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In multi-principal element alloys, dislocation motion and lattice diffusion are two key plasticity carriers, which are strongly interacted with the local chemical order. While in creep deformation, the difference between the impediment of the local chemical order on dislocation motion and lattice diffusion, along with the temperature dependency of such difference, is an intriguing topic that remains unsolved. By atomistic simulations on a typical NiCoCr system and rationalization with classic constitutive models, we found that the lattice diffusion receives less impediment compared to dislocation glide so that transition of creep mechanisms presents in a chemically ordered system. The critical stress of transition is tuned by temperature.

Abstract Induction solution heat treatment can change the mechanical characteristics and corrosion resistance properties of 308 L manufactured via wire arc additive manufacturing (WAAM). Moreover, compare with traditional heat treatment methods, this method can reduce heat treatment time and achieve in-situ local heat treatment. In this paper, in-situ induction heat treatment at 1100 °C for 2, 4, and 6 min were applied on 308 L thin-walled parts produced by WAAM. The result show that ferrite and austenite phase proportions were changed after induction solution heat treatment. Heat treatment at 1100 °C effectively reduced the δ-Fe and σ-Fe content, resulting in a slight decrease in UTS and microhardness, while YS and EL have a certain degree of increase. σ-Fe exhibits a more pronounced strengthening effect than austenite, albeit at the potential expense of steel’s elasticity. At the same time, induction heat treatment alters the ferrite to austenite ratio, which also enhances the anti-corrosion properties of the stainless steel. However, the presence of σ-Fe will cause a worsening of the corrosion resistance of the steel. In addition, as the heat treatment progresses, the ferrite’s microstructure in the deposition direction undergoes a significant transformation, changing from continuous dendrites to a few equiaxed grains.

Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression, but their roles and underlying mechanisms in colorectal cancer liver metastases (CRLMs) remain poorly understood. Methods: To explore the expression patterns and functions of lncRNAs in CRLMs, we analyzed the expression profiles of lncRNAs in CRC tissues using the TCGA database and examined the expression patterns of lncRNAs in matched normal, CRC, and CRLM tissues using clinical samples. We further investigated the biological roles of LINC02257 in CRLM using in vitro and in vivo assays, and verified its therapeutic potential in a mouse model of CRLM. Results: Our findings showed that LINC02257 was highly expressed in metastatic CRC tissues and its expression was negatively associated with overall survival. Functionally, LINC02257 promoted CRC cell growth, migration, metastasis, and inhibited cell apoptosis in vitro, and enhanced liver metastasis in vivo. Mechanistically, LINC02257 up-regulated phosphorylated c-Jun N-terminal kinase (JNK) to promote CRLM. Conclusions: Our study revealed that LINC02257 played a key role in the proliferation and metastasis of CRC cells through the LINC02257/JNK axis. Targeting this axis may represent a promising therapeutic strategy for the treatment of liver metastases in patients with CRC.

Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients’ clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.

Abstract Background We aimed to analyze the benefit of adjuvant chemotherapy in high-risk stage II colon cancer patients and the impact of high-risk factors on the prognostic effect of adjuvant chemotherapy. Methods This study is a multi-center, retrospective study, A total of 931 patients with stage II colon cancer who underwent curative surgery in 8 tertiary hospitals in China between 2016 and 2017 were enrolled in the study. Cox proportional hazard model was used to assess the risk factors of disease-free survival (DFS) and overall survival (OS) and to test the multiplicative interaction of pathological factors and adjuvant chemotherapy (ACT). The additive interaction was presented using the relative excess risk due to interaction (RERI). The Subpopulation Treatment Effect Pattern Plot (STEPP) was utilized to assess the interaction of continuous variables on the ACT effect. Results A total of 931 stage II colon cancer patients were enrolled in this study, the median age was 63 years old (interquartile range: 54–72 years) and 565 (60.7%) patients were male. Younger patients (median age, 58 years vs 65 years; P

Objective To report the diagnosis and treatment of a case of extraskeletal myxoid chondrosarcoma (EMC) in the pineal region misdiagnosed as chordoid glioma of the third ventricle, and to summarize the clinicopathological features, diagnosis and differential diagnosis of this rare tumor. Methods and Results A 42⁃year⁃old male patient with head MRI showed a space⁃occupying lesion in the pineal region and moderate enhancement on enhanced scan. After the first surgery, the histological morphology showed the boundary between tumor and brain tissue was not clear, spindle or stellate tumor cells were bunched, braided or scattered, the nuclei were small and deeply stained, and the interstitium was rich in collagen fibers and a large number of basophilic myxoid matrix. Immunohistochemical staining showed vimentin (Vim) expression in the cytoplasm of tumor cells, some of which expressed glial fibrillary acid protein (GFAP), CD34, CD99, but not cytokeratin (CK), epithelial membrane antigen (EMA) and S⁃100 protein (S⁃100). The pathological diagnosis was "chordoid glioma of the third ventricle". The tumor recurred 7 months after the first surgery, and the histological morphology of the second surgery showed obvious epithelioid features of the tumor cells, which were arranged in a cord, bundle or braided shape, with enlarged nuclei and easy to see mitotic images (up to 8/10 high magnification field). Some tumor cells were rich in cytoplasm and nuclear deviation, which were rhabdoid. The immunophenotype was the same as before, maintaining the diagnosis of "notochord glioma". The patient died of tumor progression 5 months after the second surgery. Combined with the literature, supplemental immunohistochemical staining showed that the tumor cells did not express Brachyury, thyroid transcription factor 1 (TTF⁃1), and SMARCB1/INI⁃1 proteins. Fluorescence in situ hybridization (FISH) test was positive for NR4A3 (9q22.33) gene rupture, and finally confirmed the diagnosis of EMC. Conclusions EMC in the pineal region is extremely rare, and attention should be paid to distinguishing it from the frequent mucinous tumors in the pineal region, such as chordoma, chordoid meningioma and chordoid glioma. Definite diagnosis depends on histological morphology, immunohistochemical staining and molecular detection.

Summary: Colorectal cancer (CRC) often develops slowly from adenoma, but the underlying mechanism remains unclear, hampering the prevention or treatment of colorectal adenoma-carcinoma progression. In this study, we use in-depth quantitative proteomics combined with survival analysis, revealing that the ribosome protein U3 small nucleolar RNA-associated protein 18 homolog (UTP18) is consistently upregulated in the progression of colorectal adenoma to carcinoma and is associated with adenoma recurrence, effective serodiagnosis, and poor prognosis of CRC. Furthermore, deSUMOylation induces the nucleocytoplasmic transport of UTP18, driving cell-cycle progression and tumorigenesis via mediation of the instability of p21 mRNA. In addition, the growth and ribosome biogenesis of adenoma organoids is found to be promoted by overexpression of UTP18. Thus, UTP18 contributes to multiple roles in adenogenesis and malignancy of CRC, suggesting that it could be a potential biomarker and drug target for colorectal adenoma and cancer.

BackgroundFolate was involved in oxidative stress, hepatic lipid metabolism and chronic hepatic inflammation. However, evidence about the association between serum folate level and non-alcoholic fatty liver disease (NAFLD) in general population is scarce. This study aimed to explore the relationship between serum folate level and NAFLD among adults.Methods7,146 adult participants aged 20 years and over who have complete data of serum folate level and liver function biomarkers in NHANES 2011–2018 were included. Serum folate level was measured by isotope-dilution high-performance liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). And suspected NAFLD was defined according to the United States fatty liver index (USFLI). Logistic regression and the restricted cubic spline models were performed.ResultsSerum folate level was inversely associated with the presence of NAFLD. When comparing the second, third and fourth quartiles of serum folate level to the lowest quartile, the adjusted ORs of the presence of NAFLD were 0.62 (0.49–0.78), 0.65 (0.51–0.84), and 0.43 (0.32–0.56) respectively (p for trend

With the continuous expansion of power infrastructure scale and the ceaseless growth of project funding, problems such as the opaque flow of capital, the arrears of workers’ wages and project funds, and the lack of a sound management mechanism become more and more serious. Therefore, a credit management method for infrastructure contractors of power systems based on blockchain is proposed. First, a blockchain-based framework of contractor credit management is designed for solving the infrastructure problems above. On this basis, a credit evaluation system is constructed for infrastructure contractors of power systems. Then, a credit behavior analysis method based on cross-chain technology and the credit result query mechanism based on proxy signature is proposed to realize the data interaction and the credit result query. Finally, the effectiveness and accuracy of the proposed method are illustrated by the case study. The simulation results show that the method proposed in this work can effectively reflect the credit status of power infrastructure contractors and the wages payment has the highest weight of 0.2240 among all the third level indicators with its obvious important role in power infrastructure management.

Peripheral nerve injury is common, and can lead to skeletal muscle atrophy and dysfunction. However, the underlying molecular mechanisms are not fully understood. The transcription factors have been proved to play a key role in denervated muscle atrophy. In order to systematically analyze transcription factors and obtain more comprehensive information of the molecular regulatory mechanisms in denervated muscle atrophy, a new transcriptome survey focused on transcription factors are warranted. In the current study, we used microarray to identify and analyze differentially expressed genes encoding transcription factors in denervated muscle atrophy in a rat model of sciatic nerve dissection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were used to explore the biological functions of differentially expressed transcription factors and their target genes related to skeletal muscle pathophysiology. We found that the differentially expressed transcription factors were mainly involved in the immune response. Based on correlation analysis and the expression trends of transcription factors, 18 differentially expressed transcription factors were identified. Stat3, Myod1, Runx1, Atf3, Junb, Runx2, Myf6, Stat5a, Tead4, Klf5, Myog, Mef2a, and Hes6 were upregulated. Ppargc1a, Nr4a1, Lhx2, Ppara, and Rxrg were downregulated. Functional network mapping revealed that these transcription factors are mainly involved in inflammation, development, aging, proteolysis, differentiation, regeneration, autophagy, oxidative stress, atrophy, and ubiquitination. These findings may help understand the regulatory mechanisms of denervated muscle atrophy and provide potential targets for future therapeutic interventions for muscle atrophy following peripheral nerve injury.

Abstract Compared with non-degradable materials, biodegradable biomaterials play an increasingly important role in the repairing of severe bone defects, and have attracted extensive attention from researchers. In the treatment of bone defects, scaffolds made of biodegradable materials can provide a crawling bridge for new bone tissue in the gap and a platform for cells and growth factors to play a physiological role, which will eventually be degraded and absorbed in the body and be replaced by the new bone tissue. Traditional biodegradable materials include polymers, ceramics and metals, which have been used in bone defect repairing for many years. Although these materials have more or fewer shortcomings, they are still the cornerstone of our development of a new generation of degradable materials. With the rapid development of modern science and technology, in the twenty-first century, more and more kinds of new biodegradable materials emerge in endlessly, such as new intelligent micro-nano materials and cell-based products. At the same time, there are many new fabrication technologies of improving biodegradable materials, such as modular fabrication, 3D and 4D printing, interface reinforcement and nanotechnology. This review will introduce various kinds of biodegradable materials commonly used in bone defect repairing, especially the newly emerging materials and their fabrication technology in recent years, and look forward to the future research direction, hoping to provide researchers in the field with some inspiration and reference.

Abstract Background Multiple polypoid colonic metastases are very rare which mainly originated from gastric carcinoma or melanoma. For rectal cancers, liver, lung and peritoneum are the most common metastatic sites. Here we present an unusual case with rectal adenocarcinoma and metachronous multiple colonic polypoid metastases. Case presentation A 53-year-old man who underwent radical resection for rectal cancer 2 years ago was admitted to our department for an elevation of CEA level of 18.4 ng/ml. Colonoscopy revealed ten ivory rubbery colonic polypoid lesions (about 5 mm in diameters) in the large bowel which were confirmed as signet ring cell carcinomas (SRCC) by biopsy, but full-body contrast enhanced CT and PET-CT showed no other suspicious lesion. Seven weeks later, a laparoscopic total colectomy was performed and more than 50 polypoid lesions were observed throughout the mucosal surface of the large intestine which were confirmed as metastatic SRCC by postoperative pathological examination. All the 34 paracolic lymph nodes retrieved were involved. After 4 months, diffuse abdominopelvic and multiple bone metastases were identified by CT and the patient died of the disease 1 month later. Conclusion Here we present an unusual case of multiple colonic polypoid metastases of rectal adenocarcinoma. For SRCC that is prone to have disseminated micrometastases, colonic ‘polyps’ may be the early noticeable sign of undetectable and extensive tumor spread. Instead of surgical resection of ‘the confined disease in colon’, systemic treatment maybe a more appropriate choice.

Context: Retrorectal tumours are rare with developmental cysts being the most common type. Conventionally, large retrorectal developmental cysts (RRDCs) require the combined transabdomino-sacrococcygeal approach. Aims: This study aims to investigate the surgical outcomes of the laparoscopic approach for large RRDCs. Settings and Design: A retrospective case series analysis. Subjects and Methods: Data of patients with RRDCs of 10 cm or larger in diameter who underwent the laparoscopic surgery between 2012 and 2017 at our tertiary centre were retrospectively analyzed. Statistical Analysis Used: Results are presented as median values or mean ± standard deviation for continuous variables and numbers (percentages) for categorical variables. Results: Twenty consecutive cases were identified (19 females; median age, 36 years). Average tumour size was 10.9 ± 1.1 cm. Cephalic ends of lesions ranged from S1/2 junction to S4 level. Caudally, 18 cysts extended to the sacrococcygeal hypodermis. Seventeen patients underwent the pure laparoscopy; three patients received a combined laparoscopic-posterior approach. The operating time was 167.1 ± 57.3 min for the pure laparoscopic group and 212.0 ± 24.5 min for the combined group. The intraoperative haemorrhage was 68.2 ± 49.7 and 66.7 ± 28.9 (mL), respectively. Post-operative complications included one trocar site hernia, one wound infection and one delayed rectal wall perforation. The median post-operative hospital stay was 7 days. With a median follow-up period of 36 months, 1 lesions recurred. Conclusions: The laparoscopic approach can provide a feasible and effective alternative for large RRDCs, with advantages of the minimally invasive surgery. For lesions with ultra-low caudal ends, especially those closely clinging to the rectum, a combined posterior approach is still necessary.

Background: Recently, the distinction between left- and right-sided colon cancer (LCC and RCC) has been brought into focus. RCC is associated with an inferior overall survival and progression-free survival. We aimed to perform a detailed analysis of the diversity of extracellular vesicles (EV) between LCC and RCC using quantitative proteomics and to identify for new diagnostic and prognostic biomarkers. Methods: We isolated EVs from patients with LCC, RCC and healthy volunteers, and treated colorectal cancer cell line with serum-derived EVs. We then performed a quantitative proteomics analysis of the serum-derived EVs and cell line treated with EVs. Proteomic data are available via ProteomeXchange with the identifiers PXD012283 and PXD012304. In addition, we assessed the performance of EV SPARC and LRG1 as diagnosis and prognosis biomarkers in colon cancer. Findings: The expression profile of the serum EV proteome in patients with RCC was different from that of patients with LCC. Serum-derived EVs in RCC promoted cellular mobility more significantly than EVs derived from LCC. EV SPARC and LRG1 expression levels demonstrated area under the receiver-operating characteristic curve values of 0.95 and 0.93 for discriminating patients with colon cancer from healthy controls. Moreover, the expression levels of SPARC and LRG1 correlated with tumour sidedness and were predictive of tumour recurrence. Interpretation: We identified differences in EV protein profiles between LCC and RCC. Serum-derived EVs of RCC may promote metastasis via upregulation of extracellular matrix (ECM)-related proteins, especially SPARC and LRG1, which may serve as diagnosis and prognosis biomarkers in colon cancer. Keywords: Colon cancer, Extracellular vesicles, Proteomics, Metastasis, Tumour location

The Industry 4.0 paradigm is the focus of modern manufacturing system design. The integration of cutting-edge technologies such as the Internet of things, cyber–physical systems, big data analytics, and cloud computing requires a flexible platform supporting the effective optimization of manufacturing-related processes, e.g., predictive maintenance. Existing predictive maintenance studies generally focus on either a predictive model without considering the maintenance decisions or maintenance optimizations based on the degradation models of the known system. To address this, we propose PMMI 4.0, a Predictive Maintenance Model for Industry 4.0, which utilizes a newly proposed solution PMS4MMC for supporting an optimized maintenance schedule plan for multiple machine components driven by a data-driven LSTM model for RUL (remaining useful life) estimation. The effectiveness of the proposed solution is demonstrated using a real-world industrial case with related data. The results showed the validity and applicability of this work.

HIV latency is a challenge to the success of antiretroviral therapy (ART). Hence patients may benefit from interventions that efficiently reactivate the latent virus to be eliminated by ARTs. Here we show that plasma extracellular vesicles (pEVs) can enhance HIV infection of activated CD4+ T cells and reactivate the virus in latently infected J-Lat 10.6 cells. Evaluation of the extravesicular miRNA cargo by a PCR array revealed that pEVs from HIV patients express miR-139-5p. Furthermore, we found that increased levels of miR-139-5p in J-Lat 10.6 cells incubated with pEVs corresponded with reduced expression of the transcription factor, FOXO1. pEV treatment also corresponded with increased miR-139-5p expression in stimulated PD1+ Jurkat cells, but with concomitant upregulation of FOXO1, Fos, Jun, PD-1 and PD-L1. However, J-Lat 10.6 cells incubated with miR-139-5p inhibitor-transfected pEVs from HIV ART-naïve and on-ART patients expressed reduced levels of miR-139-5p than cells treated with pEVs from healthy controls (HC). Collectively, our results indicate that pEV miR-139-5p belongs to a network of miRNAs that can promote cell activation, including latent HIV-infected cells by regulating the expression of FOXO1 and the PD1/PD-L1 promoters, Fos and Jun.

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients.

Abstract Background Reference genes are often interchangeably called housekeeping genes due to 1) the essential cellular functions their proteins provide and 2) their constitutive expression across a range of normal and pathophysiological conditions. However, given the proliferative drive of malignant cells, many reference genes such as beta-actin (ACTB) and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) which play critical roles in cell membrane organization and glycolysis, may be dysregulated in tumors versus their corresponding normal controls Methods Because Next Generation Sequencing (NGS) technology has several advantages over hybridization-based technologies, such as independent detection and quantitation of transcription levels, greater sensitivity, and increased dynamic range, we evaluated colorectal cancers (CRC) and their histologically normal tissue counterparts by NGS to evaluate the expression of 21 “classical” reference genes used as normalization standards for PCR based methods. Seventy-nine paired tissue samples of CRC and their patient matched healthy colonic tissues were subjected to NGS analysis of their mRNAs. Results We affirmed that 17 out of 21 classical reference genes had upregulated expression in tumors compared to normal colonic epithelial tissue and dramatically so in some cases. Indeed, tumors were distinguished from normal controls in both unsupervised hierarchical clustering analyses (HCA) and principal component analyses (PCA). We then identified 42 novel potential reference genes with minimal coefficients of variation (CV) across 79 CRC tumor pairs. Though largely consistently expressed across tumors and normal control tissues, a subset of high stage tumors (HSTs) as well as some normal tissue samples (HSNs) located adjacent to these HSTs demonstrated dysregulated expression, thus identifying a subset of tumors with a potentially distinct and aggressive biological profile. Conclusion While classical CRC reference genes were found to be differentially expressed between tumors and normal controls, novel reference genes, identified via NGS, were more consistently expressed across malignant and normal colonic tissues. Nonetheless, a subset of HST had profound dysregulation of such genes as did many of the histologically normal tissues adjacent to such HSTs, indicating that the HSTs so distinguished may have unique biological properties and that their histologically normal tissues likely harbor a small population of microscopically undetected but metabolically active tumors.

Abstract Background It is becoming increasingly clear that cancers can rarely be ascribed to just one or a few genomic variations. Genes generally do not function alone, but in groups that function as “networks”. This study aimed to develop a competing endogenous RNA (ceRNA) network to elucidate the role of long non-coding RNA H19 in colorectal cancer. Methods Large-scale RNA-seq data was obtained from The Cancer Genome Atlas database. Differentially expressed RNAs were identified by bioinformatics analysis, and a competing endogenous RNA network was constructed. Functional enrichment analysis and correlation analysis between competing endogenous RNAs and clinical features were performed to reveal their roles in the tumorigenesis of colorectal cancer. To verify the conclusions derived from bioinformatics analysis, we investigated the effect of lncRNA H19 knockdown in human colorectal cancer cell lines HT-29 and HCT116. Results The present study successfully identify various cancer-specific lncRNAs and pseudogenes in CRC. The lncRNA/pseudogene–miRNA–mRNA ceRNA network was constructed using 10 lncRNAs, 5 pseudogenes, 122 mRNAs and 39 miRNAs. In the ceRNA network of CRC, H19 up-regulates various cancer-related mRNA by competitively sponging various miRNA, and participates in PI3K–Akt signaling pathway in this manner. Cox regression and correlation analysis showed that H19 and some other competing endogenous RNAs in the network are associated with poor prognosis and clinical parameters such as tumor grade and metastasis. Knockdown of H19 reduces the protein level of MET, ZEB1, and COL1A1 in vitro. Conclusions H19 regulates PI3K–Akt signal pathway through a competing endogenous RNA network and predicts poor prognosis in colorectal cancer. The pseudogene RPLP0P2 may be an important oncogene like H19 and needs to be studied further.

Abstract Background Urinary catheter placement is essential before laparoscopic anterior resection for rectal cancer. Whether early removal of the catheter increases the incidence of urinary retention and urinary tract infection (UTI) is not clear. This study aims to determine the optimal time for removal of the urinary catheter after laparoscopic anterior resection of the rectum. Methods/design A total of 220 participants meeting the inclusion criteria will be randomly assigned to an experimental group or a control group. The experimental group will have their urethral catheters removed on postoperative day 2 and the control group will have their urethral catheters removed on postoperative day 7. In both groups, catheter removal will be performed when the bladder is full. The incidence of urinary retention and UTI in the two groups will be compared to determine the optimal catheter removal time. Discussion This is a prospective, single-center, randomized controlled trial to determine whether early removal of the urinary catheter after laparoscopic anterior resection of the rectum will help to decrease the incidence of postoperative acute urinary retention and UTI. Trial registration ClinicalTrials.gov, NCT03065855. Registered on 23 February 2017.

Although mice locate resources using turbulent airborne odor plumes, the stochasticity and intermittency of fluctuating plumes create challenges for interpreting odor cues in natural environments. Population activity within the olfactory bulb (OB) is thought to process this complex spatial and temporal information, but how plume dynamics impact odor representation in this early stage of the mouse olfactory system is unknown. Limitations in odor detection technology have made it difficult to measure plume fluctuations while simultaneously recording from the mouse's brain. Thus, previous studies have measured OB activity following controlled odor pulses of varying profiles or frequencies, but this approach only captures a subset of features found within olfactory plumes. Adequately sampling this feature space is difficult given a lack of knowledge regarding which features the brain extracts during exposure to natural olfactory scenes. Here we measured OB responses to naturally fluctuating odor plumes using a miniature, adapted odor sensor combined with wide-field GCaMP6f signaling from the dendrites of mitral and tufted (MT) cells imaged in olfactory glomeruli of head-fixed mice. We precisely tracked plume dynamics and imaged glomerular responses to this fluctuating input, while varying flow conditions across a range of ethologically-relevant values. We found that a consistent portion of MT activity in glomeruli follows odor concentration dynamics, and the strongest responding glomeruli are the best at following fluctuations within odor plumes. Further, the reliability and average response magnitude of glomerular populations of MT cells are affected by the flow condition in which the animal samples the plume, with the fidelity of plume following by MT cells increasing in conditions of higher flow velocity where odor dynamics result in intermittent whiffs of stronger concentration. Thus, the flow environment in which an animal encounters an odor has a large-scale impact on the temporal representation of an odor plume in the OB. Additionally, across flow conditions odor dynamics are a major driver of activity in many glomerular networks. Taken together, these data demonstrate that plume dynamics structure olfactory representations in the first stage of odor processing in the mouse olfactory system.

Background T cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.Methods We studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.Results We found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.Conclusions Our study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

Background We have previously reported that the upregulation of galectin-9 (Gal-9) on CD4+ and CD8+ T cells in HIV patients was associated with impaired T cell effector functions. Gal-9 is a ligand for T cell immunoglobulin and mucin domain-3, and its expression on T cells in cancer has not been investigated. Therefore, we aimed to investigate the expression level and effects of Gal-9 on T cell functions in patients with virus-associated solid tumors (VASTs).Methods 40 patients with VASTs through a non-randomized and biomarker-driven phase II LATENT trial were investigated. Peripheral blood mononuclear cells and tumor biopsies were obtained and subjected to immunophenotyping. In this trial, the effects of oral valproate and avelumab (anti-PD-L1) was investigated in regards to the expression of Gal-9 on T cells.Results We report the upregulation of Gal-9 expression by peripheral and tumor-infiltrating CD4+ and CD8+ T lymphocytes in patients with VASTs. Our results indicate that Gal-9 expression is associated with dysfunctional T cell effector functions in the periphery and tumor microenvironment (TME). Coexpression of Gal-9 with PD-1 or T cell immunoglobulin and ITIM domain (TIGIT) exhibited a synergistic inhibitory effect and enhanced an exhausted T cell phenotype. Besides, responding patients to treatment had lower Gal-9 mRNA expression in the TME. Translocation of Gal-9 from the cytosol to the cell membrane of T cells following stimulation suggests persistent T cell receptor (TCR) stimulation as a potential contributing factor in Gal-9 upregulation in patients with VASTs. Moreover, partial colocalization of Gal-9 with CD3 on T cells likely impacts the initiation of signal transduction via TCR as shown by the upregulation of ZAP70 in Gal-9+ T cells. Also, we found an expansion of Gal-9+ but not TIGIT+ NK cells in patients with VASTs; however, dichotomous to TIGIT+ NK cells, Gal-9+ NK cells exhibited impaired cytotoxic molecules but higher Interferon gamma (IFN-γ) expression.Conclusion Our data indicate that higher Gal-9-expressing CD8+ T cells were associated with poor prognosis following immunotherapy with anti-Programmed death-ligand 1 (PD-L1) (avelumab) in our patients’ cohort. Therefore, for the very first time to our knowledge, we report Gal-9 as a novel marker of T cell exhaustion and the potential target of immunotherapy in patients with VASTs.

To evaluate the expression of immune checkpoint genes, their concordance with expression of IFNγ, and to identify potential novel ICP related genes (ICPRG) in colorectal cancer (CRC), the biological connectivity of six well documented (“classical”) ICPs (CTLA4, PD1, PDL1, Tim3, IDO1, and LAG3) with IFNγ and its co-expressed genes was examined by NGS in 79 CRC/healthy colon tissue pairs. Identification of novel IFNγ- induced molecules with potential ICP activity was also sought. In our study, the six classical ICPs were statistically upregulated and correlated with IFNγ, CD8A, CD8B, CD4, and 180 additional immunologically related genes in IFNγ positive (FPKM > 1) tumors. By ICP co-expression analysis, we also identified three IFNγ-induced genes [(IFNγ-inducible lysosomal thiol reductase (IFI30), guanylate binding protein1 (GBP1), and guanylate binding protein 4 (GBP4)] as potential novel ICPRGs. These three genes were upregulated in tumor compared to normal tissues in IFNγ positive tumors, co-expressed with CD8A and had relatively high abundance (average FPKM = 362, 51, and 25, respectively), compared to the abundance of the 5 well-defined ICPs (Tim3, LAG3, PDL1, CTLA4, PD1; average FPKM = 10, 9, 6, 6, and 2, respectively), although IDO1 is expressed at comparably high levels (FPKM = 39). We extended our evaluation by querying the TCGA database which revealed the commonality of IFNγ dependent expression of the three potential ICPRGs in 638 CRCs, 103 skin cutaneous melanomas (SKCM), 1105 breast cancers (BC), 184 esophageal cancers (ESC), 416 stomach cancers (STC), and 501 lung squamous carcinomas (LUSC). In terms of prognosis, based on Pathology Atlas data, correlation of GBP1 and GBP4, but not IFI30, with 5-year survival rate was favorable in CRC, BC, SKCM, and STC. Thus, further studies defining the role of IFI30, GBP1, and GBP4 in CRC are warranted.

ABSTRACT CD71+ erythroid cells (CECs) have a wide range of immunomodulatory properties. Here, we show that CECs are expanded in the peripheral blood of HIV patients, with a positive correlation between their frequency and the plasma viral load. CECs from HIV patients and human cord blood/placenta exacerbate HIV-1 infection/replication when cocultured with CD4+ T cells, and that preexposure of CD4+ T cells to CECs enhances their permissibility to HIV infection. However, mature red blood cells (RBCs) do not enhance HIV replication when cocultured with CD4+ T cells. We also found CECs express substantial levels of the NOX2 gene and via a mitochondrial reactive oxygen species (ROS)-dependent mechanism possibly upregulate NF-κB in CD4+ T cells once cocultured, which affects the cell cycle machinery to facilitate HIV-1 replication. The complement receptor-1 (CD35) and the Duffy antigen receptor for chemokines (DARC) as potential HIV target molecules are expressed significantly higher on CECs compared to mature red blood cells. Blocking CD35 or DARC substantially abolishes HIV-1 transmission by RBCs to uninfected CD4+ T cells but not by CECs. In contrast, we observed CECs bind to HIV-1 via CD235a and subsequently transfer the virus to uninfected CD4+ T cells, which can be partially blocked by the anti-CD235a antibody. More importantly, we found that CECs from HIV-infected individuals in the presence of antiretroviral therapy harbor infective viral particles, which mediate HIV-1 trans-infection of CD4+ T cells. Therefore, our findings provide a novel insight into the role of CECs in HIV pathogenesis as potential contributing cells in viral persistence and transmission. IMPORTANCE Immature red blood cells (erythroid precursors or CD71+ erythroid cells) have a wide range of immunomodulatory properties. In this study, we found that these erythroid precursors are abundant in the human cord blood/placental tissues, in the blood of HIV-infected and anemic individuals. We observed that these cells exacerbate HIV-1 replication/infection in target cells and even make HIV target cells more permissible to HIV infection. In addition, we found that HIV gets a free ride by binding on the surface of these cells and thus can travel to different parts of the body. In agreement, we noticed a positive correlation between the plasma viral load and the frequency of these cells in HIV patients. More importantly, we observed that infective HIV particles reside inside these erythroid precursors but not mature red blood cells. Therefore, these cells by harboring HIV can play an important role in HIV pathogenesis.

Abstract Background Current library preparation protocols for Illumina HiSeq and MiSeq DNA sequencers require ≥2 nM initial library for subsequent loading of denatured cDNA onto flow cells. Such amounts are not always attainable from samples having a relatively low DNA or RNA input; or those for which a limited number of PCR amplification cycles is preferred (less PCR bias and/or more even coverage). A well-tested sub-nanomolar library preparation protocol for Illumina sequencers has however not been reported. The aim of this study is to provide a much needed working protocol for sub-nanomolar libraries to achieve outcomes as informative as those obtained with the higher library input (≥ 2 nM) recommended by Illumina’s protocols. Results Extensive studies were conducted to validate a robust sub-nanomolar (initial library of 100 pM) protocol using PhiX DNA (as a control), genomic DNA (Bordetella bronchiseptica and microbial mock community B for 16S rRNA gene sequencing), messenger RNA, microRNA, and other small noncoding RNA samples. The utility of our protocol was further explored for PhiX library concentrations as low as 25 pM, which generated only slightly fewer than 50% of the reads achieved under the standard Illumina protocol starting with > 2 nM. Conclusions A sub-nanomolar library preparation protocol (100 pM) could generate next generation sequencing (NGS) results as robust as the standard Illumina protocol. Following the sub-nanomolar protocol, libraries with initial concentrations as low as 25 pM could also be sequenced to yield satisfactory and reproducible sequencing results.

Denervated muscle atrophy is a common clinical disease that has no effective treatments. Our previous studies have found that oxidative stress and inflammation play an important role in the process of denervated muscle atrophy. Extracellular vesicles derived from skin precursor-derived Schwann cells (SKP-SC-EVs) contain a large amount of antioxidants and anti-inflammatory factors. This study explored whether SKP-SC-EVs alleviate denervated muscle atrophy by inhibiting oxidative stress and inflammation. In vitro studies have found that SKP-SC-EVs can be internalized and caught by myoblasts to promote the proliferation and differentiation of myoblasts. Nutrient deprivation can cause myotube atrophy, accompanied by oxidative stress and inflammation. However, SKP-SC-EVs can inhibit oxidative stress and inflammation caused by nutritional deprivation and subsequently relieve myotube atrophy. Moreover, there is a remarkable dose-effect relationship. In vivo studies have found that SKP-SC-EVs can significantly inhibit a denervation-induced decrease in the wet weight ratio and myofiber cross-sectional area of target muscles. Furthermore, SKP-SC-EVs can dramatically inhibit highly expressed Muscle RING Finger 1 and Muscle Atrophy F-box in target muscles under denervation and reduce the degradation of the myotube heavy chain. SKP-SC-EVs may reduce mitochondrial vacuolar degeneration and autophagy in denervated muscles by inhibiting autophagy-related proteins (i.e., PINK1, BNIP3, LC3B, and ATG7). Moreover, SKP-SC-EVs may improve microvessels and blood perfusion in denervated skeletal muscles by enhancing the proliferation of vascular endothelial cells. SKP-SC-EVs can also significantly inhibit the production of reactive oxygen species (ROS) in target muscles after denervation, which indicates that SKP-SC-EVs elicit their role by upregulating Nrf2 and downregulating ROS production-related factors (Nox2 and Nox4). In addition, SKP-SC-EVs can significantly reduce the levels of interleukin 1β, interleukin-6, and tumor necrosis factor α in target muscles. To conclude, SKP-SC-EVs may alleviate the decrease of target muscle blood perfusion and passivate the activities of ubiquitin-proteasome and autophagy-lysosome systems by inhibiting oxidative stress and inflammatory response, then reduce skeletal muscle atrophy caused by denervation. This study not only enriches the molecular regulation mechanism of denervated muscle atrophy, but also provides a scientific basis for SKP-SC-EVs as a protective drug to prevent and treat muscle atrophy.

Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

Motivated by the concepts of quantum mechanics and particle swarm optimization (PSO), quantum-behaved particle swarm optimization (QPSO) was developed to achieve better global search ability. This paper proposes a new method to improve the global search ability of QPSO with fractional calculus (FC). Based on one of the most frequently used fractional differential definitions, the Grünwald-Letnikov definition, we introduce its discrete expression into the position updating of QPSO. Extensive experiments on well-known benchmark functions were performed to evaluate the performance of the proposed fractional-order quantum particle swarm optimization (FQPSO). The experimental results demonstrate its superior ability in achieving optimal solutions for several different optimizations.

Skeletal muscle atrophy occurs under various conditions, such as disuse, denervation, fasting, aging, and various diseases. Although the underlying molecular mechanisms are still not fully understood, skeletal muscle atrophy is closely associated with reactive oxygen species (ROS) overproduction. In this study, we aimed to investigate the involvement of ROS in skeletal muscle atrophy from the perspective of gene regulation, and further examine therapeutic effects of antioxidants on skeletal muscle atrophy. Microarray data showed that the gene expression of many positive regulators for ROS production were up-regulated and the gene expression of many negative regulators for ROS production were down-regulated in mouse soleus muscle atrophied by denervation (sciatic nerve injury). The ROS level was significantly increased in denervated mouse soleus muscle or fasted C2C12 myotubes that had suffered from fasting (nutrient deprivation). These two muscle samples were then treated with N-acetyl-L-cysteine (NAC, a clinically used antioxidant) or pyrroloquinoline quinone (PQQ, a naturally occurring antioxidant), respectively. As compared to non-treatment, both NAC and PQQ treatment (1) reversed the increase in the ROS level in two muscle samples; (2) attenuated the reduction in the cross-sectional area (CSA) of denervated mouse muscle or in the diameter of fasted C2C12 myotube; (3) increased the myosin heavy chain (MHC) level and decreased the muscle atrophy F-box (MAFbx) and muscle-specific RING finger-1 (MuRF-1) levels in two muscle samples. Collectively, these results suggested that an increased ROS level was, at least partly, responsible for denervation- or fasting-induced skeletal muscle atrophy, and antioxidants might resist the atrophic effect via ROS-related mechanisms.

Chronic lead (Pb) exposure causes cognitive deficits. This study aimed to explore the neuroprotective effect and mechanism of β-asarone, an active component from Chinese Herbs Acorus tatarinowii Schott, to alleviate impairments of spatial memory and synaptogenesis in Pb-exposed rats. Both Sprague-Dawley developmental rat pups and adult rats were used in the study. Developmental rat pups were exposed to Pb throughout the lactation period and β-asarone (10, 40mg kg-1, respectively) was given intraperitoneally from postnatal day 14 to 21. Also, the adult rats were exposed to Pb from embryo stage to 11 weeks old and β-asarone (2.5, 10, 40mg kg-1, respectively) was given from 9 to 11 weeks old. The level of β-asarone in brain tissue was measured by High Performance Liquid Chromatography. The Morris water maze test and Golgi-Cox staining method were used to assess spatial memory ability and synaptogenesis. The protein expression of NR2B subunit of NMDA receptor, Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and Wnt family member 7A (Wnt7a) in hippocampus, as well as mRNA expression of Arc/Arg3.1 and Wnt7a, was also explored. We found that β-asarone could pass through the blood brain barrier quickly. And β-asarone effectively attenuated Pb-induced reduction of spine density in hippocampal CA1 and dentate gyrus areas in a dose-dependent manner both in developmental and adult rats, meanwhile the Pb-induced impairments of learning and memory were partially rescued. In addition, β-asarone effectively up-regulated the protein expression of NR2B, Arc and Wnt7a, as well as the mRNA levels of Arc/Arg3.1 and Wnt7a, which had been suppressed by Pb exposure. The results suggest the neuroprotective properties of β-asarone against Pb-induced memory impairments, and the effect is possibly through the regulation of synaptogenesis, which is mediated via Arc/Arg3.1 and Wnt pathway.

We present a feature extraction method to emphasize the interrelationship between gray and white matter and identify tissue distribution abnormalities in schizophrenia. This approach utilizes novel features called structural phase and magnitude images. The phase image indicates the relative contribution of gray and white matter, and the magnitude image reflects the overall tissue concentration. Three different analyses are applied to the phase and magnitude images obtained from 120 healthy controls and 120 schizophrenia patients. First, a single-subject subtraction analysis is computed for an initial evaluation. Second, we analyze the extracted features using voxel based morphometry (VBM) to detect voxelwise group differences. Third, source based morphometry (SBM) analysis was used to determine abnormalities in structural networks that co-vary in a similar way. Six networks were identified showing significantly lower white-to-gray matter in schizophrenia, including thalamus, right precentral-postcentral, left pre/post-central, parietal, right cuneus-frontal, and left cuneus-frontal sources. Interestingly, some networks look similar to functional patterns, such as sensory-motor and vision. Our findings demonstrate that structural phase and magnitude images can naturally and efficiently summarize the associated relationship between gray and white matter. Our approach has wide applicability for studying tissue distribution differences in the healthy and diseased brain.