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Binocular disparity provides critical information about three-dimensional (3D) structures to support perception and action. In the past decade significant progress has been made in uncovering human brain areas engaged in the processing of binocular disparity signals. Yet, the fine-scale brain processing underlying 3D perception remains unknown. Here, we use ultra-high-field (7T) functional imaging at submillimeter resolution to examine fine-scale BOLD fMRI signals involved in 3D perception. In particular, we sought to interrogate the local circuitry involved in disparity processing by sampling fMRI responses at different positions relative to the cortical surface (i.e., across cortical depths corresponding to layers). We tested for representations related to 3D perception by presenting participants (male and female, N = 8) with stimuli that enable stable stereoscopic perception [i.e., correlated random dot stereograms (RDS)] versus those that do not (i.e., anticorrelated RDS). Using multivoxel pattern analysis (MVPA), we demonstrate cortical depth-specific representations in areas V3A and V7 as indicated by stronger pattern responses for correlated than for anticorrelated stimuli in upper rather than deeper layers. Examining informational connectivity, we find higher feedforward layer-to-layer connectivity for correlated than anticorrelated stimuli between V3A and V7. Further, we observe disparity-specific feedback from V3A to V1 and from V7 to V3A. Our findings provide evidence for the role of V3A as a key nexus for disparity processing, which is implicated in feedforward and feedback signals related to the perceptual estimation of 3D structures. SIGNIFICANCE STATEMENT Binocular vision plays a significant role in supporting our interactions with the surrounding environment. The fine-scale neural mechanisms that underlie the brain9s skill in extracting 3D structures from binocular signals are poorly understood. Here, we capitalize on recent advances in ultra-high-field functional imaging to interrogate human brain circuits involved in 3D perception at submillimeter resolution. We provide evidence for the role of area V3A as a key nexus for disparity processing, which is implicated in feedforward and feedback signals related to the perceptual estimation of 3D structures from binocular signals. These fine-scale measurements help bridge the gap between animal neurophysiology and human fMRI studies investigating cross-scale circuits, from micro circuits to global brain networks for 3D perception.

Objective To evaluate the effectiveness of botulinum toxin A (BTX-A) in the treatment of hemiplegic shoulder pain. Data Sources PubMed, EMBASE, Elsevier, Springer, Cochrane Library, Physiotherapy Evidence Database, CNKI, and VIP were researched from the earliest records to September 1, 2020. Study Selection Randomized controlled trials that compared shoulder BTX-A injections vs a control intervention in patients with a history of hemiplegic shoulder pain after stroke were selected. Among the 620 records screened, 9 trials with 301 eligible patients were included. Data Extraction Outcome data were pooled according to follow-up intervals (1, 2, 4, and 12 wk). The primary evaluation indices were pain reduction (visual analog scale [VAS] score) and range of motion (ROM) improvement. The second evaluation indices were upper limb functional improvement, spasticity improvement, and incidence of adverse events. Cochrane risk-of-bias was used to assess the methodological quality of studies independently by 2 evaluators. Data Synthesis Meta-analysis revealed a statistically significant decrease in the VAS score in the BTX group vs the control group at 1, 4, and 12 weeks postinjection (wk 1: standardized mean difference [SMD], 0.91; 95% confidence interval [CI], 0.27 to 1.54; wk 4: SMD, 1.63; 95% CI, 0.76 to 2.51; wk 12: SMD, 1.96; 95% CI, 1.44 to 2.47). Furthermore, the meta-analysis demonstrated a statistically significant increase in abduction at 1, 4, and 12 weeks postinjection (wk 1: SMD, 3.71; 95% CI, 0 to 7.41; wk 4: SMD, 8.8; 95% CI, 2.22 to 15.37; wk 12: SMD, 19.59; 95% CI, 9.05 to 30.13) and external rotation at 1, 2, 4 weeks postinjection (wk 1: SMD, 5.67; 95% CI, 0.88 to 10.47; wk 2: SMD, 9.62; 95% CI, 5.57 to 13; wk 4: SMD, 6.89; 95% CI, 2.45 to 11.33) in the BTX group. Conclusions BTX-A injection provided greater analgesic effects and increased shoulder abduction and external rotation ROM compared with steroid or placebo injection for the treatment of HSP.

Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism; however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remains unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in the prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be over-expressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP over-expression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression and, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.

Background. Allergic rhinitis (AR) affects millions of people and is lack of effective treatment. CD40 is an important costimulatory molecule in immunity. However, few studies have focused on the role of CD40 in AR. Methods. In this study, we built mouse model of chronic AR. The mice were divided into the AR, control, intravenous CD40 siRNA, and nasal CD40 siRNA groups ( n = 6 each). We detected OVA-sIgE, IL-4, IL-5, IL-13, IL-10, IFN-γ, and TGF-β levels in serum and supernatant by ELISA, CD40+ splenic DCs, and Foxp3+ Tregs by flow cytometry and CD40 mRNA by RT2-PCR. We also used PAS and MT stains to assess tissue remodelling. Results. (1) The OVA-sIgE, IL-4, IL-5, and IL-13 levels in the serum or supernatant of nasal septal membrane of AR mice were significantly higher than control. After treated with CD40 siRNA, those indicators were significantly decreased. The IFN-γ, IL-10, and TGF-β levels in AR mice were significantly lower than that in control and were increased by administration of CD40 siRNA. (2) AR mice had significantly fewer Foxp3+ Tregs in the spleen than control mice. After treated with CD40 siRNA, AR mice had significantly more Foxp3+ Tregs. (3) AR mice exhibited a significantly higher CD40 mRNA levels than control. Administration of CD40 siRNA significantly reduced the CD40 mRNA level. (4) The AR mice showed significantly greater collagen deposition than the control in MT staining. Applications of CD40 siRNA significantly reduced the collagen deposition in AR mice. Conclusion. CD40 siRNA therapy shows promise for chronic AR as it significantly attenuated allergic symptoms and Th2-related inflammation and upregulated Foxp3+ Tregs. CD40 plays a role in tissue remodelling in AR, which can be inhibited by CD40 siRNA application.

Emerging documents revealed that E2 enzyme family has been implicated in regulating the progression of numerous human cancers. Ubiquitin-conjugating enzyme E2 J1 (UBE2J1), a member of E2 enzyme family, has been reported to participate in the biological process of medulloblastoma, while little is known about its functionality in endometrial cancer (EC). Gene expression at the mRNA and protein levels were identified using RT-qPCR and western blot analysis, separately. The alteration on cell proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) process was determined through 5-Ethynyl-2ʹ-deoxyuridine, cell adhesion, wound healing and transwell assays as well as western blot analysis. The role of UBE2J1 in xenograft tumor in mice was determined. Luciferase reporter and chromatin immunoprecipitation assays were conducted to reveal the undering mechanism of UBE2J1. Our results indicated that UBE2J1 displayed high level in EC tissues and cells and predicted poor prognosis of EC patients. In addition, UBE2J1 depletion inhibited cell proliferation, adhesion, motion, EMT process invitro, and repressed tumor growth invivo. Rescue assays manifested that ethyl 2-amino-6-chloro-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate treatment reversed the effects of UBE2J1 on PI3K/AKT pathway activation and malignant phenotypes of EC cells. Finally, zinc finger X-chromosomal protein (zfx), with high expression in EC tissues, was verified to activate UBE2J1 transcription by binding to UBE2J1 promoter. In conclusion, all facts signified that zfx-induced upregulation of UBE2J1 accelerated the progression of EC via regulating the PI3K/AKT signaling pathway, which suggested that UBE2J1 might be of great significance in probing into the underlying therapeutic strategies of EC.

Background Facing the global threat of emerging resistance to antibiotics, tigecycline, a novel glycylcycline antibiotic, is developed to against multidrug-resistant pathogens, but not recommended for the treatment of complicated urinary tract infection (cUTI). We performed a summary of the literatures to characterize and evaluate the efficacy and safety of tigecycline in patients with cUTI. Methods We searched PubMed, EMBASE, Cochrane and Clinical Trials using appropriate syntax to retrieve potential articles up to Jan 2020. General information, pathogen, medication regimen, comorbidities of patients from eligible literatures were recorded. Univariate logistic regression analysis was used to detect the potential factors associated with clinical cure. Results Nineteen articles comprising 31 cases were included. The subpopulation with transplantation (25.8% of the patients) was the most common comorbidity, and cUTIs were mainly caused by Klebsiella pneumoniae (K. pneumoniae) (48.28%) in our research. Tigecycline 100 mg per day as monotherapy was most common. Clinical cure was reported as majority (77.4%), and microbiological eradication cases accounted for the most (65.2%) among the clinical cure cases. Univariate analysis showed that K. pneumoniae caused cUTI and tigecycline as a single treatment have significant meaning to clinical outcomes (P=0.044 and P=0.034, respectively). Conclusions Clinical and microbiological outcomes of tigecycline treatment revealed high rate of successful response. Tigecycline monotherapy may have a role in the treatment of cUTI except that caused by the pathogen K. pneumoniae. Further randomized controlled trials was still needed to evaluate tigecycline monotherapy for cUTI.

Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five‐year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF‐selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan‐RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan‐RAF and S100B pathways.

Lysosomes are membrane-bound organelles that regulate protein degradation and cellular organelle recycling. Homeostatic alteration by lysosomotropic compounds has been suggested as a potential approach for the treatment of cancer. However, because of the high false-negative rate resulting from strong fluorescent background noise, few luminescent high-throughput screening methods for lysosomotropic compounds have been developed for cancer therapy. Imidazole is a five-membered heterocycle that can act within the acidic interior of lysosomes. To develop an efficient lysosomotropic compound screening system, we introduced an imidazole group to iridium-based complexes and designed a long-lifetime lysosomal probe to monitor lysosomal activity in living cells. By integrating time-resolved emission spectroscopy (TRES) with the novel iridium-based lysosomal probe, a high-throughput screening platform capable of overcoming background fluorescent interference in living cells was developed for discovering lysosomotropic drugs. As a proof-of-concept, 400 FDA/EMA-approved drugs were screened using the TRES system, revealing five compounds as potential lysosomotropic agents. Significantly, the most promising potent lysosomotropic compound (mitoxantrone) identified in this work would have showed less activity if screened using a commercial lysosomal probe because of interference from the intrinsic fluorescence of mitoxantrone. We anticipate that this TRES-based high-throughput screening system could facilitate the development of more lysosomotropic drugs by avoiding false results arising from the intrinsic fluorescence of both bioactive compounds and/or the cell background.

Gastrin-releasing peptide receptor (GRPr) plays proliferative and inflammatory roles in living systems. Here, we report a highly selective GRPr antagonist (JMV594)-tethered iridium(III) complex for probing GRPr in living cancer cells and immune cells. This probe exhibited desirable photophysical properties and also displayed negligible cytotoxicity, overcoming the inherent toxicity of the iridium(III) complex. Its long emission lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using a time-resolved technique. This probe selectively visualized living cancer cells via specific binding to GRPr, while it also modulated the function of GRPr on TNF-α secretion in immune cells. To our knowledge, this is the first peptide-conjugated iridium(III) complex developed as a GRPr bioimaging probe and modulator of GRPr activity. This theranostic agent shows great potential at unmasking the diverse roles of GRPr in living systems.

Aim To describe the role of endoscopic transnasal canaliculorhinostomy (ETC) in refractory common canalicular obstruction (CCO) associated with an absent or unidentifiable lacrimal sac. Methods The records of patients with refractory CCO who underwent ETC at the Eye Hospital of Wenzhou Medical University from October 2007 to December 2016 were retrospectively reviewed. Results Fifty-six patients (56 eyes) with refractory CCO were recruited into the study. Eight patients were excluded due to the presence of a residual lacrimal sac or failure to complete the follow-up duration. The anatomic and functional success rates were both 85.4% (41/48) at a mean follow-up of 18.6mo. Five cases failed as a result of ostial synechia and two failed because of ostial obstruction by granulation. Postoperative complications included mild nasal bleeding in 5 cases, dried nasal feeling in 8 cases, and olfactory dysfunction in 4 cases. Conclusion Although being surgically challenging, ETC has comparable findings to its external approach counterpart or conjunctivodacryocystorhinostomy (CDCR) with Jones tube. And it may prove to be a novel alternate surgical technique for patients with refractory CCO without identifiable lacrimal sac.

Malignant melanoma is a very aggressive form of skin cancer, with a low long-term survival rate. Developing multifunctional theranostic agents to simultaneously track and inhibit the activity of tumor targets is a potential strategy for combating melanoma metastasis. S100B expression is directly correlated with the degree of malignant metastatic melanoma and is overexpressed in the majority of malignant melanoma patients. Herein, the Ir(III) complex

Chemical treatment is the vital pattern for colon cancer patients after surgery. Irinotecan and tegafur-gimeracil-oteracil potassium (S-1) combined chemotherapy is effective on metastatic colorectal cancer (mCRC). Nevertheless, patients receiving this combined chemotherapy might suffer the adverse drug reaction (ADR), such as myelosuppression and/or diarrhea, which could lead to poor prognosis. Here, we report a 76-year-old Chinese female who died due to the toxicity of combined therapy with irinotecan and S-1. This patient received irinotecan and S-1 combined therapy for 6 sessions after laparoscopic radical operation on colon cancer. After 6 sessions of chemotherapy, myelosuppression and severe diarrhea appeared with delirious accompanied. Antineoplastic agents were stopped immediately due to the appearance of III grade myelosuppression and IV grade diarrhea. Loperamide and octreotide were used to stop diarrhea, while granulocyte colony-stimulating factor (G-CSF) and recombinant human IL (IL-11) were used to improve blood cell count. Meanwhile, intravenous fluid replacement was continuously transfused to maintain water electrolyte balance. The patient remained continuous insanity and died 4 days after admission because of multiple organ failure, cardiac insufficiency, sever myelosuppression and ascending colon cancer. Myelosuppression is the principal toxicity associated with chemotherapy. And delayed-onset diarrhea is most frequently reported ADR of irinotecan, which could also be induced by S-1. Moreover, neurotoxicity is rarely reported as ADR for both irinotecan and S-1. Postoperative adjuvant chemotherapy should be carefully selected according to specific condition of patient. Blood routine examination should be monitored, and clinical manifestations should be carefully observed to ensure the safety and effectiveness of chemotherapy during the treatment.

Dual-functional theranostics are powerful tools that can allow for the in-field understanding of cancer pathology, yet their use is held back by the paucity of suitable theranostics for living systems. Moreover, typical in vitro screening conditions for probe molecules do not necessarily generate candidates that can function effectively in the natural in cellulo environment, limiting their follow-up use in living systems. We introduce herein a general strategy for the development of an iridium(iii) theranostic by grafting a well-known inhibitor as a “binding unit” onto an iridium(iii) complex precursor as a “signaling unit”. To further optimize their emissive properties, we explored the effect of imaging behavior by incorporating different substituents onto the parental “signaling unit”. This design concept was validated by a series of tailored iridium(iii) theranostics 2a–2h for the visualization and inhibition of EGFR in living cancer cells. By comprehensively assessing the theranostic potency of 2a–2h in both in vitro and in cellulo contexts, probe 2f containing electron-donating methoxy groups on the “signaling unit” was discovered to be the most promising candidate theranostic with desirable photophysical/chemical properties. Probe 2f selectively bound to EGFR in vitro and in cellulo, enabling it to selectively discriminate living EGFR-overexpressing cancer cells from normal cells that express low levels of EGFR with an “always-on” luminescence signal output. In particular, its long-lived lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using time-resolved techniques. Complex 2f simultaneously visualized and inhibited EGFR in a dose-dependent manner, leading to a reduction in the phosphorylation of downstream proteins ERK and MEK, and inhibition of the activity of downstream transcription factor AP1. Notably, complex 2f is comparable to the parental EGFR inhibitor 1b, in terms of both inhibitory activity against EGFR and cytotoxicity against EGFR-overexpressing cancer cells. This tailored dual-functional iridium(iii) theranostic toolkit provides an alternative strategy for the personalized diagnosis and treatment of cancers., In order to optimise dual-functional theranostics for application in living systems, we developed an iridium(iii) theranostic by grafting an inhibitor as a “binding unit” onto an iridium(iii) complex precursor as a “signaling unit”.

The capacity of RNA viruses to adapt to new hosts and rapidly escape the host immune system is largely attributable to de novo genetic diversity that emerges through mutations in RNA. Although the molecular spectrum of de novo mutations—the relative rates at which various base substitutions occur—are widely recognized as informative towards understanding the evolution of a viral genome, little attention has been paid to the possibility of using molecular spectra to infer the host origins of a virus. Here, we characterize the molecular spectrum of de novo mutations for SARS-CoV-2 from transcriptomic data obtained from virus-infected cell lines, enabled by the use of sporadic junctions formed during discontinuous transcription as molecular barcodes. We find that de novo mutations are generated in a replication-independent manner, typically on the genomic strand, and highly dependent on mutagenic mechanisms specific to the host cellular environment. De novo mutations will then strongly influence the types of base substitutions accumulated during SARS-CoV-2 evolution, in an asymmetric manner favoring specific mutation types. Consequently, similarities between the mutation spectra of SARS-CoV-2 and the bat coronavirus RaTG13 which have accumulated since their divergence strongly suggest that SARS-CoV-2 evolved in a host cellular environment highly similar to that of bats before its zoonotic transfer into humans. Collectively, our findings provide data-driven support for the natural origin of SARS-CoV-2., Graphical Abstract

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are a promising biomarker for predicting stroke outcomes; however, their prognostic validity is not well-understood in patients who have undergone intravenous thrombolysis. This study was designed to evaluate the prognostic value of NT-proBNP levels in patients with acute ischemic stroke treated with intravenous thrombolysis.Methods: Patients with ischemic stroke who underwent intravenous thrombolysis between April 2015 and December 2020 were analyzed. Demographic information, information related to intravenous thrombolysis, medical history, and laboratory test results were collected. Outcomes, such as hemorrhagic transformation, early neurologic deterioration, poor 3-month functional outcomes, and 3-month mortality were recorded. Correlations between NT-proBNP levels and the above outcomes were analyzed, an individualized prediction model based on NT-proBNP levels for functional outcomes was developed, and a nomogram was drafted.Results: A total of 404 patients were included in the study. Elevated NT-proBNP levels were independently associated with hemorrhagic transformation, poor 3-month functional outcomes, and 3-month mortality, while early neurological deterioration was not. An association between NT-proBNP levels and hemorrhagic transformation was noted. An individualized prediction model for poor functional outcomes was established, which was composed of ln(NT-proBNP), National Institutes of Health Stroke Scale (NIHSS), and baseline glucose, with good discrimination [area under the curve (AUC) 0.764] and calibration (P > 0.05).Conclusion: To the best of our knowledge, this is the first report on the association between NT-proBNP levels and hemorrhagic transformation in patients who have undergone intravenous thrombolysis. The 3-month functional outcomes and mortality were found to be associated with NT-proBNP levels. An individualized prediction model based on NT-proBNP levels to predict the 3-month functional outcomes was established. Our results suggest that NT-proBNP levels could be used as a prognostic biomarker in patients with acute ischemic stroke treated with intravenous thrombolysis.

Drugs are related to the lives and health of patients. Mining and discovering potential adverse drug reactions from a large number of unstructured texts play an important role in drug research and pharmacovigilance. It is a hot research issue in the field of biomedicine in recent years. A large number of scholars have discovered a large amount of information on adverse drug reactions from different data sources through effective machine learning methods. This paper reviews the research progress in recent years to provide a reference for future research.

BACKGROUND Concomitant allergic fungal rhinosinusitis (AFRS) and allergic bronchopulmonary aspergillosis (ABPA) are extremely rare, with no more than 20 cases reported in the English literature. CASE SUMMARY A 52-year-old female patient complained of right-sided nasal obstruction, rhinorrhea, sneezing, epistaxis, and hyposmia for a period of around 5 mo. Nasal examination detected paleness and edema of the nasal mucous membrane and a polyp in the right middle meatus. A computed tomography (CT) scan of the sinuses revealed a ground-glass opacity filling the right maxillary and ethmoid sinuses, along with bone absorption in the medial wall of the right maxillary sinus. Magnetic resonance images were obtained with T1-weighted, T2-weighted, and gadolinium-enhanced T1-weighted sequences. A well-defined mass, located in the right maxillary and ethmoid sinuses and displaying obvious hypointense features, was observed on both T1- and T2-weighted images, with peripheral enhancement on gadolinium-enhanced T1-weighted images. The patient also has a 20-year history of cough and dyspnea. Chest CT revealed columned and cystiform bronchiectasis in the bilateral bronchus, surrounded by a large number of spotted and funicular high-density lesions. The level of serum total IgE was > 5000 kU/L. Serum IgE levels related to house dust and aspergillus showed a positive result, with the values being 3.5 kU/L and 1.2 kU/L. We performed functional endoscopic sinus surgery under local anesthesia. After surgery, topical glucocorticoids and saline irrigation were applied in the nasal cavity until the present time. An oral glucocorticoid (methylprednisolone 16 mg/d) and antifungal agent (itraconazole 200 mg/d) were also used for a period of 4 wk. Montelukast was prescribed at 10 mg/d until the present time. An endoscopic examination showed that the patient was recovering well at 3 mo after surgery. CONCLUSION Since different specialists treat ABPA and AFRS, their coexistence may be overlooked. AFRS accompanied by ABPA requires surgical therapy combined with medical control to improve the symptoms.

The peptidyl-prolyl isomerase Pin1 is correlated with the progression of cervical cancer via regulating numerous oncogenic and tumor suppressor pathways. p65 is a crucial regulator of tumorigenesis that is regulated by Pin1, and p65 signaling suppression can enhance the antitumor efficacy of doxorubicin (DOX). Here, we utilized a structural mimicry approach to synthesize a series of dibenzothiophene analogues and evaluated their ability to inhibit Pin1 activity. Compound 1a was identified as a potent Pin1 inhibitor that inhibited p65 signaling in vitro and in cervical cancer cells. Moreover, compound 1a enhanced the cytotoxicity of DOX in cervical cancer cells via reducing p65 nuclear accumulation and enhancing DOX uptake. These compounds are promising scaffolds for developing more potent Pin1 inhibitors against cervical cancer, either alone or in combination with anticancer drugs such as DOX.

Grafted embryonic central neural tissue pieces can recover function of hemisected spinal cord in neonatal rats and promote axonal growth in adults. However, spinal cord segments from adults have not been used as donor segments for allogeneic transplantation. Here, we utilized adult spinal cord tissue grafts (aSCGs) as donor constructs for repairing complete spinal cord injury (SCI). Moreover, to provide a favourable microenvironment for SCI treatment, a growth factor cocktail containing three growth factors (brain-derived neurotrophic factor, neurotrophin-3 and vascular endothelial growth factor), was applied to the aSCG transplants. We found that the locomotor function was significantly improved 12 weeks after transplantation of aSCGs into the spinal cord lesion site in adult rats. Transplantation of aSCGs combined with these growth factors enhanced neuron and oligodendrocyte survival and functional restoration. These encouraging results indicate that treatment of complete SCI by transplanting aSCGs, especially in the presence of growth factors, has a positive effect on motor functional recovery, and therefore could be considered as a possible therapeutic strategy for SCI.

The effective therapeutic approach of cerebral infarction is limited because of its underlying complexity. Recently, multiple long noncoding RNAs (lncRNAs) have been identified in the pathogenesis of cerebral infarction. Here, the current study aims to explore the interaction among lncRNA cyclin-dependent kinase inhibitor-2B-antisense RNA 1 (CDKN2B-AS1), transcription factor B-cell lymphoma/leukemia 11A (BCL11A), and MAPKK kinase kinase 1 (MAP4K1) and further investigate whether they affect cerebral infarction progression. The expression of CDKN2B-AS1, BCL11A, and MAP4K1 was altered in lymphocytes extracted from patients with cerebral infarction. In order to identify their roles in regulatory T (Treg) cells, the proliferation and apoptosis of the CD4+CD25+ Treg cells were examined, and levels of IL-4, IL-10, and TGF-β were determined. Also, the RNA crosstalk among CDKN2B-AS1, BCL11A, and MAP4K1 was validated. Finally, we established a rat model of middle cerebral arterial occlusion to evaluate the neurologic impairment and cerebral infarction volume. The results revealed that lymphocytes in patients with cerebral infarction presented with the up-regulated expression of CDKN2B-AS1. Moreover, BCL11A could specifically bind to CDKN2B-AS1 and MAP4K1 promoter so as to inhibit MAP4K1. Moreover, it was observed that down-regulated CDKN2B-AS1 inhibited CD4+CD25+ Treg-cell proliferation, reduced levels of IL-4, IL-10, and TGF-β and cerebral infarction volume, and elevated MAP4K1 expression. Collectively, our study provides evidence that CDKN2B-AS1 silencing could increase MAP4K1 expression to inhibit the CD4+CD25+ Treg-cell proliferation by reducing enrichment of transcription factor BCL11A, thereby protecting against cerebral infarction progression, highlighting a promising therapeutic strategy for treating cerebral infarction.-Lei, J.-J., Li, H.-Q., Mo, Z.-H., Liu, K.-J., Zhu, L.-J., Li, C.-Y., Chen, W.-L., Zhang, L. Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription.

We have designed for the first time a dual-functional luminescent probe and inhibitor of neuraminidase (NA), a key influenza target. The lead iridium(iii) complex exhibited enhanced inhibition against NA compared to the FDA-approved antiviral drug, oseltamivir, and could detect NA even in the presence of an autofluorescent background.

BACKGROUND Invasive fungal rhinosinusitis (IFR) caused by Cunninghamella is very rare but has an extremely high fatality rate. There have been only seven cases of IFR caused by Cunninghamella reported in English and, of these, only three patients survived. In this article, we present another case of IFR caused by Cunninghamella, in which the patient was initially treated successfully but then deteriorated due to a relapse of leukemia 2 mo later. CASE SUMMARY A 50-year-old woman presented with a 2-mo history of right ocular proptosis, blurred vision, rhinorrhea and nasal obstruction. Nasal endoscopic examination showed that the middle turbinate had become necrotic and fragile. Endoscopic sinus surgery and enucleation of the right orbital contents were performed successively. Additionally, the patient was treated with amphotericin B both systematically and topically. Secretion cultivation of the right eye canthus showed infection with Cunninghamella, while postoperative pathology also revealed fungal infection. The patient’s condition gradually stabilized after surgery. However, the patient underwent chemotherapy again due to a relapse of leukemia 2 mo later. Unfortunately, her leukocyte count decreased dramatically, leading to a fatal lung infection and hemoptysis. CONCLUSION Aggressive surgical debridements, followed by antifungal drug treatment both systematically and topically, are the most important fundamental treatments for IFR.

The ability to discriminate between stimuli relies on a chain of neural operations associated with perception, memory and decision-making. Accumulating studies show learning-dependent plasticity in perception or decision-making, yet whether perceptual learning modifies mnemonic processing remains unclear. Here, we trained human participants of both sexes in an orientation discrimination task, while using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to separately examine training-induced changes in working memory (WM) representation. fMRI decoding revealed orientation-specific neural patterns during the delay period in primary visual cortex (V1) before, but not after, training, whereas neurodisruption of V1 during the delay period led to behavioral deficits in both phases. In contrast, both fMRI decoding and disruptive effect of TMS showed that intraparietal sulcus (IPS) represented WM content after, but not before, training. These results suggest that training does not affect the necessity of sensory area in representing WM information, consistent with the sensory recruitment hypothesis in WM, but likely alters the coding format of the stored stimulus in this region. On the other hand, training can render WM content to be maintained in higher-order parietal areas, complementing sensory area to support more robust maintenance of information.SIGNIFICANCE STATEMENTThere has been accumulating progresses regarding experience-dependent plasticity in perception or decision-making, yet how perceptual experience moulds mnemonic processing of visual information remains less explored. Here, we provide novel findings that learning-dependent improvement of discriminability accompanies altered WM representation at different cortical levels. Critically, we suggest a role of training in modulating cortical locus of WM representation, providing a plausible explanation to reconcile the discrepant findings between human and animal studies regarding the recruitment of sensory or higher-order areas in WM.

The ubiquitin-proteasome system oversees cellular protein degradation in order to regulate various critical processes, such as cell cycle control and DNA repair. Ubiquitination can serve as a marker for mutation, chemical damage, transcriptional or translational errors, and heat-induced denaturation. However, aberrant ubiquitination and degradation of tumor suppressor proteins may result in the growth and metastasis of cancer. Hence, targeting the ubiquitination cascade reaction has become a potential strategy for treating malignant diseases. Meanwhile, computer-aided methods have become widely accepted as fast and efficient techniques for early stage drug discovery. This review summarizes ubiquitination regulators that have been discovered via virtual screening and their applications for cancer treatment.

Background: Ameloblastoma is an odontogenic tumor occurring in jaws, with local aggressiveness and postoperative recurrence. This study was aim to investigate the clinical and radiographic risk factors for recurrence in ameloblastoma. Methods: Patients diagnosed with ameloblastoma between March 2009 and March 2019 were retrospectively analyzed. Clinical and Radiological data and follow-up records were collected. Survival analyses were performed by Kaplan-Meier and log-rank tests, as well as Cox proportional hazards model. Results: One hundred and fifty-eight patients (104 males and 54 females were enrolled. The overall recurrence rate for ameloblastoma was 13.29%, and 10.76% recurred within 5 years. Most of the tumors were located in mandible (86.71%), while the rest 21 cases were in maxilla (13.29%). More than half cases (55.06%) showed multilocular radiolucency, 61 cases (38.61%) showed unilocular radiolucency. Significant differences were found with amelobastoma recurrence rate related to treatment modality, impacted tooth and root resorption (P =0.002, 0.022 and 0.007 respectively). Conclusions: Treatment modality, impacted tooth and root resorption all showed statistically significant associations with the recurrence rate in ameloblastoma. However, due to the limitation of this study, further studies are needed to reveal the true mechanism of ameloblastoma recurrence.

BACKGROUND: Rational use of antibiotics received great attention in China, therefore the multifaceted antimicrobial stewardship (MAMS) is urgently required in hospital management. We conducted this study to assess the impact of a MAMS programme on antimicrobial use in a tertiary teaching hospital in Shanghai. METHODS: This retrospective observational study was conducted at a tertiary teaching hospital in Shanghai. The MAMS programme involved multifaceted interventions consisting of a quality premium with financial incentives, antibiotic restriction, audit and feedback, and education. Data were extracted from the electronic medical records of inpatients to analyse monthly and annual antibiotic consumption and the percentage of antibiotic prescriptions during 2017-2020. Segmented regression analysis of the interrupted time series was used to contrast antimicrobial use during 2019-2020, with non-MAMS data from the 2017-2018 period as the historical control. RESULTS: With MAMS implementation, antibiotic consumption decreased from 63.3 (59.3, 67.2) defined daily doses (DDDs) per 100 patient-days (PD) to 43.3 (39.0, 49.8) DDDs/100 PD (P

Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1β and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.

Objective. To perform a systematic evaluation of the efficacy and safety of combined treatment of Shenmai injection and chemotherapy for lung cancer. Methods. A literature search for randomized controlled trials (RCTs) describing the treatment of lung cancer by Shenmai injection and chemotherapy or chemotherapy alone was performed using the PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Value In Paper (VIP), China BioMed, and Wanfang databases. The databases were searched for entries published before September 1, 2019. Results. Thirty-seven RCTs, comprising a total of 2808 cases, were included in the present meta-analysis. Of these, 1428 cases were treated by Shenmai injection plus chemotherapy, and 1380 cases were treated only by chemotherapy. The results of meta-analysis showed that the combined treatment (Shenmai injection plus chemotherapy) increased the short-term efficacy of treatment (relative risk [RR] = 1.183, 95% confidence interval [CI] = 1.043–1.343, P < 0.01 ) and improved patients’ quality of life (RR = 1.514, 95%CI = 1.211–1.891, P < 0.01 ) compared with chemotherapy alone. With regard to the adverse effects, the combined treatment markedly reduced the incidence of white blood cell (WBC) reduction (RR = 0.846, 95%CI = 0.760–0.941, P < 0.01 ), platelet reduction (RR = 0.462, 95% CI = 0.330–0.649, P < 0.01 ), and hemoglobin reduction (RR = 0.462, 95% CI = 0.330–0.649, P < 0.01 ) and alleviated drug-induced liver injury (RR = 0.677, 95%CI = 0.463–0.990, P < 0.05 ). However, it did not offer a significant protective effect (RR = 0.725, 95%CI = 0.358–1.468, P < 0.05 ). The effect of the combined treatment on the occurrence of vomiting was considerable (RR = 0.889, 95%CI = 0.794–0.996, P < 0.05 ), and the combined treatment markedly increased the immunity of patients with lung cancer. Conclusion. The combined treatment of Shenmai injection plus chemotherapy enhanced the short-term efficacy of chemotherapy, improved the patient quality of life, alleviated the adverse effects of chemotherapeutics, and increased the patient immunity. These results should be confirmed by large-scale, high-quality RCTs.

Background:. Arteriosclerosis obliterans (ASO) is a major cause of adult limb loss worldwide. Autophagy of vascular endothelial cell (VEC) contributes to the ASO progression. However, the molecular mechanism that controls VEC autophagy remains unclear. In this study, we aimed to explore the role of the GRB2 associated binding protein 1 (GAB1) in regulating VEC autophagy. Methods:. In vivo and in vitro studies were applied to determine the loss of adapt protein GAB1 in association with ASO progression. Histological GAB1 expression was measured in sclerotic vascular intima and normal vascular intima. Gain- and loss-of-function of GAB1 were applied in VEC to determine the effect and potential downstream signaling of GAB1. Results:. The autophagy repressor p62 was significantly downregulated in ASO intima as compared to that in healthy donor (0.80 vs. 0.20, t = 6.43, P

Simple Summary The analysis of circulating tumor cells (CTC) is a mainstay of liquid biopsy of solid malignancies. However, research to date has not yet determined a universal and specific marker for CTCs of pancreatic cancer. Genetically engineered mouse models (GEMMs) of pancreatic cancer, can mimic the human disease very closely. This study aimed to identify potential biomarkers for CTCs in a GEMM of pancreatic cancer and further validate markers in human samples. Therefore, we analyzed single-cell RNA sequencing data of murine pancreatic CTCs and performed advanced bioinformatic analyses. We demonstrated that the focal adhesion pathway is functionally enriched in pancreatic CTCs. In addition, we suggest Gas2l1/GAS2L1 as a potential surface marker of pancreatic CTCs. In combination with Epcam/EPCAM, Gas2l1/GAS2L1 identify the majority of pancreatic CTCs. Furthermore, pancreatic cancer patients with overexpression of GAS2L1 have an unfavorable prognostic outcome. Abstract Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.

Background Coronavirus disease 2019 (COVID-19), also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, first manifested in December 2019, and spread rapidly worldwide. Facing this lethal disease, there is an urgent need to develop potent therapies against SARS-CoV-2 infection. SARS-CoV-2 phylogenetically and symptomatically resembles SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Numerous agents have been utilised during the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) epidemics, which may show some benefit against SARS-CoV-2. Methods MEDLINE, EMBASE, Cochrane Library, CBM Disc, China National Knowledge Infrastructure, Wanfang Data, and the China Science and Technology Journal Database will be searched. Manual searches will be conducted by searching pre-printing websites, clinical trial registers, and screening the reference lists of inclusive studies. The screening of all citations and the selection of inclusive articles will be conducted by two reviewers. Randomised controlled trials (RCTs) and controlled cohort studies reporting antiviral therapies, including ribavirin, remdesivir, lopinavir/ritonavir, arbidol, chloroquine, hydroxychloroquine, and interferon, for SARS, MERS, and COVID-19 will be included. The primary outcomes will be mortality, incidence of acute respiratory distress syndrome, and utilisation of mechanical ventilation and intensive care unit admission. The secondary outcomes will be improvement in symptoms and chest radiography results, virus clearance, changes in blood test results, and serum tests. The quality of the retrieved RCTs and observational studies will be appraised according to the Cochrane risk of bias tool and the Newcastle-Ottawa Scale, respectively. If feasible, we will perform a fixed- or random-effects meta-analysis. Discussion This systematic review and meta-analysis will summarise all the available evidence for the efficacy and safety of current therapeutic options in SARS-CoV, MERS-CoV, or SARS-CoV-2-infected patients. The findings of this study may inform subsequent antiviral interventions for patients with COVID-19. Study registration The protocol of this study has been submitted to the PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/), and the registration number is CRD42020168639.

Background: Although laryngopharyngeal reflux (LPR) has been implicated in various upper aerodigestive tract and laryngeal diseases, the underlying mechanisms remain elusive. In this study, we investigated the role of gastric acidified pepsin in laryngeal precancerosis. Methods: The in vitro and in vivo effects of acidified pepsin on H+/K+-ATPase expression and autophagy/mitophagy induction in mouse laryngeal epithelial cells were assessed by hematoxylin and eosin staining, immunohistochemistry, CCK-8 assay, flow cytometry, Western blotting, and quantitative real-time PCR. Additionally, the levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosal specimens were assessed by immunohistochemical staining. Results: Acidified pepsin (pH=3) enhanced the growth and survival of mouse laryngeal epithelial cells in vitro and promoted laryngeal mucosal thickening and laryngeal epithelial cell growth in vivo. Furthermore, acidified pepsin promoted autophagy/mitophagy induction, accompanied by a significant decrease in mitochondrial membrane potential (MMP). Inhibition of autophagy by chloroquine abolished the ability of acidified pepsin to promote mitophagy and cell growth in laryngeal epithelial cells. Additionally, chloroquine promoted cell apoptosis and further reduced MMP in laryngeal epithelial cells treated with acidified pepsin. The expression levels of pepsin and H+/K+-ATPase α and β subunits in 31 human laryngeal mucosa specimens were 51.6%, 48.4%, and 48.4%, respectively. Importantly, the pepsin level was correlated with the H+/K+-ATPase β subunit level. H+/K+-ATPase upregulation in laryngeal epithelial cells in response to acidified pepsin was essential for the mitophagy-promoting effect of acidified pepsin. H+/K+-ATPase knockout or inhibition further reduced MMP in the presence of acidified pepsin. Conclusions: Our findings suggest that in an acidic environment, pepsin promotes laryngeal epithelial cell growth and survival by upregulating H+/K+-ATPase and activating mitophagy, potentially leading to laryngeal precancerosis.

Objective. To develop and validate a risk assessment model for the prediction of the acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) in patients with idiopathic pulmonary fibrosis (IPF). Methods. We enrolled a total of 110 patients with IPF, hospitalized or treated as outpatients at Xuzhou Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine from July 2012 to July 2020. Of these, 78 and 32 patients were randomly assigned to training and test groups, respectively. The risk factors for AE-IPF were analyzed using logistic regression analysis, and a nomographic model was constructed. The accuracy, degree of calibration, and clinical usefulness of the model were assessed with the consistency index (C-index), calibration diagram, and decision curve analysis (DCA). Finally, the stability of the model was tested using internal validation. Results. The results of logistic regression analysis showed that a history of occupational exposure, diabetes mellitus (DM), essential hypertension (EH), and diffusion capacity for carbon monoxide (DLCO)% predicted were independent risk factors for AE-IPF prediction. The nomographic model was constructed based on these independent risk factors, and the C-index was 0.80. The C-index for the internal validation was 0.75, suggesting that the model had good accuracy. The decision curve indicated that for a threshold value of 0.04–0.66, greater clinical benefit was obtained with the AE-IPF risk prediction model. Conclusion. A customized AE-IPF prediction model based on a history of occupational exposure, DM, EH, and DLCO% predicted provided a reference for the clinical prediction of AE-IPF.

Adapting to the environment statistics by reducing brain responses to repetitive sensory information is key for efficient information processing. Yet, the fine-scale computations that support this adaptive processing in the human brain remain largely unknown. Here, we capitalize on the sub-millimetre resolution afforded by ultra-high field imaging to examine BOLD-fMRI signals across cortical depth and discern competing hypotheses about the brain mechanisms (feedforward vs. feedback) that mediate adaptive visual processing. We demonstrate suppressive recurrent processing within visual cortex, as indicated by stronger BOLD decrease in superficial than middle and deeper layers for gratings that were repeatedly presented at the same orientation. Further, we show dissociable connectivity mechanisms for adaptive processing: enhanced feedforward connectivity within visual cortex, while feedback occipito-parietal connectivity, reflecting top-down influences on visual processing. Our findings provide evidence for a circuit of local recurrent and feedback interactions that mediate rapid brain plasticity for adaptive information processing.

The ability to discriminate between stimuli relies on a chain of neural operations associated with perception, memory and decision-making. Accumulating studies show learning-dependent plasticity in perception or decision-making, yet whether perceptual learning modifies mnemonic processing remains unclear. Here, we trained participants on an orientation discrimination task, while using fMRI and TMS to separately examine training-induced changes in working memory (WM) representation. Although fMRI decoding revealed orientation-specific neural patterns during delay period in early visual cortex (V1) before, but not after, training, neurodisruption of V1 during delay period led to behavioral deficit in both phases. In contrast, both fMRI decoding and disruptive effect of TMS showed that intraparietal sulcus (IPS) represent WM content after, but not before, training. These results suggest that sensory engagement for WM is relatively independent of training but the coding format may be altered, whereas the involvement of parietal area in WM depends on training.

Background: Emerging evidence shows that coronavirus disease 2019 (COVID-19) is commonly complicated by coagulopathy, and venous thromboembolism (VTE) is considered to be a potential cause of unexplained death. Information on the incidence of VTE in COVID-19 patients, however, remains unclear.Method: English-language databases (PubMed, Embase, Cochrane), Chinese-language databases (CNKI, VIP, WANFANG), and preprint platforms were searched to identify studies with data of VTE occurrence in hospitalized COVID-19 patients. Pooled incidence and relative risks (RRs) of VTE were estimated by a random-effects model. Variations were examined based on clinical manifestations of VTE (pulmonary embolism-PE and deep vein thrombosis-DVT), disease severity (severe patients and non-severe patients), and rate of pharmacologic thromboprophylaxis (≥60 and

Graphical abstract, The rapidly progressing of coronavirus disease 2019 (COVID-19) pandemic has become a global concern. This meta-analysis aimed at evaluating the efficacy and safety of current option of therapies for severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS) besides COVID-19, in an attempt to identify promising therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. We searched PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies that evaluated therapies (hydroxychloroquine, lopinavir/ritonavir-based therapy, and ribavirin-based therapy, etc.) for SARS, MERS, and COVID-19. The primary outcomes were mortality, virological eradication and clinical improvement, and secondary outcomes were improvement of symptoms and chest radiography results, incidence of acute respiratory disease syndrome (ARDS), utilization of mechanical ventilation, and adverse events (AEs). Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models, and the quality of evidence was appraised using GRADEpro. Eighteen articles (5 RCTs, 2 prospective cohort studies, and 11 retrospective cohort studies) involving 4,941 patients were included. Compared with control treatment, anti-coronary virus interventions significantly reduced mortality (RR 0.65, 95% CI 0.44-0.96; I2 = 81.3%), remarkably ameliorate clinical improvement (RR 1.52, 95% CI 1.05-2.19) and radiographical improvement (RR 1.62, 95% CI 1.11-2.36, I2 = 11.0 %), without manifesting clear effect on virological eradication, incidence of ARDS, intubation, and AEs. Subgroup analyses demonstrated that the combination of ribavirin and corticosteroids remarkably decreased mortality (RR 0.43, 95% CI 0.27-0.68). The lopinavir/ritonavir-based combination showed superior virological eradication and radiographical improvement with reduced rate of ARDS. Likewise, hydroxychloroquine improved radiographical result. For safety, ribavirin could induce more bradycardia, anemia and transaminitis. Meanwhile, hydroxychloroquine could increase AEs rate especially diarrhea. Overall, the quality of evidence on most outcomes were very low. In conclusion, although we could not draw a clear conclusion for the recommendation of potential therapies for COVID-19 considering the very low quality of evidence and wide heterogeneity of interventions and indications, our results may help clinicians to comprehensively understand the advantages and drawbacks of each anti-coronavirus agents on efficacy and safety profiles. Lopinavir/ritonavir combinations might observe better virological eradication capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concerns especially bradycardia. Thus, large RCTs objectively assessing the efficacy of antiviral therapies for SARS-CoV-2 infections should be conducted with high priority.

Learning and experience are critical for translating ambiguous sensory information from our environments to perceptual decisions. Yet, evidence on how training molds the adult human brain remains controversial, as fMRI at standard resolution does not allow us to discern the finer-scale mechanisms that underlie sensory plasticity. Here, we combine ultra-high field (7T) functional imaging at sub-millimetre resolution with orientation discrimination training to interrogate experience-dependent plasticity across cortical depths. Our results provide evidence for recurrent plasticity, by contrast to sensory encoding vs. feedback mechanisms. We demonstrate that learning alters orientation-specific representations in superficial rather than middle V1 layers, suggesting changes in read-out rather than input signals. Further, learning increases feedforward rather than feedback layer-to-layer connectivity in occipito-parietal regions, suggesting that sensory plasticity gates perceptual decisions. Our findings propose finer-scale plasticity mechanisms that re-weight sensory signals to inform improved decisions, bridging the gap between micro- and macro-circuits of experience-dependent plasticity.

Pulmonary fibrosis is a progressively aggravating lethal disease that is a serious public health concern. Although the incidence of this disease is increasing, there is a lack of effective therapies. In recent years, the pathogenesis of pulmonary fibrosis has become a research hotspot. p53 is a tumor suppressor gene with crucial roles in cell cycle, apoptosis, tumorigenesis, and malignant transformation. Previous studies on p53 have predominantly focused on its role in neoplastic disease. Following in-depth investigation, several studies have linked it to pulmonary fibrosis. This review covers the association between p53 and pulmonary fibrosis, with the aim of providing novel ideas to improve the clinical diagnosis, treatment, and prognosis of pulmonary fibrosis.

Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4′,5-trihydroxy-stilbene-3-β-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition., Graphical abstract fx1, Highlights • Fructose decreases miR-200a expression to impair Keap1/Nrf2 pathway in NAFLD. • MiR-200a-driven oxidative stress is a causer in fructose-induced NAFLD. • Polydatin elevates miR-200a to regulate Keap1/Nrf2 pathway in fructose-induced NAFLD. • Polydatin lowers fructose-caused oxidative stress, inflammation and lipid deposition. • Enhancement of miR-200a expression by polydatin is a therapeutic strategy for NAFLD.

Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.

Depression is a mental illness comorbid risk factor for glucose intolerance worldwide. Chaihu-shugan san, a ‘Shu-Gan’ formula in traditional Chinese medicine, is clinically used in the treatment of depression. The aim of this study was to investigate whether Chaihu-shugan san improved glucose tolerance with its antidepressant activity in rat model of depression and explore the mechanisms underlying its action on liver-brain inflammation axis. After 6 weeks of chronic unpredictable mild stress (CUMS) procedure, male Wistar rats were given Chaihu-shugan san water extract (925 and 1850 mg/kg) by gavage for the next 6 consecutive weeks. Sucrose consumption test was used to assess animal depressive-like behaviors. Oral glucose tolerance test (OGTT) was employed to define the status of glucose tolerance in rats. Serum alanine aminotransferase (ALT) and interleukin-1 beta (IL-1β) were measured by commercial kits, respectively. Western blot was used to detect the expression of key proteins in inflammatory signaling cascades including toll-like receptor 4 (TLR4), myeloid differentiation protein 88 (MyD88), nuclear factor-kappa B (NF-κB), Nod-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), cysteinyl aspartate specific proteinase-1 (Caspase-1) and IL-1β, as well as insulin signaling in liver and prefrontal cortex of rats. Immunohistochemical staining or immunofluorescence staining of NF-κB, and nuclear/cytoplasmic ratio of NF-κB by Western blot were used to describe its nuclear entry in liver and prefrontal cortex of rats. RT-qPCR and Western blot analysis, as well as microRNA-155 (miR-155) mimic or inhibitor transfection were used to explore possible association of MyD88 and miR-155. In this study, Chaihu-shugan san increased sucrose consumption and reduced serum glucose levels in CUMS rats, showing its antidepressant activity with glucose tolerance improvement. Chaihu-shugan san reduced serum levels of ALT and IL-1β in this animal model. Furthermore, this formula inhibited hepatic and prefrontal cortical inflammatory response by suppressing TLR4/MyD88/NF-κB pathway and NLRP3 inflammasome activation, and improved insulin signaling in CUMS rats. More importantly, Chaihu-shugan san up-regulated miR-155 expression in liver and prefrontal cortex of CUMS rats. These results provide direct evidence that Chaihushugan San can ameliorate depressive-like behaviors by inhibiting liver-brain inflammation axis.

AIM To study the role of microbial metabolites in the modulation of biochemical and physiological processes in irritable bowel syndrome (IBS). METHODS In the current study, using a metabolomic approach, we analyzed the key metabolites differentially excreted in the feces of control mice and mice with IBS, with or without Clostridium butyricum (C. butyricum) treatment. C57BL/6 mice were divided into control, IBS, and IBS + C. butyricum groups. In the IBS and IBS + C. butyricum groups, the mice were subjected to water avoidance stress (WAS) for 1 h/d for ten days. Gas chromatography/mass spectrometry (GC-MS) together with multivariate analysis was employed to compare the fecal samples between groups. RESULTS WAS exposure established an appropriate model of IBS in mice, with symptoms of visceral hyperalgesia and diarrhea. The differences in the metabolite profiles between the control group and IBS group significantly changed with the progression of IBS (days 0, 5, 10, and 17). A total of 14 differentially excreted metabolites were identified between the control and IBS groups, and phenylethylamine was a major metabolite induced by stress. In addition, phenylalanine metabolism was found to be the most relevant metabolic pathway. Between the IBS group and IBS + C. butyricum group, 10 differentially excreted metabolites were identified. Among these, pantothenate and coenzyme A (CoA) biosynthesis metabolites, as well as steroid hormone biosynthesis metabolites were identified as significantly relevant metabolic pathways. CONCLUSION The metabolic profile of IBS mice is significantly altered compared to control mice. Supplementation with C. butyricum to IBS mice may provide a considerable benefit by modulating host metabolism.

BACKGROUND: A bibliometric analysis was performed to reveal the current status of investigations in infectious diseases in patients with liver transplantation (LT) and to prioritize future research needs. METHODS: The present study comprehensively retrieved publications relevant to infectious diseases in LT recipients published between 2010 and 2020. The search was conducted on the Web of Science (WoS) database. A bibliometric analysis was conducted through machine learning and visualization tools, including VOSviewer, Bibliographic Item Co-Occurrence Matrix Builder, and Graphical Clustering Toolkit. Research hotspots and trends in the field were assessed, while the contributions and collaborations of countries, institutions, and authors were documented. RESULTS: A total of 691 publications were analyzed. Research output sharply increased in 2015, with a fast drop afterward. “Liver transplantation” was the most frequent keyword, with strong links to “hepatitis C virus” and “infection”. Study areas included risk factors of infectious diseases in LT recipients, pathogens causing post-transplantation infections, antibacterial therapy and prophylaxis for peritransplant infection complications, living donor LT, and pediatric LT. The efficacy and safety of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection among liver transplant recipients has attracted recent research interest. Didier Samuel was the most productive author, while Xavier Forns was the top-cited author. Shanghai Jiao Tong University was the most productive contributor, and Gilead Sciences was the most cited organization. Moreover, the USA was the greatest contributor. Gastroenterology was the most cited journal, while Liver Transplantation was the most prolific journal. CONCLUSIONS: This bibliometric analysis will better understand the research status of infectious complications in LT recipients and forecast future research trends. Priority should be given to identifying risk factors for peritransplantation infections and effective treatments against infectious complications in the coming years.

The aim of the present study was to investigate the role of the cancer‑testis antigen family 45 member A1 (CT45A1) in the proliferation, apoptosis, invasion and metastasis of lung cancer cells, and the associated molecular mechanisms. Western blotting determined that the expression of CT45A1 in normal lung cells was far lower than that observed in lung cancer cells. Following the transfection of CT45A1 small (or short) interfering (si)RNA and its negative control into A549 cells using Lipofectamine 2000, the CT45A1 protein and mRNA levels were determined further by western blotting and reverse transcription‑polymerase chain reaction. Following CT45A1 siRNA transfection, the levels of CT45A1 in lung cancer cells were markedly reduced (P

Objective:To investigate the role of local allergic inflammation and Staphylococcus aureus enterotoxins in chronic rhinosinusitis with nasal polyps.Methods:This study included 36 patients with chronic rhinosinusitis with nasal polyps and 18 controls. Total immunoglobulin E, eosinophil cationic protein, staphylococcal enterotoxin types A and B specific immunoglobulin E, staphylococcal enterotoxin types A and B, and myeloperoxidase levels were determined.Results:Four patients with chronic rhinosinusitis with nasal polyps had a local allergy. All chronic rhinosinusitis with nasal polyps patients tested negative for staphylococcal enterotoxin types A and B specific immunoglobulin E. The chronic rhinosinusitis with nasal polyps group had significantly elevated staphylococcal enterotoxin types A and B levels in the supernatant. Fourteen patients belonged to the eosinophilic chronic rhinosinusitis with nasal polyps group and the others were characterised as having non-eosinophilic chronic rhinosinusitis with nasal polyps.Conclusion:Local allergy may play a role in chronic rhinosinusitis with nasal polyps, independent of staphylococcal enterotoxin superantigens. Staphylococcal enterotoxins may be important in the pathogenesis of chronic rhinosinusitis with nasal polyps; however, their roles as superantigens were not confirmed in this study. In Chinese subjects, chronic rhinosinusitis with nasal polyps usually manifests as a neutrophilic inflammation.