Novel mechanistic insights underlying fungal allergic inflammation.

The worldwide prevalence of asthma and allergic disorders (allergic rhinitis, atopic dermatitis, food allergy) has been steadily rising in recent decades. It is now estimated that up to 20% of the global population is afflicted by an allergic disease, with increasing incidence rates in both high- and low-income countries. The World Allergy Organization estimates that the total economic burden of asthma and allergic rhinitis alone is approximately $21 billion per year. While allergic stimuli are a complex and heterogenous class of inputs including parasites, pollens, food antigens, drugs, and metals, it has become clear that fungi are major drivers of allergic disease, with estimates that fungal sensitization occurs in 20-30% of atopic individuals and up to 80% of asthma patients. Fungi are eukaryotic microorganisms that can be found throughout the world in high abundance in both indoor and outdoor environments. Understanding how and why fungi act as triggers of allergic type 2 inflammation will be crucial for combating this important health problem. In recent years, there have been significant advances in our understanding of fungi-induced type 2 immunity, however there is still much we don't understand, including why fungi have a tendency to induce allergic reactions in the first place. Here, we will discuss how fungi trigger type 2 immune responses and posit why this response has been evolutionarily selected for induction during fungal encounter.

In Situ Formation of SnSe2/SnSe Vertical Heterostructures toward Polarization Selectable Band Alignments.

2D van der Waals (vdW) layered semiconductor vertical heterostructures with controllable band alignment are highly desired for nanodevice applications including photodetection and photovoltaics. However, current 2D vdW heterostructures are mainly obtained via mechanical exfoliation and stacking process, intrinsically limiting the yield and reproducibility, hardly achieving large-area with specific orientation. Here, large-area vdW-epitaxial SnSe2/SnSe heterostructures are obtained by annealing layered SnSe. These in situ Raman analyses reveal the optimized annealing conditions for the phase transition of SnSe to SnSe2. The spherical aberration-corrected transmission electron microscopy investigations demonstrate that layered SnSe2 epitaxially forms on SnSe surface with atomically sharp interface and specific orientation. Optical characterizations and theoretical calculations reveal valley polarization of the heterostructures that originate from SnSe, suggesting a naturally adjustable band alignment between type-II and type-III, only relying on the polarization angle of incident lights. This work not only offers a unique and accessible approach to obtaining large-area SnSe2/SnSe heterostructures with new insight into the formation mechanism of vdW heterostructures, but also opens the intriguing optical applications based on valleytronic nanoheterostructures.

Disability independent of cerebral white matter demyelination in progressive multiple sclerosis.

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.

Single-cell RNA sequencing to reveal non-parenchymal cell heterogeneity and immune network of acetaminophen-induced liver injury in mice.

The role of non-parenchymal cells (NPCs) in the early phase of acetaminophen (APAP)-induced liver injury (AILI) remains unclear. Therefore, single-cell sequencing (scRNA-seq) was performed to explore the heterogeneity and immune network of NPCs in the livers of mice with AILI. Mice were challenged with saline, 300 mg/kg APAP, or 750 mg/kg APAP (n = 3 for each group). After 3 h, the liver samples were collected, digested, and subjected to scRNA-seq. Immunohistochemistry and immunofluorescence were performed to confirm the expression of Makorin ring finger protein 1 (Mkrn1). We identified 14 distinct cell subtypes among the 120,599 cells. A variety of NPCs were involved, even in the early stages of AILI, indicating highly heterogeneous transcriptome dynamics. Cholangiocyte cluster 3, which had high deleted in malignant brain tumors 1 (Dmbt1) expression, was found to perform drug metabolism and detoxification functions. Liver sinusoidal endothelial cells exhibited fenestrae loss and angiogenesis. Macrophage cluster 1 displayed a M1 polarization phenotype, whereas cluster 3 tended to exhibit M2 polarization. Kupffer cells (KCs) exhibited pro-inflammatory effects due to the high expression of Cxcl2. qRT-PCR and western blotting verified that the LIFR-OSM axis might promote the activation of MAPK signaling pathway in RAW264.7 macrophages. Mkrn1 was highly expressed in the liver macrophages of AILI mice and AILI patients. Interaction patterns between macrophages/KCs and other NPCs were complex and diverse. NPCs were highly heterogeneous and were involved in the immune network during the early phase of AILI. In addition, we propose that Mkrn1 may serve as a potential biomarker of AILI.

Overview and Comparison of Chinese and Western Medical Treatments for Osteoporosis.

Objective: Traditional Chinese medicine (TCM) can achieve similar effects to Western medicine in increasing bone mineral density, improving the destruction of bone micro-structure, inhibiting bone resorption, etc. However, there exist great differences between TCM and Western medicine in terms of theoretical basis and treatment methods. Therefore, to gain insights into their differences in treating osteoporosis (OP), we compared the disease name, etiology, pathogenesis, and clinical effectiveness to explore the potential benefits of combining the two approaches. Methods Overview: The method of literature review is used in the study. We firstly use academic databases such as PubMed and CNKI to search relevant literature on the understanding of OP in TCM and Western medicine in the past 10 years, then exclude the literature that is not relevant to the study topic or does not meet the study purpose, and finally compare and summarize the findings, views and conclusions of the literature. Key Findings or Insights: In the study, we find that the integrated approach of TCM and Western medicine can provide a gentler and more individualized treatment for patients with OP. By combining the conditioning means of Chinese herbs, compound prescription, acupuncture, moxibustion and Tuina can make up for the adverse reactions and side effects of Western medicine. Besides, TCM can make use of the clinical trials and animal experiments of Western medicine to prove the effectiveness of TCM theories and promote the clinical application. Practical Implications: By exploring the differences between TCM and Western medicine and the potential benefits of their combination, this study can provide a theoretical basis for the individualized treatment of OP. Especially for the patients with postmenopausal OP, senile OP, long-term hormone use, hyperthyroidism and other secondary OP, this study can provide a more comprehensive rehabilitation guidance, prevent the recurrence of these diseases, and improve the quality of patients' life. Recommendations or Future Directions: It is suggested that further clinical trials should be conducted to evaluate the effectiveness of the integrated treatment.

Adhesion to the Brain Endothelium Selects Breast Cancer Cells with Brain Metastasis Potential.

Tumor cells metastasize from a primary lesion to distant organs mainly through hematogenous dissemination, in which tumor cell re-adhesion to the endothelium is essential before extravasating into the target site. We thus hypothesize that tumor cells with the ability to adhere to the endothelium of a specific organ exhibit enhanced metastatic tropism to this target organ. This study tested this hypothesis and developed an in vitro model to mimic the adhesion between tumor cells and brain endothelium under fluid shear stress, which selected a subpopulation of tumor cells with enhanced adhesion strength. The selected cells up-regulated the genes related to brain metastasis and exhibited an enhanced ability to transmigrate through the blood-brain barrier. In the soft microenvironments that mimicked brain tissue, these cells had elevated adhesion and survival ability. Further, tumor cells selected by brain endothelium adhesion expressed higher levels of MUC1, VCAM1, and VLA-4, which were relevant to breast cancer brain metastasis. In summary, this study provides the first piece of evidence to support that the adhesion of circulating tumor cells to the brain endothelium selects the cells with enhanced brain metastasis potential.

The potent analgesia of intrathecal 2R, 6R-HNK via TRPA1 inhibition in LF-PENS-induced chronic primary pain model.

BACKGROUND: Chronic primary pain (CPP) is an intractable pain of unknown cause with significant emotional distress and/or dysfunction that is a leading factor of disability globally. The lack of a suitable animal model that mimic CPP in humans has frustrated efforts to curb disease progression. 2R, 6R-hydroxynorketamine (2R, 6R-HNK) is the major antidepressant metabolite of ketamine and also exerts antinociceptive action. However, the analgesic mechanism and whether it is effective for CPP are still unknown. METHODS: Based on nociplastic pain is evoked by long-term potentiation (LTP)-inducible high- or low-frequency electrical stimulation (HFS/LFS), we wanted to develop a novel CPP mouse model with mood and cognitive comorbidities by noninvasive low-frequency percutaneous electrical nerve stimulation (LF-PENS). Single/repeated 2R, 6R-HNK or other drug was intraperitoneally (i.p.) or intrathecally (i.t.) injected into naïve or CPP mice to investigate their analgesic effect in CPP model. A variety of behavioral tests were used to detect the changes in pain, mood and memory. Immunofluorescent staining, western blot, reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and calcium imaging of in cultured dorsal root ganglia (DRG) neurons by Fluo-8-AM were used to elucidate the role and mechanisms of 2R, 6R-HNK in vivo or in vitro. RESULTS: Intrathecal 2R, 6R-HNK, rather than intraperitoneal 2R, 6R-HNK or intrathecal S-Ketamine, successfully mitigated HFS-induced pain. Importantly, intrathecal 2R, 6R-HNK displayed effective relief of bilateral pain hypersensitivity and depressive and cognitive comorbidities in a dose-dependent manner in LF-PENS-induced CPP model. Mechanically, 2R, 6R-HNK markedly attenuated neuronal hyperexcitability and the upregulation of calcitonin gene-related peptide (CGRP), transient receptor potential ankyrin 1 (TRPA1) or vanilloid-1 (TRPV1), and vesicular glutamate transporter-2 (VGLUT2) in peripheral nociceptive pathway. In addition, 2R, 6R-HNK suppressed calcium responses and CGRP overexpression in cultured DRG neurons elicited by the agonists of TRPA1 or/and TRPV1. Strikingly, the inhibitory effects of 2R, 6R-HNK on these pain-related molecules and mechanical allodynia were substantially occluded by TRPA1 antagonist menthol. CONCLUSIONS: In the newly designed CPP model, our findings highlighted the potential utility of intrathecal 2R, 6R-HNK for preventing and therapeutic modality of CPP. TRPA1-mediated uprgulation of CGRP and neuronal hyperexcitability in nociceptive pathways may undertake both unique characteristics and solving process of CPP.

Modeling the spread dynamics of multiple-variant coronavirus disease under public health interventions: A general framework.

The COVID-19 pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a single-stranded positive-stranded RNA virus with a high multi-directional mutation rate. Many new variants even have an immune-evading property, which means that some individuals with antibodies against one variant can be reinfected by other variants. As a result, the realistic is still suffering from new waves of COVID-19 by its new variants. How to control the transmission or even eradicate the COVID-19 pandemic remains a critical issue for the whole world. This work presents an epidemiological framework for mimicking the multi-directional mutation process of SARS-CoV-2 and the epidemic spread of COVID-19 under realistic scenarios considering multiple variants. The proposed framework is used to evaluate single and combined public health interventions, which include non-pharmaceutical interventions, pharmaceutical interventions, and vaccine interventions under the existence of multi-directional mutations of SARS-CoV-2. The results suggest that several combined intervention strategies give optimal results and are feasible, requiring only moderate levels of individual interventions. Furthermore, the results indicate that even if the mutation rate of SARS-CoV-2 decreased 100 times, the pandemic would still not be eradicated without appropriate public health interventions.

Analysis of Fatty Acid Metabolism in Fetal and Failing Hearts by Single-Cell RNA Sequencing Revealed SLC27A6 as a Critical Gene in Heart Maturation.

Background: Heart failure is associated with shifts in substrate preferences and energy insufficiency. Although cardiac metabolism has been explored at the organ level, the metabolic changes at the individual cell level remain unclear. This study employed single-cell ribonucleic acid (RNA) sequencing to investigate the cell-type-specific characteristics of gene expression related to fatty acid metabolism. Methods: Single-cell RNA sequencing data from fetal hearts were processed to analyze gene expression patterns related to fatty acid metabolism. Immunofluorescence staining and Western blotting techniques were employed to validate the expression of specific proteins. Additionally, calcium recording and contractility measurements were performed to assess the functional implications of fatty acid metabolism in cardiomyocytes. Results: Based on single-cell RNA sequencing data analysis, we found that a decrease in overall energy requirements underlies the downregulation of fatty acid oxidation-related genes in the later period of heart maturation and the compensatory increase of fatty acid metabolism in individual cardiomyocytes during heart failure. Furthermore, we found that solute carrier family 27 member 6 (SLC27A6), a fatty acid transport protein, is involved in cardiac maturation. SLC27A6 knockdown in human induced pluripotent stem cell-derived cardiomyocytes resulted in an immature cardiomyocyte transcriptional profile, abnormal morphology, impaired Ca2+ handling activity, and contractility. Conclusions: Overall, our study offers a novel perspective for exploring cardiac fatty acid metabolism in fetal and failing hearts along with new insights into the cellular mechanism underlying fatty acid metabolic alterations in individual cardiac cells. It thus facilitates further exploration of cardiac physiology and pathology.

Sensitivity of T1/T2-weighted ratio in detection of cortical demyelination is similar to magnetization transfer ratio using post-mortem MRI.

BACKGROUND: Detecting cortical demyelination using magnetic resonance imaging (MRI) in multiple sclerosis (MS) remains a challenge. Magnetization transfer ratio (MTR), T1-weighted/T2-weighted ratio (T1T2R), and T2-weighted (T2w) signal are sensitive to cortical demyelination, but their accuracy is unknown. OBJECTIVES: To quantify the sensitivity, specificity, and accuracy of postmortem T1T2R, MTR, and T2w in detecting cortical demyelination. METHODS: In situ postmortem MRIs from 9 patients were used to measure T1T2R, MTR, and T2w along the midline of cortical gray matter and classified as normal or abnormal. MRIs were co-registered and compared to hemispheric myelin staining. The sensitivity, specificity, and accuracy of T1T2R, MTR, and T2w in detecting cortical demyelination were measured. RESULTS: The mean age (standard deviation) at death was 64.7 (+/-13.7) years with a disease duration of 23.8 (+/-10.5) years. The sensitivity was 78% for MTR, 75% for T1T2R, and 63% for T2w. The specificity was 46% (T2w), 13% (T1T2R), and 29% (MTR). The accuracy was 71% (T2w), 39% (MTR), and 42% (T1T2R). There were no significant differences between different MRI measures in cortical demyelination or intracortical/subpial lesion detection. CONCLUSIONS: Although somewhat sensitive, the modest specificity of conventional MRI modalities for cortical demyelination indicates that they are influenced by cortical changes other than demyelination. Improved acquisition and post-processing are needed to reliably measure cortical lesion load.

Protecting mitochondria via inhibiting VDAC1 oligomerization alleviates ferroptosis in acetaminophen-induced acute liver injury.

Acetaminophen (APAP) overdose is a common cause of drug-induced liver injury (DILI). Ferroptosis has been recently implicated in APAP-induced liver injury (AILI). However, the functional role and underlying mechanisms of mitochondria in APAP-induced ferroptosis are unclear. In this study, the voltage-dependent anion channel (VDAC) oligomerization inhibitor VBIT-12 and ferroptosis inhibitors were injected via tail vein in APAP-injured mice. Targeted metabolomics and untargeted lipidomic analyses were utilized to explore underlying mechanisms of APAP-induced mitochondrial dysfunction and subsequent ferroptosis. As a result, APAP overdose led to characteristic changes generally observed in ferroptosis. The use of ferroptosis inhibitor ferrostatin-1 (or UAMC3203) and iron chelator deferoxamine further confirmed that ferroptosis was responsible for AILI. Mitochondrial dysfunction, which is associated with the tricarboxylic acid cycle and fatty acid ß-oxidation suppression, may drive APAP-induced ferroptosis in hepatocytes. APAP overdose induced VDAC1 oligomerization in hepatocytes, and protecting mitochondria via VBIT-12 alleviated APAP-induced ferroptosis. Ceramide and cardiolipin levels were increased via UAMC3203 or VBIT-12 in APAP-induced ferroptosis in hepatocytes. Knockdown of Smpd1 and Taz expression responsible for ceramide and cardiolipin synthesis, respectively, aggravated APAP-induced mitochondrial dysfunction and ferroptosis in hepatocytes, whereas Taz overexpression protected against these processes. By immunohistochemical staining, we found that levels of 4-hydroxynonenal (4-HNE) protein adducts were increased in the liver biopsy samples of patients with DILI compared to that in those of patients with autoimmune liver disease, chronic viral hepatitis B, and non-alcoholic fatty liver disease (NAFLD). In summary, protecting mitochondria via inhibiting VDAC1 oligomerization attenuated hepatocyte ferroptosis by restoring ceramide and cardiolipin content in AILI.

Stimulation of vascular smooth muscle cell proliferation by stiff matrix via the IKCa channel-dependent Ca2+ signaling.

Vascular stiffening, an early and common characteristic of cardiovascular diseases (CVDs), stimulates vascular smooth muscle cell (VSMC) proliferation which reciprocally accelerates the progression of CVDs. However, the mechanisms by which extracellular matrix stiffness accompanying vascular stiffening regulates VSMC proliferation remain largely unknown. In the present study, we examined the role of the intermediate-conductance Ca2+ -activated K+  (IKCa ) channel in the matrix stiffness regulation of VSMC proliferation by growing A7r5 cells on soft and stiff polydimethylsiloxane substrates with stiffness close to these of arteries under physiological and pathological conditions, respectively. Stiff substrates stimulated cell proliferation and upregulated the expression of the IKCa channel. Stiff substrate-induced cell proliferation was suppressed by pharmacological inhibition using TRAM34, an IKCa channel blocker, or genetic depletion of the IKCa channel. In addition, stiff substrate-induced cell proliferation was also suppressed by reducing extracellular Ca2+ concentration using EGTA or intracellular Ca2+ concentration using BAPTA-AM. Moreover, stiff substrate induced activation of extracellular signal-regulated kinases (ERKs), which was inhibited by treatment with TRAM34 or BAPTA-AM. Stiff substrate-induced cell proliferation was suppressed by treatment with PD98059, an ERK inhibitor. Taken together, these results show that substrates with pathologically relevant stiffness upregulate the IKCa channel expression to enhance intracellular Ca2+ signaling and subsequent activation of the ERK signal pathway to drive cell proliferation. These findings provide a novel mechanism by which vascular stiffening regulates VSMC function.

Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages.

OBJECTIVE: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates. METHODS: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML. RESULTS: With PML (n = 26 total, n = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, p < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages. CONCLUSION: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.

A critical role of the KCa 3.1 channel in mechanical stretch-induced proliferation of rat bone marrow-derived mesenchymal stem cells.

Mechanical stimulation is an important factor regulating mesenchymal stem cell (MSC) functions such as proliferation. The Ca2+ -activated K+ channel, KCa 3.1, is critically engaged in MSC proliferation but its role in mechanical regulation of MSC proliferation remains unknown. Here, we examined the KCa 3.1 channel expression and its role in rat bone marrow-derived MSC (BMSC) proliferation in response to mechanical stretch. Application of mechanical stretch stimulated BMSC proliferation via promoting cell cycle progression. Such mechanical stimulation up-regulated the KCa 3.1 channel expression and pharmacological or genetic inhibition of the KCa 3.1 channel strongly suppressed stretch-induced increase in cell proliferation and cell cycle progression. These results support that the KCa 3.1 channel plays an important role in transducing mechanical forces to MSC proliferation. Our finding provides new mechanistic insights into how mechanical stimuli regulate MSC proliferation and also a viable bioengineering approach to improve MSC proliferation.

Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1α/VEGF pathway.

F-box proteins, a type of substrate-recognition complexes consisting of SKP1-cullin 1-F-box protein (SCF) E3 ligase, can critically affect many cellular processes because of the ubiquitylation and subsequent degradation of target proteins. This study investigated the effect of FBXO22 on melanoma angiogenesis, migration, and invasion. Results showed that FBXO22 staining intensity was increased in malignant melanoma (MM) compared with that in skin tissue (P˂0.001). The percentage of high FBXO22 expression in MM (74.3%) was markedly higher than that in paracancerous and skin tissues (0%) (P˂0.001). FBXO22 was also overexpressed in MM tissues compared with that in normal skin tissues. FBXO22 knockdown in vitro inhibited MM cell migration, invasion, and angiogenesis (P < 0.001). In vivo studies confirmed that using nude mice with knocked down FBXO22 reduced the formation of blood vessels and decreased the positive rate of CD31 (P < 0.05). HIF-1α expression varied with FBXO22, indicating that FBXO22 regulated the expression of HIF-1α and VEGFA and that FBXO22 was a regulator of HIF-1α and VEGF for the control of tumor angiogenesis. In conclusion, FBXO22 promoted the migration and invasion of tumor cells and melanoma angiogenesis via HIF-1α upregulation. This study demonstrated that FBXO22 knockdown suppressed tumor progression and metastasis, suggesting that FBXO22 might be developed as a novel target for treating patients with MM.

Heart Regeneration in Adult Mammals after Myocardial Damage.

Heart regeneration remains a critical question in current basic research and clinical practice. The adult mammalian heart exhibits a very limited regeneration capacity. In contrast, adult zebrafish and neonatal mice retain a remarkable ability of heart regeneration after damage. Understanding the mechanisms of heart regeneration would be very valuable to help design efficient treatment strategies against myocardial damage and heart failure. While inherent regeneration of the heart occurs after damage with varying efficiency among species, regeneration may also be induced exogenously. In this study, we briefly review the different approaches and current progress in improving heart regeneration.

Atomic-level polarization reversal in sliding ferroelectric semiconductors.

Intriguing "slidetronics" has been reported in van der Waals (vdW) layered non-centrosymmetric materials and newly-emerging artificially-tuned twisted moiré superlattices, but correlative experiments that spatially track the interlayer sliding dynamics at atomic-level remain elusive. Here, we address the decisive challenge to in-situ trace the atomic-level interlayer sliding and the induced polarization reversal in vdW-layered yttrium-doped γ-InSe, step by step and atom by atom. We directly observe the real-time interlayer sliding by a 1/3-unit cell along the armchair direction, corresponding to vertical polarization reversal. The sliding driven only by low energetic electron-beam illumination suggests rather low switching barriers. Additionally, we propose a new sliding mechanism that supports the observed reversal pathway, i.e., two bilayer units slide towards each other simultaneously. Our insights into the polarization reversal via the atomic-scale interlayer sliding provide a momentous initial progress for the ongoing and future research on sliding ferroelectrics towards non-volatile storages or ferroelectric field-effect transistors.

Walking out of the light verb jungle: Exploring the translation strategies of light verb constructions in Chinese-English consecutive interpreting.

Cross-linguistic features of light verb constructions (LVCs) profile a major facet of the typological difference between Chinese and English. By adopting a theory-driven, context-based interpreting task, this study explores the effectiveness and variability of translation strategies in dealing with 12 target LVCs extracted from a Chinese-English Consecutive Interpreting test to capture effective translation strategies fit for Chinese English-as-foreign-language (EFL) learners (N = 66). Appropriate rates and entropy values denoting variability of strategy selection are calculated by using 12 LVC segments and nine strategies, respectively. A correlation test is also carried out for vocabulary knowledge and the appropriate rates of LVCs to assess the efficacy of learners' vocabulary knowledge in interpreting performance. Results show the general preferences for strategy selection among Chinese EFL learners as well as typical structural patterns in LVC translation. The degree of lightness of the light verbs exerts a reverse effect on the appropriate rates and consistency of strategy selection, and the positive correlation between vocabulary knowledge and LVCs' appropriate rates suggests the need to incorporate the constructional teaching into the EFL learning curriculum. Thus felicitous conditions of applying the strategies have been proposed.