC1. These results indicate that the ratio between monopartite begomoviruses and betasatellites tend to become constant as infection progresses, and is modulated by βC1, but a higher betasatellite/begomovirus ratio in virally inoculated plants promotes virus transmission by whiteflies. Our findings provide novel insights into the association between begomoviruses and betasatellites.

The triplet-based knowledge in large-scale knowledge bases is most likely lacking in structural logic and problematic of conducting knowledge hierarchy. In this paper, we introduce the concept of metaknowledge to knowledge engineering research for the purpose of structural knowledge construction. Therefore, the Metaknowledge Extraction Framework and Document Structure Tree model are presented to extract and organize metaknowledge elements (titles, authors, abstracts, sections, paragraphs, etc.), so that it is feasible to extract the structural knowledge from multi-modal documents. Experiment results have proved the effectiveness of metaknowledge elements extraction by our framework. Meanwhile, detailed examples are given to demonstrate what exactly metaknowledge is and how to generate it. At the end of this paper, we propose and analyze the task flow of metaknowledge applications and the associations between knowledge and metaknowledge.

Background and Objectives: As an extensively used tree species in landscaping and afforestation in China, lacebark pine (Pinus bungeana Zucc.) seedlings are in high demand. However, the small number of fine roots and the low growth rate of lacebark pine seedlings increase the risks encountered during transplant and extend the nursery time for outplanting. We aimed to find out whether a microbial inoculant would promote root growth and accordingly, shorten the nursery cultivation time. Materials and Methods: One-year-old lacebark pine seedlings were treated with the inoculant Bacillus subtilis 8–32 six times from June to September. At each application time, five treatments of undiluted microbial inoculants (UM), 30 times diluted microbial inoculants (30 DM), 40 times diluted microbial inoculants (40 DM), 50 times diluted microbial inoculants (50 DM), and distilled water as a control (CTRL) were administered to the seedlings. In the end, all the seedlings were harvested to measure the root growth, aboveground growth, and the physiological indices. Results: Root and stem growth was enhanced by the inoculants in terms of the increased number of root tips, the length and surface area of the roots, the biomass of the roots and stems, as well as the increase in height and basal stem diameter. The chlorophyll a/b of the needles was increased, in spite of the fact that the total chlorophyll content was decreased by the microbial inoculant treatments at the end of the growth phase. Meanwhile, the maximum photochemical efficiency (Fv/Fm) of the needles was increased by the inoculant treatments. The soluble sugar content was additionally translocated into the stems in the UM treatment, suggesting the change in carbon allocation. The content of available potassium, phosphorus, and ammonium nitrogen in the potting soil was increased in the 30 DM group, and the content of soil organic matter was increased in all the inoculant treatments. Conclusions: The microbial inoculant Bacillus subtilis 8–32, in appropriate concentrations, could be applied to promote root and shoot growth and improve the seedling quality of the lacebark pine during cultivation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for advanced Parkinson's disease (PD). The G2385R variant of LRRK2 is a risk factor for PD in Han Chinese individuals. We retrospectively compared the clinical outcomes of STN-DBS surgery between PD Han Chinese G2385R variant carriers and non-carriers. Fifty-seven PD patients with bilateral STN-DBS were enrolled, including 8 G2385R+ variant carriers (G2385R+ group) and 49 non-carriers (G2385R– group). Clinical data included Unified Parkinson's Disease Rating Scale (UPDRS) parts I to IV, levodopa equivalent daily dose (LEDD), Mini-Mental State Examination Scale (MMSE) score, and Hamilton Depression Rating Scale (HAMD) score measured prior to DBS and 12 months post-DBS. DBS settings were also recorded. All PD patients benefited from STN-DBS surgery. There were no statistical differences between the two groups in terms of motor function, daily living activities, and LEDD reductions at 12 months post-DBS. The rigidity of the post-surgical G2385R+ group was significantly improved compared with that of the G2385R– group (P = 0.045). Post-surgical voltage in the G2385R+ group was significantly higher than that in the G2385R– group (P = 0.033). STN-DBS outcomes were not influenced by the LRRK2 G2385R variant in Han Chinese patients.

The purpose of this study was to investigate the residue elimination of ceftiofur hydrochloride in milk of postpartum cows after intramammary infusing at dry-off. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to detect ceftiofur hydrochloride residue in milk. Through preprocessing, ceftiofur hydrochloride was derivatized into a more stable compound dedfuroyl ceftiofur acetamide (DCA) for further analysis. The linear range of DCA was 0.1 to 50 μg kg−1. Average recoveries of DCA were 82.52–105.86%. The intra-day and interday coefficients of variation (CV) were 2.95–9.82 and 6.41–7.43%, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) scores were 0.05 and 0.1 μg kg−1, respectively. These parameters showed this method was reliable and valid. Twelve cows were administrated 10 mL ceftiofur hydrochloride by intramammary infusion (corresponding to 500 mg ceftiofur) to each udder after the last milking before the dry-off period. Milk was collected from each udder of cow at 12, 24, 36, 48, 60 and 72 h after calving and was mixed for each time point and each cow, then subjected to UPLC-MS/MS analysis. The results showed, the DCA concentrations in all milk samples were less than LOQ and the maximum residue limit (MRL) 100 μg kg−1, which suggested the withdrawal time of ceftiofur hydrochloride intramammary infusion used for preventing and curing mastitis in dry cows was 0 day. The study provided guidance for the clinical applications of ceftiofur hydrochloride intramammary infusion (dry cow).

The detection of chemical contaminants is critical to ensure dairy safety. These contaminants include veterinary medicines, antibiotics, pesticides, heavy metals, mycotoxins, and persistent organic pollutants (POPs). Immunoassays have recently been used to detect contaminants in milk because of their simple operation, high speed, and low cost. This article describes the latest developments in the most important component of immunoassays — antibodies, and then reviews the four major substrates used for immunoassays (i.e., microplates, membranes, gels, and chips) as well as their use in the detection of milk contaminants. The paper concludes with prospects for further applications of these immunoassays.

Torenia benthamiana Hance is an endemic plant species distributed in southern China. In this study, we report and characterize the complete plastid genome sequence of T. benthamiana in order to provide genomic resources helpful for promoting its conservation and garden utilization. The complete plastome is 153,526 bp in length and contains the typical quadripartite structure of angiosperm plastome, including two inverted repeat (IR) regions of 24,638 bp, a large single-copy (LSC) region of 85,417 bp, and a small single-copy (SSC) region of 18,833 bp. The plastome contains 114 genes, consisting of 80 unique protein-coding genes, 30 unique tRNA gene, and 4 unique rRNA genes. The overall A/T content in the plastome of T. benthamiana is 62.40%. The complete plastome sequence of T. benthamiana will provide a useful resource for the conservation and garden utilization of this species as well as for the phylogenetic studies of Linderniaceae.

Dengue counts among the most commonly encountered arboviral diseases, representing the fastest spreading tropical illness in the world. It is prevalent in 128 countries, and each year >2.5 billion people are at risk of dengue virus infection worldwide. Neurological signs of dengue infection are increasingly reported. In this review, the main neurological complications of dengue virus infection, such as central nervous system (CNS), peripheral nervous system, and ophthalmic complications were discussed according to clinical features, treatment and possible pathogenesis. In addition, neurological complications in children were assessed due to their atypical clinical features. Finally, dengue infection and Japanese encephalitis were compared for pathogenesis and main clinical manifestations.