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Differentiating iNPH from other neurodegenerative diseases is challenging. Only a portion of the patients clinically suspected of iNPH would respond to surgical intervention. CSF tap test is usually used to predict surgery outcomes and hence aid clinical decision-making, but the work-up varies. Introduce the CSF tap test conducted at our center and examine its power by analyzing data from a series of iNPH cases underwent shunt placement. Analyze common features in the past medical history of our patients and investigate whether they are related to the etiology of iNPH.Data from 20 patients who were positive in the tap tests pre-operatively and received ventriculoperitoneal shunting were retrospectively analyzed. Pre-operative and post-operative performance data were analyzed. History of any underlying medical conditions was taken into consideration. Patients with negative tap test results of same period were also followed-up.We performed VP shunt placement in 20 NPH patients from October 2019 to February 2022. 90% of them exhibited improvement in at least 1 of the clinical triad, proving the predictive power of the PUMCH test workflow. The underlying conditions like hypertension, diabetes and insufficiency in cerebral blood supply were also found to be associated with the onset of NPH.Our evaluation system is a valid tool for NPH assessment and can guide clinical decision-making. Comorbidities should be taken into consideration as they contribute to the pathogenesis and progression of NPH. Better identification of potential iNPH patients will lower the burden exerted on the family and the aging society.

The sperm-associated antigen 5 (SPAG5) is an important protein in mitosis and cell cycle checkpoint regulation, with more attention as a novel oncogene in various cancers. High level of SPAG5 expression has been detected in our clinical gastric cancer (GC) samples and The Cancer Genome Atlas GC data. However, the bio-function and potential mechanism of SPAG5 in GC remain unclear. In this study, we investigated the role of SPAG5 in GC development and the correlation between SPAG5 and 5-fluorouracil (5-FU) treatment. SPAG5 expression was increased in GC samples compared with that in normal tissues (80.8% vs. 22.0%), which was apparently associated with a worse outcome. Biological experiments showed that knockdown of SPAG5 induced apoptosis and suppressed proliferation in cells and animal models. Downregulation of SPAG5 enhanced the sensitivity of 5-FU in GC cells. Gene microarray chip identified 856 upregulated and 787 downregulated genes in SPAG5 silencing cells. Furthermore, 12 significant genes, including CDKN1A, CDKN1B, EIF4E, MAPK1, and HSP90B1, belonged to the PI3K/AKT signaling pathway using ingenuity pathway analysis. Meanwhile, real-time PCR and Western blotting results showed that knockdown of SPAG5 inhibited PI3K/AKT signaling pathway. Collectively, SPAG5 promotes the growth of GC cells by regulating PI3K/AKT signaling pathway, which could be the promising target gene in GC therapy.

Because the nature of numerical information is intuitive and comprehensible, it has been widely used to form a basis for decision making, yet numerical information based on historical principle does not reflect messages about future corporate performance. To confront this issue, one may consider textual information that can transmit future corporate potential without any hysteresis. The key point is how to digest an extensive amount of textual information and identify those topics most likely to precede changes in operation status. Topic modeling can categorize these textual disclosures based on their underlying content and help examine which topics have a strong relevance to corporate operations. To extract decisive words from textual information, we set up a statistical-based approach with objectivity as opposed to frequently used heuristics (i.e., dictionary-based approaches with human involvement). Joint utilization of topic modelling and a statistical-based approach can compress an excessive amount of textual information into a manageable size in a timely manner and further realize a discrepancy among various topics in terms of relevance and influence on corporate operations. Our results benefit managers and current and future investors in how to structure regulatory filings and how word choices are decisive to them in their decision judgments.

The growth of pollen tubes, which depends on actin filaments, is pivotal for plant reproduction. Pharmacological experiments showed that while oryzalin and brefeldin A treatments had no significant effect on the lipid droplets (LDs) trafficking, while 2,3-butanedione monoxime (BDM), latrunculin B, SMIFH2, and cytochalasin D treatments slowed down LDs trafficking, in such a manner that only residual wobbling was observed, suggesting that trafficking of LDs in pollen tube is related to F-actin. While the trafficking of LDs in the wild-type pollen tubes and in myo11-2, myo11b1-1, myo11c1-1, and myo11c2-1 single mutants and myo11a1-1/myo11a2-1 double mutant were normal, their trafficking slowed down in a myosin-XI double knockout (myo11c1-1/myo11c2-1) mutant. These observations suggest that Myo11C1 and Myo11C2 motors are involved in LDs movement in pollen tubes, and they share functional redundancy. Hence, LDs movement in Arabidopsis pollen tubes relies on the actomyosin system.

Stimuli-responsive color-changing and shape-changing hydrogels are promising intelligent materials for visual detections and bio-inspired actuations, respectively. However, it is still an early stage to integrate the color-changing performance and shape-changing performance together to provide bi-functional synergistic biomimetic devices, which are difficult to design but will greatly expand further applications of intelligent hydrogels. Herein, we present an anisotropic bi-layer hydrogel by combining a pH-responsive rhodamine-B (RhB)-functionalized fluorescent hydrogel layer and a photothermal-responsive shape-changing melanin-added poly (N-isopropylacrylamide) (PNIPAM) hydrogel layer with fluorescent color-changing and shape-changing bi-functional synergy. This bi-layer hydrogel can obtain fast and complex actuations under irradiation with 808 nm near-infrared (NIR) light due to both the melanin-composited PNIPAM hydrogel with high efficiency of photothermal conversion and the anisotropic structure of this bi-hydrogel. Furthermore, the RhB-functionalized fluorescent hydrogel layer can provide rapid pH-responsive fluorescent color change, which can be integrated with NIR-responsive shape change to achieve bi-functional synergy. As a result, this bi-layer hydrogel can be designed using various biomimetic devices, which can show the actuating process in the dark for real-time tracking and even mimetic starfish to synchronously change both the color and shape. This work provides a new bi-layer hydrogel biomimetic actuator with color-changing and shape-changing bi-functional synergy, which will inspire new strategies for other intelligent composite materials and high-level biomimetic devices.

Stimuli-responsive actuating hydrogels response to the external stimulus with complex deformation behaviors based on the programmable anisotropic structure design are one of the most important smart soft materials, which have great potential applications in artificial muscles, smart values, and mini-robots. However, the anisotropic structure of one actuating hydrogel can only be programmed one time, which can only provide single actuating performance, and subsequently, has severely limited their further applications. Herein, we have explored a novel SMP/hydrogel hybrid actuator through combining polyurethane shape memory polymer (PU SMP) layer and pH-responsive polyacrylic-acid (PAA) hydrogel layer by a napkin with UV-adhesive. Owing to both the super-hydrophilicity and super-lipophilicity of the cellulose-fiber based napkin, the SMP and the hydrogel can be bonded firmly by the UV-adhesive in the napkin. More importantly, this bilayer hybrid 2D sheet can be programmed by designing a different temporary shape in heat water which can be fixed easily in cool water to achieve various fixed shapes. This hybrid with a fixed temporary shape can achieve complex actuating performance based on the bi-functional synergy of temperature-triggered SMP and pH-responsive hydrogel. The relatively high modulus PU SMP achieved high to 87.19% and 88.92% shape-fixing ratio, respectively, correspond to bending and folding shapes. The hybrid actuator can actuate with the 25.71 °/min actuating speed. Most importantly, one SMP/hydrogel bi-layer hybrid sheet was repeatedly programmed at least nine times in our research to fix various temporary 1D, 2D and 3D shapes, including bending, folding and spiraling shapes. As a result, only one SMP/hydrogel hybrid can provide various complex stimuli-responsive actuations, including the reversable bending-straightening, spiraling-unspiraling. A few of the intelligent devices have been designed to simulate the movement of the natural organisms, such as bio-mimetic “paw”, “pangolin” and “octopus”. This work has developed a new SMP/hydrogel hybrid with excellent multi-repeatable (≥9 times) programmability for high-level complex actuations, including the 1D to 2D bending and the 2D to 3D spiraling actuations, which also provides a new strategy to design other new soft intelligent materials and systems.

BACKGROUNDQuantitative flow ratio (QFR) is a new method to estimate fractional flow reserve based on three-dimensional quantitative coronary angiography, from which angiography-derived microcirculatory resistance (AMR) without guidewires and adenosine is derived as an indicator of microvascular dysfunction. This study aimed to assess coronary microvascular dysfunction (CMD) in patients with ST-segment elevation myocardial infarction (STEMI) by AMR.METHODSA retrospective collection of 506 STEMI patients who successfully underwent percutaneous coronary intervention (PCI) from June 1, 2020, to September 28, 2021, was divided into the CMD group and the non-CMD group based on the value of AMR, while we used propensity score matching (PSM) to adjust for baseline characteristics. The primary endpoint was the 1-year rate of major adverse cardiac events (MACE), a composite of death from any cause, myocardial infarction, readmission for heart failure, or ischemia-driven revascularization.RESULTSThe 1-year rate of MACE in CMD group was higher than that in the non-CMD group (post-match HR 1.954, 95% CI:1.025 to 3.726; 14.1% vs. 7.3%, P=0.042); Subgroup analysis showed that the readmission rate of heart failure (HF) was higher in the CMD group than in the non-CMD group (post-match HR 5.082, 95% CI:1.471 to 17.554; 7.9% vs. 1.6%. P=0.010). The results of survival analysis suggested that AMR ≥250mmHg*s/m was an independent predictor of the primary endpoint in STEMI patients (post-match adjusted HR 2.265, 95% CI: 1.136 to 4.515, P = 0.020). CONCLUSION: As an indicator of microvascular dysfunction, AMR can be a viable alternative to invasive wire-based IMR in STEMI patients.

Objectives: To explore the correlation and significance of serum insulin-like growth factor-1 (IGF-1) and bone metabolism markers in patients with non-traumatic avascular necrosis of femoral head (N-ANFH). Methods: A prospective study was conducted on the patients with control and N-ANFH cohorts admitted from the orthopedic department of The Sixth Affiliated Hospital of Guangzhou Medical University from July 2020 to February 2023. The control (n=25) and N-ANFH cohorts (n=30) were randomly selected using block randomization method. The gender, age, body mass index (BMI), IGF-1, bone metabolism markers, including type I collagen hydroxyl terminal peptide β special sequence (β-CTX), N-terminal mid-fragment of osteocalcin (N-MID), total aminoterminal propeptide of type I procollagen (T-PINP), serum 25-hydroxyvitamin (D25(OH)D), parathormone and bone density, were compared between the two cohorts. Single and multiple factor logistic regression analysis were applied to study the correlation between dependent variable and N-ANFH. The expression pattern of IGF-1 in bone tissue from control and N-ANFH cohorts was detected by immunofluorescence (IF). Bone mineral density (BMD) was evaluated by dual-energy X-ray absorptiometry (DXA) scanning. Pearson correlation analysis was used to analyze the relationship between IGF-1 and BMD, the value of IGF-1 in the diagnosis N-ANFH was evaluated by receiver operating characteristic curve (ROC) analysis. Results: The bone metabolism markers of the control cohort were significantly higher than those of the N-ANFH cohort (p< 0.05), and IF revealed that the expression level of IGF-1 in the control cohort was significantly higher than that of the N-ANFH cohort. The expression level of IGF-1 was positively correlated with hip BMD (r= 0.7569, p= 0.0001). The area under ROC curve (AUC) in the diagnosis of N-ANFH was 0.7373, p= 0.0026, with a cutoff value of 139.6, corresponding sensitivity of 80%, and a specificity of 64%. Conclusion: The bone metabolism level of N-ANFH is significantly reduced, and IGF-1 is not only closely related to the level of osteoporosis, but also one of vital biomarkers for diagnosing N-ANFH, suggesting that decreased bone metabolism level and osteoporosis may be the main causes of N-ANFH.

Hydrogel-based wet electrodes are the most important biosensors for electromyography (EMG), electrocardiogram (ECG), and electroencephalography (EEG); but, are limited by poor strength and weak adhesion. Herein, a new nanoclay-enhanced hydrogel (NEH) has been reported, which can be fabricated simply by dispersing nanoclay sheets (Laponite XLS) into the precursor solution (containing acrylamide, N, N′-Methylenebisacrylamide, ammonium persulfate, sodium chloride, glycerin) and then thermo-polymerizing at 40 °C for 2 h. This NEH, with a double-crosslinked network, has nanoclay-enhanced strength and self-adhesion for wet electrodes with excellent long-term stability of electrophysiology signals. First of all, among existing hydrogels for biological electrodes, this NEH has outstanding mechanical performance (93 kPa of tensile strength and 1326% of breaking elongation) and adhesion (14 kPa of adhesive force), owing to the double-crosslinked network of the NEH and the composited nanoclay, respectively. Furthermore, this NEH can still maintain a good water-retaining property (it can remain at 65.4% of its weight after 24 h at 40 °C and 10% humidity) for excellent long-term stability of signals, on account of the glycerin in the NEH. In the stability test of skin–electrode impedance at the forearm, the impedance of the NEH electrode can be stably kept at about 100 kΩ for more than 6 h. As a result, this hydrogel-based electrode can be applied for a wearable self-adhesive monitor to highly sensitively and stably acquire EEG/ECG electrophysiology signals of the human body over a relatively long time. This work provides a promising wearable self-adhesive hydrogel-based electrode for electrophysiology sensing; which, will also inspire the development of new strategies to improve electrophysiological sensors.

Since the gene encoding mobilised colistin resistance (mcr-1) was first reported in China in 2015, it has been reported in various Enterobacteriaceae worldwide. Escherichia coli, one of the main pathogens causing diarrhoea, is the most prevalent, clinically identified species carrying mcr-1. This study aimed to investigate the epidemiologic and genomic characteristics of mcr-1 in Escherichia coli from patients in Shanghai.Faecal samples were collected from hospitals in Shanghai between 2012 and 2015. Polymerase chain reaction was performed to detect mcr-1, and molecular characteristics of the mcr-1-positive E. coli was determined by antimicrobial susceptibility testing and whole-genome sequencing.We detected 40 (3.9%) mcr-1-positive E. coli strains from faecal samples in clinical settings between 2012 and 2015 in Shanghai. Mcr-1 was detected in 4 types of E. coli, including atypical enteropathogenic E. coli (aEPEC), enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), and enteroaggregative E. coli (EAEC). Most strains harbouring mcr-1 were isolated from children aged7 years. Whole-genome sequencing revealed that nearly half of the strains that carried quinolone resistance- or β-lactam resistance-related genes were multidrug-resistant. IncX4 was the predominant type in mcr-1-positive E. coli in Shanghai, but the other types of mcr-1-harbouring plasmids are highly diverse in genetic context.These data suggest that mcr-1 is prevalent in E. coli strains, especially those identified in diarrhoeal patients in Shanghai, and strengthening the surveillance of mcr-1 transmission, especially in children, is essential.

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Purpose:Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer potentially through an “MT2A–NF-κB pathway” with unclear mechanisms. This study explored the role of a transcription factor, myeloid zinc-finger 1 (MZF1), in MT2A-NF-κB pathway and its clinical significance in gastric cancer.Experimental Design:MZF1 expression and function in gastric cancer were investigated in vitro and in vivo. The relationship between MZF1 and MT2A was determined by gain-of-function and loss-of-function assays in gastric cancer cells and an immortalized gastric cell line GES-1. The prognostic value of MZF1 expression in association with MT2A was evaluated using IHC in two cohorts.Results:MZF1 was epigenetically silenced in human gastric cancer cell lines and primary tumors. Overexpression of MZF1 in gastric cancer cells suppressed cell proliferation and migration, as well as the growth of xenograft tumors in nude mice. Knocking-down of MZF1 transformed GES-1 cells into a malignant phenotype characterized by increased cell growth and migration. Mechanistically, MZF1 was upregulated in both GC and GES-1 cells by MT2A ectopically expressed or induced upon treatment with a garlic-derived compound, diallyl trisulfide (DATS). MZF1 associated with MT2A was colocalized in the nuclei of GES-1 cells to target the promoter of NF-κB inhibitor alpha (NFKBIA). Clinically, MT2A and MZF1 were progressively downregulated in clinical specimens undergoing gastric malignant transformation. Downregulation of MT2A and MZF1 was significantly correlated with poorer patient prognosis.Conclusions:MT2A exerts its anti-gastric cancer effects by complexing with MZF1 to target NFKBIA. MT2A/MZF1 may serve as a valuable prognostic marker and a novel therapeutic target for human gastric cancer.

Supplementary Materials and Methods

Supplementary Data from Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects.Significance:Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.

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Differential expression of the ligands for NK cell inhibitory and stimulatory receptor by BCSCs or non-BCSCs.

Supplementary Tables 1-8 PDF file 178K, Supplementary Table 1. The expression of IGF-1R, �-catenin and POU5F1 in 200 cases of lung adenocarcinoma; Supplementary Table 2. Top 10 gene ontology classification of genes related to the biological process of LACSLCs; Supplementary Table 3. Top 10 gene ontology classification of genes related to the cellular components of LACSLCs; Supplementary Table 4. Top 10 gene ontology classification of genes involved in the molecular functions of LACSLCs; Supplementary Table 5. Expression profile of up-regulated genes identified by cDNA array and qRT-PCR in A549 LACSLCs; Supplementary Table 6. Expression profile of down-regulated genes identified by cDNA array and qRT-PCR in A549 LACSLCs; Supplemental Table 7. Antibodies used for immunostaining analysis; Supplemental Table 8. Sequences of the primers used for qRT-PCR

Characterization of stem-like properties of ALDH+ cells isolated from primary breast cancer specimens.

Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation–inducing agent, all-trans retinoic acid, restored the miR20a–MICA/MICB axis and sensitized BCSC to NK cell–mediated killing, thereby reducing immune escape–associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a–MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746–57. ©2014 AACR.

Activation and cytotoxicity of NK cells by interaction with BCSCs or non-BCSCs.

Table S1. The levels of ALDH1+ cells and CD56+ cells and the clinical parameters of breast cancers. Table S2. Univariate analysis of potential prognostic factors for the ALDH1low and ALDH1high subgroups of breast cancers. Table S3. Multivariate analysis of potential prognostic factors for the ALDH1low and ALDH1high subgroups of breast cancers. Table S4. Patient characteristics of primary breast cancers for culture. Table S5. Antibodies used in the study. Table S6. Primers used for cloning coding sequence of MICA and MICB. Table S7. Primers sequences that were used in the qRT-PCR. Table S8. Small interference RNA sequences for knockdown of MICA and MICB expression. Table S9. Primers used for cloning of MICA-3’UTR and MICB-3’UTR. Table S10. Nucleotide sequences of MICA-3’UTR and MICB-3’UTR with mutant binding sites for miRNA-20a.

The effect of ATRA on the sensitivity to NK cell killing, survival, and lung metastasis of BCSCs

Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR—mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. Cancer Res; 73(10); 3181–9. ©2013 AACR.

Knockdown of MICA or MICB in non-BCSCs.

Supplementary Table 9 PDF file 167K, Supplementary Table 9. Clinicopathological features and IHC staining index of ALDH1A1, IGF-1R, �-catenin and POU5F1 in 200 patients with LAC

Supplementary Figures 1-8 PDF file 1850K, Supplementary Figure 1. LACSLCs derived from A549 and H358 cell lines; Supplementary Figure 2. Sphere LACSLCs derived from A549 cell line expressed high levels of CSLCs transcription factors including SOX2 and POU5F1 with low expression of differentiated markers CK8/CK18;Supplementary Figure 3. Immunofluorescence staining of CD133 and ALDH1A1;Supplementary Figure 4. Correlation of IGF-1R and ALDH1A1 with poor DSS in LAC patients;Supplementary Figure 5. Insulin signaling/IGF pathway is highly correlated with expression genes in LACSLCs;Supplementary Figure 6. Disruption of IGF-1R signaling pathway inhibits the self-renewal and the tumorigenic potential of human LACSLCs;Supplementary Figure 7. MEK inhibitor PD98059 has no effect on POU5F1; Expression of IGF-1, �-catenin and POU5F1 in fresh LAC specimens and A549 LACSLCs

Suppression of MICA/B by overexpressing miR-20a in BCSCs.

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Background Colony-stimulating factor 3 (CSF3) is a cytokine associated with inflammation, which mainly stimulates myeloid stem cell maturation, proliferation, and migration into circulation. However, the significance of CSF3 in colorectal cancer (CRC) remains unclear. Here, we aimed to examine the expression and impacts of CSF3 in CRC. Methods CSF3 expression was examined in CRC tissues and cells by IHC staining and western blot. RNA interference was used to silence CSF3 in CRC cells. The effects of CSF3 on biological behaviors such as proliferation and migration of CRC cells were examined in vitro and in vivo. Results CSF3 was highly expressed in CRC tissues and cells. CSF3 high level was correlated to patients’ age, with a feature of a higher pathological stage, more distant lymphatic metastasis and more severe lymph node invasion. Knocking down CSF3 led to decreased proliferation and migration, increased apoptosis, arrested cell cycle in vitro as well as impaired tumor growth in vivo. Mechanistically, CSF3 regulates CRC cell proliferation and apoptosis dependent on enhances p65 phosphorylation to facilitate NF-κB-mediated transcriptional activity. Conclusion Our study demonstrated that CSF3 interacts with the NF-κB signaling pathway to promote the progression of CRC. CSF3 might be a potential therapeutic target for CRC patients.

IntroductionInfluenza A virus (IAV)-induced dysbiosis may predispose to severe bacterial superinfections. Most studies have focused on the microbiota of single mucosal surfaces; consequently, the relationships between microbiota at different anatomic sites in IAV-infected mice have not been fully studied.MethodsWe characterized respiratory and gut microbiota using full-length 16S rRNA gene sequencing by Nanopore sequencers and compared the nasopharyngeal, oropharyngeal, lung and gut microbiomes in healthy and IAV-infected mice.ResultsThe oropharyngeal, lung and gut microbiota of healthy mice were dominated by Lactobacillus spp., while nasopharyngeal microbiota were comprised primarily of Streptococcus spp. However, the oropharyngeal, nasopharyngeal, lung, and gut microbiota of IAV-infected mice were dominated by Pseudomonas, Escherichia, Streptococcus, and Muribaculum spp., respectively. Lactobacillus murinus was identified as a biomarker and was reduced at all sites in IAV-infected mice. The microbiota composition of lung was more similar to that of the nasopharynx than the oropharynx in healthy mice.DiscussionThese findings suggest that the main source of lung microbiota in mice differs from that of adults. Moreover, the similarity between the nasopharyngeal and lung microbiota was increased in IAV-infected mice. We found that IAV infection reduced the similarity between the gut and oropharyngeal microbiota. L. murinus was identified as a biomarker of IAV infection and may be an important target for intervention in post-influenza bacterial superinfections.

This study examines whether a negative interest rate policy (NIRP) which is mainly used in Denmark, Sweden, Switzerland, and Japan can interfere exchange rate, protect exports, and promote economic growth. We apply Tsay’s (1998) multivariate threshold model to examine the impact of exchange rate misalignment on the economic growth rate with the rate of change in exports as the threshold variable. The empirical results show that in Sweden, the investment contributes to economic growth irrespective of any type of regime, and only when exports threshold value exceeds 3.32% does local currency devaluation contribute to economic growth. In Switzerland, Japan, and Denmark, we have the same result with Sweden that investment will benefit economic growth irrespective of any type in its regime. However, currency devaluation does not significantly affect economic growth. Based on these findings, we suggest that if policymakers wish to use the influence of exchange rate misalignment to promote economic growth, currency depreciation is suggested to be sufficient enough to have an effect. Keywords: Negative Interest Rate Policy; Multivariate Threshold; Economic Growth; Exchange Rate Misalignment; Currency Devaluation JEL Classification Number: F00; O11; O40

IntroductionNanopore sequencing has been widely used in clinical metagenomic sequencing for pathogen detection with high portability and real-time sequencing. Oxford Nanopore Technologies has recently launched an adaptive sequencing function, which can enrich on-target reads through real-time alignment and eject uninteresting reads by reversing the voltage across the nanopore. Here we evaluated the utility of adaptive sequencing in clinical pathogen detection.MethodsNanopore adaptive sequencing and standard sequencing was performed on a same flow cell with a bronchoalveolar lavage fluid sample from a patient with Chlamydia psittacosis infection, and was compared with the previous mNGS results.ResultsNanopore adaptive sequencing identified 648 on-target stop receiving reads with the longest median read length(688bp), which account for 72.4% of all Chlamydia psittaci reads and 0.03% of total reads in enriched group. The read proportion matched to C. psittaci in the stop receiving group was 99.85%, which was much higher than that of the unblock (C. psittaci compared with standard nanopore sequencing. The proportion of C. psittaci reads in adaptive sequencing is close to that of standard nanopore sequencing and mNGS, but generated lower genome coverage than mNGS.DiscussionNanopore adaptive sequencing can effectively identify target C. psittaci reads in real-time, but how to increase the targeted data of pathogens still needs to be further evaluated.

In plants, thousands of nucleus-encoded proteins translated in the cytosol are sorted to chloroplasts and mitochondria by binding to specific receptors of the TOC (translocon at the outer membranes of chloroplasts) and TOM (translocon at the outer membranes of mitochondria) complexes for import into those organelles. The degradation pathways for these receptors are unclear. Here, we discovered a converged ubiquitin-proteasome pathway for the degradation ofArabidopsis thalianaTOC and TOM tail-anchored receptors. The receptors are ubiquitinated by E3 ligase(s) and pulled from the outer membranes by the AAA+ATPase CDC48, after which a previously characterized cytosolic protein, TTOP, binds to the exposed transmembrane domains (TMDs) at the C termini of the receptors and CDC48, and delivers the complexes to the 26S proteasome.