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Abstract Hemorrhagic fever with renal syndrome (HFRS) occurs throughout Eurasia with considerable morbidity and mortality. Currently, the absence of specific treatments or effective antiviral drugs for hantavirus infection makes developing safe and effective vaccines a high priority. Here, we report the development of three novel nucleic acid vaccine candidates, mRNA, naked DNA, and DNA encapsulated in lipid nanoparticles, encoding the glycoproteins of the Hantaan virus (HTNV). To comprehensively evaluate the potential of candidate HTNV nucleic acid vaccines in preventing HFRS, we focus on evaluating their immunogenicity and efficacy in mice and comparing them with an inactivated vaccine as the benchmark. Our findings reveal that all candidate vaccines activated instant and sustained immune responses, offering comparable in vivo protective efficacy to the inactivated vaccines. Notably, compared to the inactivated vaccine, mRNA vaccine induced stronger virus-specific T-helper 1 cell immune response, while DNA-LNP elicited higher levels of neutralizing antibodies in mice. These results mark a significant step in developing nucleic acid vaccines for HTNV, suggesting that sequential immunization with DNA and mRNA vaccines could further amplify the advantages of nucleic acid vaccines.

Underwater images typically exhibit low quality due to complex imaging environments, which impede the development of the Space-Air-Ground-Sea Integrated Network (SAGSIN). Existing physical models often ignore the light absorption and attenuation properties of water, making them incapable of resolving details and resulting in low contrast. To address this issue, we propose the attenuated incident optical model and combine it with a background segmentation technique for underwater image restoration. Specifically, we first utilize the features to distinguish the foreground region of the image from the background region. Subsequently, we introduce a background light layer to improve the underwater imaging model and account for the effects of non-uniform incident light. Afterward, we employ a new maximum reflection prior in the estimation of the background light layer to achieve restoration of the foreground region. Meanwhile, the contrast of the background region is enhanced by stretching the saturation and brightness components. Extensive experiments conducted on four underwater image datasets, using both classical and state-of-the-art (SOTA) algorithms, demonstrate that our method not only successfully restores textures and details but is also beneficial for processing images under non-uniform lighting conditions.

Introduction Benign prostatic hyperplasia (BPH) is a condition commonly seen among men aged over 40, significantly affecting their quality of life and typically accompanied by lower urinary tract symptoms (LUTS). Acupuncture presents a potentially effective treatment option; however, the exact effects remain uncertain. Therefore, we design this multicentre randomised trial to evaluate the efficacy and safety of electroacupuncture (EA) for relieving LUTS in men with BPH.Methods and analysis A two-arm, sham-controlled, subject-blinded and assessor-blinded trial will be conducted in 11 hospitals in China to compare EA with sham electroacupuncture (SA) in treating moderate to severe LUTS of BPH among men aged 40–80. A total of 306 eligible male patients will be recruited and assigned at a 1:1 ratio to receive either EA or SA for 24 sessions over a succession of 8 weeks, with 24 weeks of follow-up. The primary outcome will be the proportions of participants with at least 30% reduction in the International Prostate Symptom Score total score from baseline at weeks 8 and 20. All statistical analyses will be conducted in accordance with the intention-to-treat principle, and a two-tailed p value less than 0.05 will be considered statistically significant.Ethics and dissemination The trial has been approved by the institutional review board of Guang’anmen Hospital (2022-203-KY), as well as other recruitment centres. Each participant will receive the detailed information of the trial, and sign the written informed consent. The results of the trial are expected to be published in a peer-reviewed journal.Trial registration number NCT05585450.

Abstract Cervical cancer (CC) is the most common gynecologic malignancy, which seriously threatens the health of women. Lipid metabolism is necessary for tumor proliferation and metastasis. However, the molecular mechanism of the relationship between CC and lipid metabolism remains poorly defined. We revealed the expression of IGF2BP3 in CC exceeded adjacent tissues, and was positively associated with tumor stage using human CC tissue microarrays. The Cell Counting Kit-8, colony formation assay, 5-ethynyl-2′-deoxyuridine assay, transwell assays, wound-healing assays, and flow cytometry assessed the role of IGF2BP3 in proliferation and metastasis of CC cells. Besides, exploring the molecular mechanism participating in IGF2BP3-driven lipid metabolism used RNA-seq, which determined SCD as the target of IGF2BP3. Further, lipid droplets, cellular triglyceride (TG) contents, and fatty acids were accessed to discover that IGF2BP3 can enhance lipid metabolism in CC. Moreover, RIP assay and methylated RNA immunoprecipitation experiments seeked the aimed-gene-binding specificity. Lastly, the IGF2BP3 knockdown restrained CC growth and lipid metabolism, after which SCD overexpression rescued the influence in vitro and in vivo using nude mouse tumor-bearing model. Mechanistically, IGF2BP3 regulated SCD mRNA m6A modifications via IGF2BP3-METTL14 complex, thereby enhanced CC proliferation, metastasis, and lipid metabolism. Our study highlights IGF2BP3 plays a crucial role in CC progression and represents a therapeutic latent strategy. It is a potential tactic that blocks the metabolic pathway relevant to IGF2BP3 with the purpose of treating CC.

Marburg hemorrhagic fever (MHF) is a fatal infectious disease caused by Marburg virus (MARV) infection, and MARV has been identified as a priority pathogen for vaccine development by the WHO. The glycoprotein (GP) of MARV mediates viral adhesion and invasion of host cells and therefore can be used as an effective target for vaccine development. Moreover, DNA vaccines have unique advantages, such as simple construction processes, low production costs, and few adverse reactions, but their immunogenicity may decrease due to the poor absorption rate of plasmids. Lysosome-associated membrane protein 1 (LAMP1) can direct antigens to lysosomes and endosomes and has great potential for improving the immunogenicity of nucleic acid vaccines. Therefore, we constructed a DNA vaccine based on a codon-optimized MARV GP (ID MF939097.1) fused with LAMP1 and explored the effect of a LAMP targeting strategy on improving the immunogenicity of the MARV DNA vaccine. ELISA, ELISpot, and flow cytometry revealed that the introduction of LAMP1 into the MARV DNA candidate vaccine improved the humoral and cellular immune response, enhanced the secretion of cytokines, and established long-term immune protection. Transcriptome analysis revealed that the LAMP targeting strategy significantly enriched antigen processing and presentation-related pathways, especially the MHC class II-related pathway, in the candidate vaccine. Our study broadens the strategic vision for enhanced DNA vaccine design and provides a promising candidate vaccine for MHF prevention.

Vaccines has long been the focus of antiviral immunotherapy research. Viral epitopes are thought to be useful biomarkers for immunotherapy (both antibody-based and cellular). In this study, we designed a novel vaccine molecule, the Hantaan virus (HTNV) glycoprotein (GP) tandem Th epitope molecule (named the Gnc molecule), in silico. Subsequently, computer analysis was used to conduct a comprehensive and in-depth study of the various properties of the molecule and its effects as a vaccine molecule in the body. The Gnc molecule was designed for DNA vaccines and optimized with a lysosomal-targeting membrane protein (LAMP) strategy. The effects of GP-derived Th epitopes and multiepitope vaccines were initially verified in animals. Our research has resulted in the design of two vaccines based on effective antiviral immune targets. The effectiveness of molecular therapies has also been preliminarily demonstrated in silico and in laboratory animals, which lays a foundation for the application of a vaccines strategy in the field of antivirals.

Abstract Background Hand osteoarthritis (OA) is a prevalent disorder in the general population. Patients with hand OA often report symptoms of pain, stiffness, and functional limitations, which cause clinical burden and impact on quality of daily life. However, the efficacy of current therapies for hand OA is limited. Other therapies with better effects and less adverse events are in urgent need. Acupuncture is well known for analgesia and has been proved effective in treating basal thumb joint arthritis. This study aims to clarify the efficacy and safety of acupuncture treatment for clinical symptomatic improvement of hand OA. Methods This will be a sham-controlled, randomized, multi-center clinical trial. A total of 340 participants will be recruited and randomly allocated to either traditional acupuncture group or sham acupuncture group. All participants will receive 12 treatment sessions over 4 weeks and 2 follow-up assessments in the following 3 months at week 8 and week 16. The primary outcome will be the proportion of responders at week 5. Secondary outcomes will include visual analog scale, Australian Canadian Osteoarthritis Hand Index, Functional Index for hand OA, the number of symptomatic joints, hand grip strength and pinch strength, global assessment, the World Health Organization Quality of Life abbreviated version and expectations. Safety will be evaluated during the whole process of the trial. All outcomes will be analyzed following the intention-to-treat principle. Discussion This prospective trial will provide high-quality evidence on evaluating the efficacy and safety of acupuncture treatment for hand OA. Results of this trial might contribute in offering a new option to clinical recommendations. Trial registration ClinicalTrials.gov Identifier: NCT05267093. Registered 23 February 2022.

Background: Acupuncture can improve chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Ejaculation frequencies might impact the conditions of CP/CPPS. The present study aimed to explore the impact of different ejaculation frequencies on the effect of acupuncture among men with CP/CPPS. Methods: This was a secondary analysis of the data from a multicenter, randomized, clinical trial. Eligible participants were patients with moderate to severe CP/CPPS, who had taken 8-week acupuncture treatment, and followed until week 32. Participants fell into the category of 0–3, 4–7, or at least 8 according to their monthly ejaculation frequencies reported at baseline. The primary outcome was the proportion of responders, defined as men who reported at least 6 points reduction from baseline in the National Institute of Health-Chronic Prostatitis Symptom Index (NIHCPSI) total score at weeks 8 and 32. Results: 214 participants were included in this secondary analysis, of whom 42 reported a monthly ejaculation frequency of 0–3, 89 reported a frequency of 4–7, and 83 reported a frequency of at least 8. At week 8, 52.20% participants with an ejaculation frequency of 0–3 responded to the acupuncture treatment, 65.38% participants with a frequency of 4–7 responded, and 63.09% participants with a frequency of at least 8 responded. At week 32, 56.14%, 59.57%, and 68.36% participants responded in the three groups, respectively. No significant differences were observed between three groups (all P>0.05). Conclusion: Acupuncture can improve symptoms of CP/CPPS, regardless of ejaculation frequencies. Ejaculation frequencies may not affect the efficacy of acupuncture on CP/CPPS among Chinese men. Trial registration: ClinicalTrials.gov, NCT03213938

Abstract Ulcerative colitis (UC) is a non-specific inflammatory bowel disease that causes ulcers and erosions in the colonic mucosa and becomes chronic with cycles of amelioration and exacerbation. Because its exact etiology remains largely unclear, and the primary therapy is limited to symptomatic treatment, the development of new therapeutic agent for UC is highly desired. Because one of the disease pathogenesis is involvement of oxidative stress, it is likely that an appropriate antioxidant will be an effective therapeutic agent for UC. Our silicon (Si)-based agent, when ingested, allowed for stable and persistent generation of massive amounts of hydrogen in the gastrointestinal tract. We demonstrated the Si-based agent alleviated the mental symptom as well as the gastrointestinal symptoms, inflammation, and oxidation associated with dextran sodium sulfate-induced UC model through Hydrogen and antioxidant sulfur compounds. As the Si-based agent was effective in treating UC in the brain and large intestine of mice, it was considered to be capable of suppressing exacerbations and sustaining remission of UC.

Summary: Increasing pollution of heavy metals poses great risks to animals globally. Their survival likely relies on an ability to detect and avoid harmful heavy metal ions (HMIs). Currently, little is known about the neural mechanisms of HMI detection. Here, we show that Drosophila and related species of Drosophilidae actively avoid toxic HMIs at micromolar concentrations. The high sensitivity to HMIs is biologically relevant. Particularly, their sensitivity to cadmium is as high as that to the most bitter substance, denatonium. Detection of HMIs in food requires Gr66a+ gustatory neurons but is independent of bitter-taste receptors. In these neurons, the ionotropic receptors IR76b, IR25a, and IR7a are required for the perception of heavy metals. Furthermore, IR47a mediates the activation of a distinct group of non-Gr66a+ gustatory neurons elicited by HMIs. Together, our findings reveal a surprising taste quality represented by noxious metal ions.

Summary: The courtship ritual is a dynamic interplay between males and females. Courtship successfully leading to copulation is determined by the intention of both parties which is conveyed by complex action sequences. In Drosophila, the neural mechanisms controlling the female’s willingness to mate, or sexual receptivity, have only recently become the focus of investigations. Here, we report that pre-mating sexual receptivity in females requires activity within a subset of serotonergic projection neurons (SPNs), which positively regulate courtship success. Of interest, a male-derived sex peptide, SP, which was transferred to females during copulation acted to inhibit the activity of SPN and suppressed receptivity. Downstream of 5-HT, subsets of 5-HT7 receptor neurons played critical roles in SP-induced suppression of sexual receptivity. Together, our study reveals a complex serotonin signaling system in the central brain of Drosophila which manages the female’s desire to mate.

(1) Background and Purpose: Ebola virus (EBOV) is the causative agent of Ebola virus disease (EVD), which causes extremely high mortality and widespread epidemics. The only glycoprotein (GP) on the surface of EBOV particles is the key to mediating viral invasion into host cells. DNA vaccines for EBOV are in development, but their effectiveness is unclear. The lack of immune characteristics resides in antigenic MHC class II reactivity. (2) Methods: We selected MHC-II molecules from four human leukocyte antigen II (HLA-II) superfamilies with 98% population coverage and eight mouse H2-I alleles. IEDB, NetMHCIIpan, SYFPEITHI, and Rankpep were used to screen MHC-II-restricted epitopes with high affinity for EBOV GP. Further immunogenicity and conservation analyses were performed using VaxiJen and BLASTp, respectively. EpiDock was used to simulate molecular docking. Cluster analysis and binding affinity analysis of EBOV GP epitopes and selected MHC-II molecules were performed using data from NetMHCIIpan. The selective GP epitopes were verified by the enzyme-linked immunospot (ELISpot) assay using splenocytes of BALB/c (H2d), C3H, and C57 mice after DNA vaccine pVAX-GPEBO immunization. Subsequently, BALB/c mice were immunized with Protein-GPEBO, plasmid pVAX-GPEBO, and pVAX-LAMP/GPEBO, which encoded EBOV GP. The dominant epitopes of BALB/c (H-2-I-AdEd genotype) mice were verified by the enzyme-linked immunospot (ELISpot) assay. It is also used to evaluate and explore the advantages of pVAX-LAMP/GPEBO and the reasons behind them. (3) Results: Thirty-one HLA-II-restricted and 68 H2-I-restricted selective epitopes were confirmed to have high affinity, immunogenicity, and conservation. Nineteen selective epitopes have cross-species reactivity with good performance in MHC-II molecular docking. The ELISpot results showed that pVAX-GPEBO could induce a cellular immune response to the synthesized selective peptides. The better immunoprotection of the DNA vaccines pVAX-LAMP/GPEBO coincides with the enhancement of the MHC class II response. (4) Conclusions: Promising MHC-II-restricted candidate epitopes of EBOV GP were identified in humans and mice, which is of great significance for the development and evaluation of Ebola vaccines.

Abstract Background The crosstalk between the ubiquitin‐proteasome and the immune system plays an important role in the health and pathogenesis of viral infection. However, there have been few studies of ubiquitin activation in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Methods We investigated the effect of ubiquitination on SARS‐CoV‐2 infection and patient prognosis by integrating published coronavirus disease 2019 (COVID‐19) multi‐transcriptome data and bioinformatics methods. Results The differential expression of COVID‐19 samples revealed changed ubiquitination in most solid and hollow organs, and it was activated in lymphatic and other immune tissues. In addition, in the respiratory system of COVID‐19 patients, the immune response was mainly focused on the alveoli, and the expression of ubiquitination reflected increasing immune infiltration. Ubiquitination stratification could significantly differentiate patients' prognosis and inflammation levels through the general transcriptional analysis of the peripheral blood of patients with COVID‐19. Moreover, high ubiquitination levels were associated with a favourable prognosis, low inflammatory response, and reduced mechanical ventilation and intensive care unit. Moreover, high ubiquitination promoted a beneficial immune response while inhibiting immune damage. Finally, prognostic stratification and biomarker screening based on ubiquitination traits played an important role in clinical management and drug development. Conclusion Ubiquitination characteristics provides new ideas for clinical intervention and prognostic guidance for COVID‐19 patients.

In this paper, two iron salts, ferrous chloride (FeCl2) and ferric chloride (FeCl3), are directly added into an aeration tank for phosphorus removal, and their effects on the biochemical system are studied; the water quality parameters such as pH and alkalinity are also investigated. The extent of influence of the added iron salts on the pH and alkalinity of aerated solutions is demonstrated to be FeCl3 > FeCl2. When the dosage of iron ions is 20 mg/L, the decrease in pH and alkalinity caused by FeCl3 is 0.5 and 65 mg/L, which is higher than FeCl2 by 2% and 26%. The initial phosphorus removal effect of FeCl2 is worse than that of FeCl3, but after continued aeration and oxidation, the phosphorus removal effect of FeCl2 can be improved; however, the final phosphorus removal effect is basically the same as that of FeCl3 added directly. The results show that FeCl2 is preferred when iron salt is added directly into the aeration tank to remove phosphorus. The proposed scheme can reduce the effect of iron salts on the alkalinity of the biochemical system on the premise of ensuring the phosphorus removal effect of the system, and is conducive to ensuring the stable operation of the biochemical system.

BackgroundImpaired glucose tolerance (IGT) is associated with being overweight/obesity and is a powerful risk factor for the disease of diabetes. In addition to lifestyle intervention that shows limited clinical application, acupuncture treatment has been a feasible treatment method for IGT in clinical practice. However, the effectiveness of acupuncture treatment has not been proved in evidence-based practice. Therefore, we design a multicenter randomized controlled trial to evaluate the efficacy and safety of acupuncture treatment for IGT in people with overweight/obesity.MethodsThe trial will be conducted at hospitals in three different sites in China. A total of 196 participants will be recruited and randomly assigned at a ratio of 1:1 to either to the acupuncture group or the sham acupuncture (SA) group. Both groups will receive 30 sessions of treatment for 12 consecutive weeks and will be provided with lifestyle intervention and a 24-week follow-up. The primary outcome will be change in the baseline value of 2-h blood glucose (2hPG) on the 12th week. Additionally, the expectancy of acupuncture, blinding, and safety will also be assessed. All statistical analyses will be performed by two-sided test, and a p-value of less than 0.05 will be considered statically significant.DiscussionThis study aims to provide quantitative clinical evidence of acupuncture effectiveness and safety in treating IGT in people who are overweight/obese.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT05347030].

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

BackgroundThe association between preterm birth and neurodevelopmental delays have been well examined, however, reliable estimates for the full range of gestational age (GA) are limited, and few studies explored the impact of post-term birth on child development.ObjectiveThis study aimed to examine the long-term neuropsychological outcomes of children born in a full range of GA with a national representative sample in China.MethodsIn this retrospective population-based cohort study, a total of 137,530 preschoolers aged 3–5 years old (65,295/47.5% females and 72,235/52.5% males) were included in the final analysis. The Ages and Stages Questionnaires-Third Edition (ASQ-3) was completed by parents to evaluate children's neurodevelopment. The associations between GA and neurodevelopment were analyzed by a generalized additive mixed model with thin plate regression splines. Logistic regression was also conducted to examine the differences in children's development with different GAs.ResultsThere was a non-linear relationship between GA and children's neurodevelopmental outcomes with the highest scores at 40 weeks gestational age. The adjusted risks of GAs (very and moderately preterm, late-preterm, early-term, and post-term groups) on suspected developmental delays were observed in communication (OR were 1.83, 1.28, 1.13, and 1.21 respectively, each p < 0.05), gross motor skill (OR were 1.67, 1.38, 1.10, and 1.05 respectively, each p < 0.05), and personal social behavior (OR were 1.01, 1.36, 1.12, and 1.18 respectively, each p < 0.05). The adjusted OR of very and moderately preterm, late-preterm, and early-term were observed in fine motor skills (OR were 1.53, 1.22, and 1.09 respectively, each p < 0.05) and problem-solving (OR were 1.33, 1.12, and 1.06 respectively, each p < 0.05).ConclusionGAs is a risk factor for neurodevelopmental delays in preschoolers after controlling for a wide range of covariates, and 40–41 weeks may be the ideal delivery GA for optimal neurodevelopmental outcomes. Close observation and monitoring should be considered for early- and post-term born children as well as pre-term children.

BackgroundOpioid-induced constipation (OIC) is one of the most prevalent adverse events associated with cancer patients who receive opioid analgesics for moderate to severe pain. Acupuncture may be an effective treatment for OIC. We designed this trial to assess the efficacy and safety of electroacupuncture for OIC in cancer patients.MethodsThis is a multicenter, sham-controlled, parallel-group, subject- and assessor-blinded randomized trial. A total of 100 cancer patients with OIC will be randomly assigned to either the electroacupuncture group or the sham electroacupuncture group at a ratio of 1:1. Patients in each group will receive a total of 24-session treatment over 8 weeks, three sessions a week and 30 min each session. Thereafter, patients will be followed up for another 8 weeks. The primary outcome will be the proportion of responders, defined as a patient who has ≥3 spontaneous bowel movements (SBMs)/wk and ≥ increase of 1 SBM from baseline simultaneously for at least 6 out of 8 weeks of the treatment period. The secondary outcomes will include the mean weekly SBMs and complete spontaneous bowel movements, the mean Bristol Stool Form Scale score for stool consistency, the mean score for straining of SBM, the total and subscale scores of Patient Assessment of Constipation-Symptom questionnaires, and the total and subscale scores of Patient Assessment of Constipation-Quality of Life questionnaire. Patients' global assessment of treatment effectiveness, patients' expectation toward the effectiveness of acupuncture and safety of acupuncture will also be assessed. All efficacy analyses will be performed in the intention-to-treat population.DiscussionTo improve the adherence to intervention protocols, the majority of the participants will be recruited from an inpatient setting. The results will help to determine the clinical effects and safety of electroacupuncture for the treatment of OIC among patients with cancer.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT03797586, registered on 4 January 2019, https://clinicaltrials.gov/ct2/show/NCT03797586.

BackgroundPost-hemorrhoidectomy pain (PHP) remains one of the complications of hemorrhoidectomy and can delay patient's recovery. Current clinical guideline on PHP remains skeptical on the effectiveness of acupuncture, which has been applied for PHP in practice with inconsistent evidence.ObjectivesThis systematic review aimed to evaluate the effectiveness of acupuncture on PHP by reviewing existing evidence.MethodsNine databases such as PubMed and Embase were searched for randomized controlled trials (RCTs) from inception to 30th September 2021. The outcome measures on pain level after hemorrhoidectomy, dose of rescue analgesic drug used, quality of life, adverse events, etc., were extracted and analyzed in a narrative approach.ResultsFour RCTs involving 275 patients were included in the analysis. One study showed that the visual analog scale (VAS) score was significantly lower in the electro-acupuncture (EA) group compared to that in the sham acupuncture (SA) group at 6, 24 h after surgery and during the first defecation (p < 0.05). Similar trends were found in the verbal rating scale (VRS) and Wong-Baker Faces scale (WBS) score but at different time points. Another study also found EA was effective on relieving pain during defecation up to 7 days after surgery when compared with local anesthetics (p < 0.05). However, two studies evaluating manual acupuncture (MA) compared with active medications for PHP showed inconsistent results on effectiveness. Variability was found in the quality of included studies.ConclusionsAlthough benefit of acupuncture on PHP, especially EA on defecation after surgery, was observed at some time points, evidence on effectiveness of acupuncture on PHP was not conclusive.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, PROSPERO, identifier: CRD42018099961.

Robust social attraction in fruit flies relies on two prominent senses, vision and olfaction, which converge to central brain neurons. The neurons of the γ lobe of the mushroom bodies integrate sensory information and modulate social affinity.

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common condition secondary to degenerative changes. Acupuncture may be effective for treating DLSS. However, there is a lack of sufficient evidence showing the efficacy of acupuncture. The aim of this study is to assess the efficacy and safety of acupuncture for relieving neurogenic claudication in patients with DLSS. Methods A total of 196 patients will be randomly assigned to an acupuncture group or a sham acupuncture group at a ratio of 1:1. Patients will receive 18 sessions of treatment for 6 continuous weeks. The primary outcome will be the change in the Modified Roland-Morris Disability Questionnaire score from baseline to week 6. The secondary outcomes will include the change in the scores from baseline for the Numerical Rating Scale, Swiss Spinal Stenosis Questionnaire, and Anxiety and Depression Scale. Additionally, the expectancy of acupuncture, blinding, and safety will also be assessed. All analysis will be performed based on intention-to-treat. Discussion The aim of this study is to evaluate the efficacy and safety of acupuncture for the treatment of neurogenic claudication in patients with DLSS. A limitation of this study is that acupuncturists cannot be blinded according to the characteristics of acupuncture, which may introduce some bias. Trial registration ClinicalTrials.gov NCT03784729 and protocol ID 2018-161-KY. Registered on 18 December 2018.

Abstract Background Among women suffering from urinary incontinence (UI), about one-third are diagnosed with mixed urinary incontinence (MUI), among which urgency-predominant MUI causes more shame and inconvenience to patients. The treatments for urgency-predominant MUI have limited guidelines and previous studies have indicated that electroacupuncture (EA) might be a safe and effective option. The present study aims to evaluate the effect of EA on women with urgency-predominant MUI. Methods The study is a multicentered, three-armed, non-inferiority randomized clinical trial. A total of 282 female patients with urgency-predominant MUI will be randomly divided into three groups, namely the EA group, sham electroacupuncture (SA) group, and solifenacin treatment group at a ratio of 1:1:1. Thirty-six sessions of acupuncture treatment over 12 weeks and solifenacin treatment over 36 weeks will be provided. The primary outcome will be the decrease of urgency urinary incontinence (UUI) episodes after 12-week treatment. Secondary outcomes will include changes in incontinence episodes, urinary frequency, urgency, severity of symptoms, and influence on quality of life, assessed using the International Consultation on Incontinence Questionnaire Short Form (ICIQ SF) and Overactive Bladder Questionnaire Short Form (OAB-q SF). All patients will be continuously followed up until week 36 and their allocations will be statistically analyzed. Discussion Though placebo of solifenacin is rather difficult to access and all patients in the trial cannot be fully blinded, the present study will serve as an introduction of three-armed, randomized, non-inferiority, and sham acupuncture-controlled clinical trials to the acupuncture field, in an attempt to compare the effects of EA and solifenacin for treating women with urgency-predominant MUI. Trial registration ClinicalTrials.gov: NCT03787654. Registered on 25 December, 2018.

BackgroundIncreasing evidence shows that the ubiquitin–proteasome system has a crucial impact on lung adenocarcinoma. However, reliable prognostic signatures based on ubiquitination and immune traits have not yet been established.MethodsBioinformatics was performed to analyze the characteristic of ubiquitination in lung adenocarcinoma. Principal component analysis was employed to identify the difference between lung adenocarcinoma and adjacent tissue. The ubiquitin prognostic risk model was constructed by multivariate Cox regression and least absolute shrinkage and selection operator regression based on the public database The Cancer Genome Atlas, with evaluation of the time-dependent receiver operating characteristic curve. A variety of algorithms was used to analyze the immune traits of model stratification. Meanwhile, the drug response sensitivity for subgroups was predicted by the “pRRophetic” package based on the database of the Cancer Genome Project.ResultsThe expression of ubiquitin genes was different in the tumor and in the adjacent tissue. The ubiquitin model was superior to the clinical indexes, and four validation datasets verified the prognostic effect. Additionally, the stratification of the model reflected distinct immune landscapes and mutation traits. The low-risk group was infiltrating plenty of immune cells and highly expressed major histocompatibility complex and immune genes, which illustrated that these patients could benefit from immune treatment. The high-risk group showed higher mutation and tumor mutation burden. Integrating the tumor mutation burden and the immune score revealed the patient’s discrepancy between survival and drug response. Finally, we discovered that the drug targeting ubiquitin and proteasome would be a beneficial prospective treatment for lung adenocarcinoma.ConclusionThe ubiquitin trait could reflect the prognosis of lung adenocarcinoma, and it might shed light on the development of novel ubiquitin biomarkers and targeted therapy for lung adenocarcinoma.

Hantaan virus (HTNV), the causative pathogen of hemorrhagic fever with renal syndrome (HFRS), is a negative RNA virus belonging to the Orthohantaviridae family. HTNV envelope glycoprotein (GP), encoded by the genomic medium segment, is immunogenic and is therefore a promising vaccine candidate. Major histocompatibility complex class I (MHC-I) epitopes derived from HTNV has been extensively studied, but little is known of MHC-II epitopes. In silico predictions based on four databases indicated that the full-length HTNV GP has 1121 15-mer epitopes, of which 289 had a high score for binding to the human and murine MHC-II superfamily. It found that epitope ILTVLKFIANIFHTS could potentially bind most MHC-II molecules covering human and murine haplotypes. Dominant epitopes were validated by enzyme-linked immunospot assay of splenocytes from immunized mice; 6 of 10 epitopes supported the predictions including TATYSIVGPANAKVP, TKTLVIGQCIYTITS, FSLLPGVAHSIAVEL, CETYKELKAHGVSCP, CGLYLDRLKPVGSAY, and NLGENPCKIGLQTSS. Conservation analysis of dominant epitopes revealed host–virus interactions without geographic stratification, thus meeting the requirements of candidate vaccines for large-population prophylaxis. These findings provide insight into hantavirus antigenicity and suggest that vaccines targeting MHC-II could provide immune protection in large population to complement symptomatic therapies for the treatment of HFRS.

Introduction Evidence specific for stress-predominant mixed urinary incontinence is still lacking at present, and acupuncture may relieve the symptoms. We plan to conduct this multi-centre, three-armed, randomised controlled trial to investigate the efficacy and safety of electroacupuncture among women with stress-predominant mixed urinary incontinence.Methods and analysis The trial will be conducted at five hospitals in China. Two hundred thirty-two eligible women will be randomly assigned (2:1:1) to the electroacupuncture, sham electroacupuncture or waiting-list group to receive either 24-session acupuncture/sham acupuncture treatment over 8 weeks and 24-week follow-up or 20-week watchful waiting. The primary outcome is the proportion of participants with at least 50% reduction in mean 24-hour stress incontinence episode frequencies from baseline to week 8. The outcome will be analysed with the intention to treatpopulation (defined as participants randomised) with a two-sided p value of less than 0.05 considered significant.Ethics and dissemination The protocol has been approved by Guang’anmen Hospital Institutional Review Board (2019-241-KY). Detailed information of the trial will be informed to the participants, and written informed consent will be obtained from every participant. Results of the trial are expected to be published in a peer-reviewed journal.Trial registration number ClinicalTrials.gov Registry (NCT04299932).

Hepatocellular carcinoma (HCC) patients are mostly diagnosed at an advanced stage, resulting in systemic therapy and poor prognosis. Therefore, the identification of a novel treatment target for HCC is important. B-cell receptor-associated protein 31 (BAP31) has been identified as a cancer/testis antigen; however, BAP31 function and mechanism of action in HCC remain unclear. In this study, BAP31 was demonstrated to be upregulated in HCC and correlated with the clinical stage. BAP31 overexpression promoted HCC cell proliferation and colony formation in vitro and tumor growth in vivo. RNA-sequence (RNA-seq) analysis demonstrated that serpin family E member 2 (SERPINE2) was downregulated in BAP31-knockdown HCC cells. Coimmunoprecipitation and immunofluorescence assays demonstrated that BAP31 directly binds to SERPINE2. The inhibition of SERPINE2 significantly decreased the BAP31-induced cell proliferation and colony formation of HCC cells and phosphorylation of Erk1/2 and p38. Moreover, multiplex immunohistochemistry staining of the HCC tissue microarray showed positive associations between the expression levels of BAP31, SERPINE2, its downstream gene LRP1, and a tumor proliferation marker, Ki-67. The administration of anti-BAP31 antibody significantly inhibited HCC cell xenograft tumor growth in vivo. Thus, these findings suggest that BAP31 promotes tumor cell proliferation by stabilizing SERPINE2 and can serve as a promising candidate therapeutic target for HCC.

Summary: Traumatic experiences generate stressful neurological effects in the exposed persons and animals. Previous studies have demonstrated that in many species, including Drosophila, the defeated animal has a higher probability of losing subsequent fights. However, the neural basis of this “loser effect” is largely unknown. We herein report that elevated serotonin (5-HT) signaling helps a loser to overcome suppressive neurological states. Coerced activation of 5-HT neurons increases aggression in males and promotes losers to both vigorously re-engage in fights and even defeat the previous winners and regain mating motivation. P1 neurons act upstream and 5-HT1B neurons in the ellipsoid body act downstream of 5-HT neurons to arouse losers. Our results demonstrate an ancient neural mechanism of regulating depressive behavioral states after distressing events.

Cystatin C is an important cysteine protease inhibitor in the human body and is proposed as a new indicator of glomerular filtration rate for the detection of kidney damage. In this article, we report an ultra-sensitive, simple, and rapid chemiluminescence immunoassay method for cystatin C detection using functionalized mesoporous silica nanoparticles. After a three step hydrolysis, the amino-functionalized MSN encapsulating dye resulted in a hydrophobic environment for fixing the dye and amino groups for biological modification. The NaIO4 immobilization method maintained the activity of the antibody notably well. The sandwich immunoassay using two monoclonal antibodies was chosen for its selectivity. The analysis demonstrated that the detection upper was 0.0029 ng/mL and linear relationship within the range of 0.0035–0.5 ng/mL (R2 = 0.9936). The relative standard deviation (RSD) for 11 parallel measurements of 0.25 ng/mL CysC was 4.7%. The automated chemiluminescence analyzer could detect 96 wells continuously. The results demonstrated that this method is ultra-sensitive, simple, and rapid for detecting cystatin C.

Prostate cancer is a common malignancy in men worldwide. Lysophosphatidic acid receptor 1 (LPAR1) is a critical gene and it mediates diverse biologic functions in tumor. However, the correlation between LPAR1 and prognosis in prostate cancer, as well as the potential mechanism, remains unclear. In the present study, LPAR1 expression analysis was based on The Cancer Genome Atlas (TCGA) and the Oncomine database. The correlation of LPAR1 on prognosis was also analyzed based on R studio. The association between LPAR1 and tumor-infiltrating immune cells were evaluated in the Tumor Immune Estimation Resource site, ssGSEA, and MCPcounter packages in R studio. Gene Set Enrichment Analysis and Gene Ontology analysis were used to analyze the function of LPAR1. TCGA datasets and the Oncomine database revealed that LPAR1 was significantly downregulated in prostate cancer. High LPAR1 expression was correlated with favorable overall survival. LPAR1 was involved in the activation, proliferation, differentiation, and migration of immune cells, and its expression was positively correlated with immune infiltrates, including CD4+ T cells, B cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, and natural killer cells. Moreover, LPAR1 expression was positively correlated with those chemokine/chemokine receptors, indicating that LPAR1 may regulate the migration of immune cells. In summary, LPAR1 is a potential prognostic biomarker and plays an important part in immune infiltrates in prostate cancer.

Cervical cancer (CC) is the most common malignant tumor in gynecology, and metastasis is an important cause of patient death. MiRNAs (microRNAs) have been found to play key roles in cervical cancer metastasis, but the effect of miR-362-3p in CC is unclear. This study aimed to investigate the role of miR-362-3p in cervical cancer migration and invasion. We compared the expression levels of miR-362-3p in cervical cancer tissues and adjacent normal cervical tissues. In CC tissues, miR-362-3p expression was significantly down-regulated, which is related to the cancer stage and patient survival. MiR-362-3p can effectively inhibit the migration and invasion of cervical cancer cells. The dual-luciferase reporter assay results showed that BCAP31 (B cell receptor associated protein 31) is a direct target protein of miR-362-3p. The results of the immunohistochemical examination of clinical tissue samples showed that BCAP31 was abnormally highly expressed in cervical cancer, which was positively correlated with the clinical stage. BCAP31 knockdown exerted similar effects as miR-362-3p overexpression. Further GSEA analysis showed that BCAP31 may participate in multiple biological processes, such as protein transport, metabolism, and organelle organization. Our results suggest that miR-362-3p inhibits migration and invasion via directly targeting BCAP31 in cervical cancer, and restoring miR-362-3p levels may be a new treatment strategy for cervical cancer in the future.

Water is essential for the survival of terrestrial animals. Animals obtain water from their food, from metabolism and, more importantly, by drinking. It is therefore vital for dehydrated animals to efficiently locate water sources in the wild. Traditional paradigm for studying the genetic basis of humidity sensation and preference use an apparatus consisting of two chambers providing a binary choice between flows of dry and moist air that maintain steep humidity gradients. Here, we introduce a novel assay to study water-seeking behavior (hygrotaxis) in Drosophila, in which dehydrated flies detect a humidity gradient and rapidly aggregate near an inaccessible water source. Our previous work using this method demonstrated that hygrotactic behavior relies on both specific sensory organs and central brain neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have been proved to be T cell-mediated autoimmune diseases. Recent researches indicate that humoral immunity is also involved in the pathogenesis of these disorders. T follicular helper (Tfh) cells are critical for B cell differentiation and antibody production. However, the role of Tfh cells in MS and EAE remains unclear. Here, we found elevated frequencies of CD4+CXCR5+PD-1+ Tfh-like cells in both MS patients and EAE. In EAE mice, Tfh-like cells, together with B cells, were found in the ectopic lymphoid structures in spinal cords. Moreover, Tfh-like cells promoted the antibody production via IL-21/IL-21R and CD40 ligand/CD40 interaction and the synergy effect of STAT3 and non-canonical NF-κB signaling pathway inside B cells. Moreover, adoptive transfer of Tfh-like cells could increase the severity and delay the remission of EAE. In conclusion, our data indicate that Tfh-like cells contribute to the pathogenesis of EAE.

Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein overexpressed in human epithelioma but with relatively low expression in normal epithelial tissues. To exploit this differential expression pattern for targeted cancer therapy, an EpCAM-targeted immunotoxin was developed and its antitumor activity was investigated in vitro. An immunotoxin (scFv2A9-PE or APE) was constructed by genetically fusing a truncated form (PE38KDEL) of Pseudomonas aeruginosa exotoxin with an anti-EpCAM single-chain variable fragment (scFv). ELISA and flow cytometry were performed to verify immunotoxin (scFv2A9-PE or APE) antigen-binding activity with EpCAM. Cytotoxicity was measured by MTT assay. Confocal microscopy was used to observe its cellular localization. The results of ELISA and flow cytometry revealed that the immunotoxin efficiently recognized recombinant and natural EpCAM. Its antigen-binding activity was relatively lower than 2A9. MTT assay confirmed potent reduction in EpCAM-positive HHCC (human hepatocellular carcinoma) cell viability (IC50 50 pM). Immunofluorescence revealed that the immunotoxin localized to endoplasmic reticulum 24 h later. In conclusion, we described the development of an EpCAM-targeted immunotoxin with potent activity against tumor cells, which may lay the foundation for future development of therapeutic antibody for the treatment of EpCAM-positive tumors.