bluuebunny/crossref_metadata_2025 huggingface dataset:
Metadynamics simulations leveraged by statistical analyses and artificial intelligence-based tools to inform the discovery of G protein-coupled receptor ligands
Authors: Salas-Estrada Leslie , Fiorillo Bianca , Filizola Marta
Published: December 2022

G Protein-Coupled Receptors (GPCRs) are a large family of membrane proteins with pluridimensional signaling profiles. They undergo ligand-specific conformational changes, which in turn lead to the differential activation of intracellular signaling proteins and the consequent triggering of a variety of biological responses. This conformational plasticity directly impacts our understanding of GPCR signaling and therapeutic implications, as do ligand-specific kinetic differences in GPCR-induced transducer activation/coupling or GPCR-transducer complex stability. High-resolution experimental structures of ligand-bound GPCRs in the presence or absence of interacting transducers provide important, yet limited, insights into the highly dynamic process of ligand-induced activation or inhibition of these receptors. We and others have complemented these studies with computational strategies aimed at characterizing increasingly accurate metastable conformations of GPCRs using a combination of metadynamics simulations, state-of-the-art algorithms for statistical analyses of simulation data, and artificial intelligence-based tools. This minireview provides an overview of these approaches as well as lessons learned from them towards the identification of conformational states that may be difficult or even impossible to characterize experimentally and yet important to discover new GPCR ligands.
Diabetes mellitus with a duration of 26 years combined with IgA nephropathy: A case report and literature review
Authors: Gou Yan-Li , Zhang Ya-Pu , Xu Yang , Li Jian-Dong , Huang Yang , Chen Hang
Published: December 2022

Background

The incidence of diabetes mellitus (DM) in China is increasing yearly and has become a major problem plaguing national public health. The diagnosis of diabetic kidney disease (DKD) is based primarily on clinical criteria, and most patients do not receive a formal evaluation by renal biopsy; thus, misdiagnosis and underdiagnosis are common. The incidence of non-diabetic kidney disease (NDKD) is also higher in those with DM. To date, many cases of IgA nephropathy (IgAN) among those with DKD have been reported, while cases of IgAN in patients with long-duration DM who did not develop DKD are less commonly reported.

Case description

A 70-year-old male patient with a diabetes duration of 26 years had proteinuria for one year. The clinical manifestations of nephrotic syndrome and IgAN were confirmed by renal biopsy. The patient received targeted treatment for three years with partial alleviation of proteinuria.

Conclusion

Renal biopsy might aid in the definitive diagnosis of DKD, NDKD, and NDKD combined with DKD. Precise therapy based on renal pathology might help to improve outcomes in the kidney.
Behavioral strategies of prehistoric and historic children from dental microwear texture analysis
Authors: Estalrrich Almudena , Krueger Kristin L.
Published: December 2022

Introduction

Reconstructing the dietary and behavioral strategies of our hominin ancestors is crucial to understanding their evolution, adaptation, and overall way of life. Teeth in general, and dental microwear specifically, provide a means to examine these strategies, with posterior teeth well positioned to tell us about diet, and anterior teeth helping us examine non-dietary tooth-use behaviors. Past research predominantly focused on strategies of adult individuals, leaving us to wonder the role children may have played in the community at large. Here we begin to address this by analyzing prehistoric and historic children through dental microwear texture analysis of deciduous anterior teeth.

Materials and Methods

Four sample groups were used: Neandertals (N = 8), early modern humans (N = 14), historic Egyptians from Amarna (N = 19) and historic high-Arctic Inuit from Point Hope, Alaska (N = 6). Anterior deciduous teeth were carefully cleaned, molded, and cast with high-resolution materials. Labial surfaces were scanned for dental microwear textures using two white-light confocal microscopes at the University of Arkansas, and a soft filter applied to facilitate data comparisons.

Results and Discussion

Results show that dental microwear texture analysis successfully differentiated the samples by all texture variables examined (anisotropy, complexity, scale of maximum complexity, and two variants of heterogeneity). Interestingly, the Neandertal and Point Hope children had similar mean values across all the texture variables, and both groups were significantly different from the Amarna, Egyptian children. These differences suggest diversity in abrasive load exposure and participation in non-dietary anterior tooth-use behaviors. Further analyses and an expanded sample size will help to strengthen the data presented here, but our results show that some prehistoric and historic children took part in similar behaviors as their adult counterparts.
Computer-aided drug design combined network pharmacology to explore anti-SARS-CoV-2 or anti-inflammatory targets and mechanisms of Qingfei Paidu Decoction for COVID-19
Authors: Wang Zixuan , Zhan Jiuyu , Gao Hongwei
Published: December 2022

Introduction

Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. Severe cases of COVID-19 are characterized by an intense inflammatory process that may ultimately lead to organ failure and patient death. Qingfei Paidu Decoction (QFPD), a traditional Chines e medicine (TCM) formula, is widely used in China as anti-SARS-CoV-2 and anti-inflammatory. However, the potential targets and mechanisms for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects remain unclear.

Methods

In this study, Computer-Aided Drug Design was performed to identify the antiviral or anti-inflammatory components in QFPD and their targets using Discovery Studio 2020 software. We then investigated the mechanisms associated with QFPD for treating COVID-19 with the help of multiple network pharmacology approaches.

Results and discussion

By overlapping the targets of QFPD and COVID-19, we discovered 8 common targets (RBP4, IL1RN, TTR, FYN, SFTPD, TP53, SRPK1, and AKT1) of 62 active components in QFPD. These may represent potential targets for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects. The result showed that QFPD might have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation-related pathways. Our work will promote the development of new drugs for COVID-19.
Vaccine-based clinical protection against SARS-CoV-2 infection and the humoral immune response: A 1-year follow-up study of patients with multiple sclerosis receiving ocrelizumab
Authors: Räuber Saskia , Willison Alice , Korsen Melanie , Kölsche Tristan , Golombeck Kristin S. , Plaack Benedikt , Schüller Julia , Huntemann Niklas , Rolfes Leoni , Schroeter Christina B. , Nelke Christopher , Regner-Nelke Liesa , Förster Moritz , Ringelstein Marius , Barnett Michael Harry , Hartung Hans-Peter , Aktas Orhan , Albrecht Philipp , Ruck Tobias , Melzer Nico , Meuth Sven G. , Kremer David
Published: December 2022

Introduction

Given the varying severity of coronavirus disease 2019 (COVID-19) and the rapid spread of Severe-Acute-Respiratory-Syndrome-Corona-Virus-2 (SARS-CoV-2), vaccine-mediated protection of particularly vulnerable individuals has gained increasing attention during the course of the pandemic.

Methods

We performed a 1-year follow-up study of 51 ocrelizumab-treated patients with multiple sclerosis (OCR-pwMS) who received COVID-19 vaccination in 2021. We retrospectively identified 37 additional OCR-pwMS, 42 pwMS receiving natalizumab, 27 pwMS receiving sphingosine 1-phosphate receptor modulators, 59 pwMS without a disease-modifying therapy, and 61 controls without MS (HC). In OCR-pwMS, anti-SARS-CoV-2(S)-antibody titers were measured prior to the first and after the second, third, and fourth vaccine doses (pv2/3/4). The SARS-CoV-2-specific T cell response was analyzed pv2. SARS-CoV-2 infection status, COVID-19 disease severity, and vaccination-related adverse events were assessed in all pwMS and HC.

Results

We found a pronounced and increasing anti-SARS-CoV-2(S)-antibody response after COVID-19 booster vaccinations in OCR-pwMS (pv2: 30.4%, pv3: 56.5%, and pv4 90.0% were antibody positive). More than one third of OCR-pwMS without detectable antibodies pv2 developed positive antibodies pv3. 23.5% of OCR-pwMS had a confirmed SARS-CoV-2 infection, of which 84.2% were symptomatic. Infection rates were comparable between OCR-pwMS and control groups. None of the pwMS had severe COVID-19. An attenuated humoral immune response was not associated with a higher risk of SARS-CoV-2 infection.

Discussion

Additional COVID-19 vaccinations can boost the humoral immune response in OCR-pwMS and improve clinical protection against COVID-19. Vaccines effectively protect even OCR-pwMS without a detectable COVID-19 specific humoral immune response, indicating compensatory, e.g., T cell-mediated immunological mechanisms.
Defective DNA polymerase beta invoke a cytosolic DNA mediated inflammatory response
Authors: Zhao Shengyuan , Goewey Ruiz Julia A. , Sebastian Manu , Kidane Dawit
Published: December 2022

Base excision repair (BER) has evolved to maintain the genomic integrity of DNA following endogenous and exogenous agent induced DNA base damage. In contrast, aberrant BER induces genomic instability, promotes malignant transformation and can even trigger cancer development. Previously, we have shown that deoxyribo-5′-phosphate (dRP) lyase deficient DNA polymerase beta (POLB) causes replication associated genomic instability and sensitivity to both endogenous and exogenous DNA damaging agents. Specifically, it has been established that this loss of dRP lyase function promotes inflammation associated gastric cancer. However, the way that aberrant POLB impacts the immune signaling and inflammatory responses is still unknown. Here we show that a dRP lyase deficient variant of POLB (Leu22Pro, or L22P) increases mitotic dysfunction associated genomic instability, which eventually leads to a cytosolic DNA mediated inflammatory response. Furthermore, poly(ADP-ribose) polymerase 1 inhibition exacerbates chromosomal instability and enhances the cytosolic DNA mediated inflammatory response. Our results suggest that POLB plays a significant role in modulating inflammatory signaling, and they provide a mechanistic basis for future potential cancer immunotherapies.
Prognostic value of TMEM59L and its genomic and immunological characteristics in cancer
Authors: Shi Chang , Zhang Lizhi , Chen Dan , Wei Hong , Qi Wenjing , Zhang Pengxin , Guo Huiqi , Sun Lei
Published: December 2022

Background

TMEM59L is a newly discovered transmembrane protein; its functions in cancer remain unknown. This study was designed to reveal the prognostic value and the functional role of TMEM59L in cancer.

Methods

The gene expression profiles, methylation data, and corresponding clinical data of TMEM59L were retrieved from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression database. Survival analysis was employed to calculate the pan-cancer prognostic value of TMEM59L. The correlation between TMEM59L expression and tumor immune microenvironment, as well as DNA methylation dynamics and genomic heterogeneity across cancers were assessed based on data from TCGA.

Results

Our findings revealed that distinct differences of TMEM59L mRNA expression were observed in different cancer types and that higher TMEM59L expression was observed in the advanced pathological stage and associated with worse prognosis in kidney renal papillary cell carcinoma, bladder urothelial carcinoma, colon adenocarcinoma, and kidney renal clear cell carcinoma. Pathway analysis indicated that TMEM59L exerted a key influence in cancer development and in immune- and cancer-associated pathways such as epithelial–mesenchymal transition and TGF-β signaling. Moreover, correlation analysis hinted at a negative correlation of TMEM59L expression with CD8 T cells, activated CD4 T cells, and several immunomodulators, including IDO1, TIGIT, PD-L1, CTLA-4, and BTLA in various cancers. Survival analysis indicated that the hypermethylation of TMEM59L gene was associated with longer survival times. A significant correlation was also observed between TMEM59L expression and immunophenoscore, homologous recombination deficiency, loss of heterozygosity, tumor stemness score, and neoantigens in various cancers. Importantly, we also identified numerous potential agents that may target TMEM59L.

Conclusion

Our study revealed the prognostic value as well as the genomic and immunological characteristics of TMEM59L in cancers, highlighting the promising potential for TMEM59L as a prognostic cancer biomarker and a therapeutic target.
Hcp1-loaded staphylococcal membrane vesicle vaccine protects against acute melioidosis
Authors: Zhu Keting , Li Gang , Li Jia , Zheng Mingxia , Peng Xiaohui , Rao Yifan , Li Ming , Zhou Renjie , Rao Xiancai
Published: December 2022

Burkholderia pseudomallei is the causal agent of melioidosis, a deadly tropical infectious disease that lacks a vaccine. On the basis of the attenuated Staphylococcus aureus RN4220-Δagr (RN), we engineered the RN4220-Δagr/pdhB-hcp1 strain (RN-Hcp1) to generate B. pseudomallei hemolysin-coregulated protein 1 (Hcp1)-loaded membrane vesicles (hcp1MVs). The immunization of BALB/c mice with hcp1MVs mixed with adjuvant by a three-dose regimen increased the serum specific IgG production. The serum levels of inflammatory factors, including TNF-α and IL-6, in hcp1MV-vaccinated mice were comparable with those in PBS-challenged mice. The partial adjuvant effect of staphylococcal MVs was observed with the elevation of specific antibody titer in hcp1MV-vaccinated mice relative to those that received the recombinant Hcp1 protein (rHcp1) or MVs derived from RN strain (ΔagrMVs). The hcp1MVs/adjuvant vaccine protected 70% of mice from lethal B. pseudomallei challenge. Immunization with hcp1MVs only protected 60% of mice, whereas vaccination with rHcp1 or ΔagrMVs conferred no protection. Moreover, mice that received hcp1MVs/adjuvant and hcp1MVs immunization had low serum TNF-α and IL-6 levels and no inflammatory infiltration in comparison with other groups. In addition, all surviving mice in hcp1MVs/adjuvant and hcp1MVs groups exhibited no culturable bacteria in their lungs, livers, and spleens five days postinfection. Overall, our data highlighted a new strategy for developing B. pseudomallei vaccine and showed that Hcp1-incorporated staphylococcal MV is a promising candidate for the prevention of acute melioidosis.
A synthetic peptide based on large yellow croaker (Larimichthys crocea) IFNG1R protein sequence has potential antimicrobial activity against Pseudomonas plecoglossicida
Authors: Lin Yijun , Yang Shunzhe , Wang Xiaohong , Xie Ruiyao , Cheng Jie , He Tianliang , Chen Xinhua , Zhang Xiang-Yang
Published: December 2022

The overuse of antibiotics leads to the emergence of bacterial resistance, which poses a serious threat to aquaculture. Antimicrobial peptides (AMPs) display excellent antimicrobial activity and are thought to be the most feasible replacements for antibiotics. The usage of AMPs as feed additives has great application prospects in aquaculture. In this study, large yellow croaker interferon-γ related gene (IFNG1R) was cloned, and a 17-amino acids (aa) short peptide named SKL17-2 was synthesized based on its protein sequence. The synthesized SKL17-2 peptide possessed a strong antimicrobial activity against Pseudomonas plecoglossicida, which could cause visceral white nodules disease (VWND) in cultured marine fish, with a minimum inhibitory concentration (MIC) of 2 μM. SKL17-2 peptide also showed weak antimicrobial activities against other tested bacteria, indicating its narrow-spectrum antimicrobial activity. This suggested that SKL17-2 peptide may not kill probiotics in intestinal flora when used as the feed additive. Furthermore, SKL17-2 had broad temperature and pH stability, low cytotoxicity, and negligible hemolysis, indicating its good biosafety and stability. Mechanistically, the synthesized SKL17-2 peptide can form α-helical structure in a membrane environment and destroy P. plecoglossicida through membrane disruption. Thus, our data showed that SKL17-2 peptide may represent a potential feed additive used for prevention and treatment of VWND.
Spatial variation of coastal wetland vulnerability to oil spill stress in the Bohai Sea
Authors: Wang Yebao , Du Peipei , Liu Jiaqi , Chen Chuntao
Published: December 2022

Due to their position at the land–sea interface, coastal wetlands are extremely vulnerable to oil spills. However, few studies have focused on the vulnerability of coastal wetlands to oil spill hazards. In this study, we developed a spatial vulnerability approach and assessment based on the vulnerability scoping diagram in the Chinese Bohai Sea, where oil spill events are serious and frequent, and aimed to assess the spatial heterogeneity of the vulnerability of coastal wetlands under oil spill stress by integrating various indicators for exposure, sensitivity, and adaptive capacity into a composite index. This study normalized and aggregated data across sub-indices and combined related information with a geographic information system (GIS) model. The weighted results indicated that oil spill sources, as well as the natural environment in which the wetlands were located, dominated the degree of vulnerability of various coastal wetlands. The vulnerability assessment results suggest that there are obvious spatial variations among the different wetlands surrounding the Bohai Sea and each wetland had a different level of vulnerability, and highlights the need to enhance adaptive capacity to reduce vulnerability. This paper provides a quantitative assessment method for determining the spatial variation of coastal wetland vulnerability under oil spill stress, which can be used to better understand potential oil spill risks in coastal wetlands to support spill prevention and improve response readiness in the future.
Three novel antioxidant peptides isolated from C-phycocyanin against H2O2-induced oxidative stress in zebrafish via Nrf2 signaling pathway
Authors: Xu Fenghua , Zhang Yun , Qiu Yuezi , Yang Fanghao , Liu Guoxiang , Dong Xiaolei , Chen Guang , Cao Can , Zhang Qian , Zhang Shanshan , Li Bing
Published: December 2022

Background

C-phycocyanin (C-PC), a phycobiliprotein from Spirulina platensis, has been confirmed to be an effective antioxidant. Duing to the large molecular weight protein, C-PC is hardly absorbed in the human gut and easy coagulates into lumps. In light of this, highly pure, easy absorption, and small molecular weight polypeptides has won the attention in the recent past. However, there are few studies on the C-PC bioactive peptides. Thus, the objective of this study was find natural multifunctional antioxidant peptides from C-PC and demonstrate their mechanisms.

Method

In this study, novel antioxidant peptides from pancreatin hydrolysate of C-PC were isolated and purified by using a multi-bioassay-guided method. The DPPH and ABTS radical scavenging in vitro and antioxidant zebrafish model in vivo were used to evaluate the antioxidant activities. Furthermore, the underlying molecular mechanisms of these peptides were investigated by measuring the level of ROS, MDA, SOD, CAT and gene expression in Nrf2 signaling pathway.

Results

Total three novel active peptides, MHLWAAK (Met-His-Leu-Trp-Ala-Ala-Lys), MAQAAEYYR (Met-Ala-Gln-Ala-Ala-Glu-Tyr-Tyr-Arg), and MDYYFEER (Met-ASP-Tyr-Tyr-Phe-Glu-Glu-Arg) were isolated and purified from pancreatin hydrolysate of C-PC. These synthesized peptides displayed high DPPH and ABTS radical scavenging ability. In addition, in a zebrafish model, the three peptides significantly protected zebrafish embryos from H2O2-induced oxidative injury without toxicity by inhibiting ROS generation, preventing MDA formation, and upregulating the activities of SOD and CAT. Further experiments showed that these peptides could significantly regulated oxidative stress via activating the Nrf2 signaling pathway.

Conclusion

This study indicates that the antioxidant peptides from C-PC could serve as powerful antioxidants for preventing and treating various diseases associated with oxidative stress.
Framing the science for technical measures used in regulatory frameworks to effectively implement government policy
Authors: Cormier Roland , Tunney Tyler , Mallet Manon
Published: December 2022

Regulatory and non-regulatory frameworks are used extensively to establish standards and guidelines for the technical measures implemented to manage freshwater and marine activities to achieve environmental policy objectives. Scientific and technical knowledge about the effectiveness of such measures is needed to ensure the success of these objectives, and yet there is general lack of scientific information on the effectiveness of technical measures. Used as conditions of approval for a variety of industry sectors, regulations and environmental quality guidelines establish the outcomes that are expected for the technical measures used in the daily activities of a given worksite. This paper suggests that the science to determine the effectiveness of technical measures should be framed from the requirements established in regulations and environmental quality guidelines. Such studies should also use methods, indicators and metrics that are often part of those requirements. This paper also puts forth that a more focused scientific effort is needed to determine the effectiveness of technical measures given the thousands of technical measures used to manage a wide range of activities.
Applications of variable thermal properties in Carreau material with ion slip and Hall forces towards cone using a non-Fourier approach via FE-method and mesh-free study
Authors: Nazir Umar , Sohail Muhammad , Mukdasai Kanit , Singh Abha , Alahmadi Reham A. , Galal Ahmed M. , Eldin Sayed M.
Published: December 2022

This research highlights the utilization of two viscosity models to study the involvement of variable properties in heat and momentum transport in a rotating Carreau fluid past over a cone. The rheology of the Carreau material is assessed by the variable dynamic viscosity over the heating cone. The transport of momentum phenomenon is modeled by considering generalized Ohm’s law in Carreau liquid and thermal transport in derived by considering variable thermal conductivity, heat flux model. The considered model is derived in the form of nonlinear PDEs with boundary layer analysis. The nonlinear PDEs are converted into coupled ODEs by using approximate transformation and converted equations are solved numerically by finite element methodology. The impact of numerous parameters is displayed graphically, and their behavior is discussed in detail.
Arterial site selection for measurement of mean arterial pressure in septic shock patients on high-dose norepinephrine
Authors: Bhaskar Bhanuprakash , Gurjar Mohan , Mishra Prabhaker , Azim Afzal , Poddar Banani , Baronia Arvind K.
Published: December 2022

Background

The guidelines of the Surviving Sepsis Campaign suggest using invasive blood pressure (IBP) measurement in septic shock patients, without specifying for a preferred arterial site for accuracy in relation to the severity of septic shock. The objective of this study was to determine the mean arterial pressure (MAP) gradient between the femoral and radial artery sites in septic shock patients.

Method

This prospective study was carried out at a 20-bed ICU in a university hospital. Simultaneous MAP measurements at femoral and radial arterial sites were obtained in septic shock patients receiving norepinephrine (≥0.1 μg/kg/min), with a pre-planned subgroup analysis for those receiving a high dose of norepinephrine (≥0.3 μg/kg/min).

Results

The median norepinephrine dose across all 80 patients studied, including 59 patients on a high dose, was 0.4 (0.28–0.7) μg/kg/min. Overall, simultaneous measurement of MAP (mmHg) at the femoral and radial arterial sites produced mean (95% CI) MAP values of 81 (79–83) and 78 (76–80), respectively, with a mean difference of 3.3 (2.67–3.93), p < 0.001. In Bland–Altman analysis of MAP measurements, the detected effect sizes were 1.14 and 1.04 for the overall and high-dose cohorts, respectively, which indicates a significant difference between the measurements taken at each of the two arterial sites. The Pearson correlation coefficient indicated a weak but statistically significant correlation between MAP gradient and norepinephrine dose among patients receiving a high dose of norepinephrine (r = 0.289; p = 0.026; 95% CI 0.036–0.508).

Conclusion

In septic shock patients, MAP readings were higher at the femoral site than at the radial site, particularly in those receiving a high dose of norepinephrine.

Clinical trial registration

[ClinicalTrials.gov], identifier [NCT03475667].
AIM™ platform: A new immunotherapy approach for viral diseases
Authors: Langan David , Wang Ruipeng , Tidwell Keshanti , Mitiku Selome , Farrell Alison , Johnson Catrina , Parks Adam , Suarez Lauren , Jain Shweta , Kim Sojung , Jones Kristi , Oelke Mathias , Zeldis Jerome
Published: December 2022

In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.
Green nanotechnology for controlling bacterial load and heavy metal accumulation in Nile tilapia fish using biological selenium nanoparticles biosynthesized by Bacillus subtilis AS12
Authors: Saad Ahmed M. , Sitohy Mahmoud Z. , Sultan-Alolama Mohamad I. , El-Tarabily Khaled A. , El-Saadony Mohamed T.
Published: December 2022

Heavy metal accumulation and pathogenic bacteria cause adverse effects on aquaculture. The active surface of selenium (Se) nanoparticles can mitigate these effects. The present study used Se-resistant Bacillus subtilis AS12 to fabricate biological Se nanoparticles (Bio-SeNPs). The double-edged Bio-SeNPs were tested for their ability to reduce the harmful effects of heavy metals and bacterial load in Nile tilapia (Oreochromis niloticus) and their respective influences on fish growth, behavior, and health. The Bio-SeNPs have a spherical shape with an average size of 77 nm and high flavonoids and phenolic content (0.7 and 1.9 g g−1 quercetin and gallic acid equivalents, respectively), resulting in considerable antioxidant and antibacterial activity. The Bio-SeNPs (3–5 μg ml−1) in the current study resolved two serious issues facing the aquaculture industry, firstly, the population of pathogenic bacteria, especially Aeromonas hydrophilia, which was reduced by 28–45% in fish organs. Secondly, heavy metals (Cd and Hg) at two levels (1 and 2 μg ml−1) were reduced by 50–87% and 57–73% in response to Bio-SeNPs (3–5 μg ml−1). Thus, liver function parameters were reduced, and inner immunity was enhanced. The application of Bio-SeNPs (3–5 μg ml−1) improved fish gut health, growth, and behavior, resulting in fish higher weight gain by 36–52% and a 40% specific growth rate, compared to controls. Furthermore, feeding and arousal times increased by 20–22% and 28–53%, respectively, while aggression time decreased by 78% compared to the control by the same treatment. In conclusion, Bio-SeNPs can mitigate the accumulation of heavy metals and reduce the bacterial load in a concentration-dependent manner, either in the fish media or fish organs.
Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2
Authors: Lin Edward , Panfil Amanda R. , Sandel Grace , Jain Pooja
Published: December 2022

The genome of retroviruses contains two promoter elements (called long terminal repeat or LTR) at the 5′ and 3′ end of their genome. Although the expression of retroviral genes generally depends on the promoter located in the 5′ LTR, the 3′ LTR also has promoter activity responsible for producing antisense transcripts. These natural antisense transcripts (NATs) are a class of RNA molecules transcribed from the opposite strand of a protein-coding gene. NATs have been identified in many prokaryotic and eukaryotic systems, as well as in human retroviruses such as human immunodeficiency virus type 1 (HIV-1) and HTLV-1/2 (human T-cell leukemia virus type 1/2). The antisense transcripts of HIV-1, HTLV-1, and HTLV-2 have been briefly characterized over the past several years. However, a complete appreciation of the role these transcripts play in the virus lifecycle and the cellular factors which regulate their transcription is still lacking. This review provides an overview of antisense transcription in human retroviruses with a specific focus on the MEF-2 family of transcription factors, the function(s) of the antisense protein products, and the application of antisense transcription models in therapeutics against HIV-1 and HTLV-1 in the context of co-infection.
Pseudomonas aeruginosa heteroresistance to levofloxacin caused by upregulated expression of essential genes for DNA replication and repair
Authors: Li Wen-Ru , Zhang Zhi-Qing , Liao Kang , Wang Bei-Bei , Liu Hui-Zhong , Shi Qing-Shan , Huang Xu-Bin , Xie Xiao-Bao
Published: December 2022

Pseudomonas aeruginosa (P. aeruginosa), a common cause of severe chronic infections, has developed heteroresistance to several antibiotics, thus hindering successful treatment. In this study, we aimed to investigate the characteristics and mechanisms underlying levofloxacin (LVX) heteroresistance in P. aeruginosa PAS71 and PAS81 clinical isolates using a combination of physiological and biochemical methods, bacterial genomics, transcriptomics, and qRT-PCR. The six P. aeruginosa strains, namely PAS71, PAS72, PAS81, PAS82, ATCC27853, and PAO1, were studied. The Kirby–Bauer (K–B), minimum inhibitory concentration (MIC) test, and population analysis profile (PAP) experimental results showed that PAS71, PAS81, ATCC27853, and PAO1 were heteroresistant to LVX, with MIC of 0.25, 1, 0.5, and 2 μg/ml, respectively; PAS72 and PAS82 were susceptible to LVX with a MIC of 0.25 and 0.5 μg/ml, respectively. The resistance of PAS71 and PAS81 heteroresistant subpopulations was unstable and had a growth fitness cost. Genomic and transcriptomic results proved that the unstable heteroresistance of PAS71 and PAS81 was caused by elevated expression of essential genes involved in DNA replication and repair, and homologous recombination, rather than their genomic single-nucleotide polymorphism (SNP) and insertion–deletion (InDel) mutations. Additionally, PAS71 and PAS81 enhanced virulence and physiological metabolism, including bacterial secretion systems and biosynthesis of siderophore group nonribosomal peptides, in response to LVX stress. Our results suggest that the upregulation of key genes involved in DNA replication and repair, and homologous recombination causes unstable heteroresistance in P. aeruginosa against LVX. This finding provides novel insights into the occurrence and molecular regulation pathway of P. aeruginosa heteroresistant strains.
MTHFR polymorphism's influence on the clinical features and therapeutic effects in patients with migraine: An observational study
Authors: Guo Jianhao , Hao Xing , Wang Rongrong , Lian Ke , Jiang Jun , Chen Na , Feng Zhiying , Rao Yuefeng
Published: December 2022

Objective

Our study aimed to evaluate the influence of methylenetetrahydrofolate reductase (MTHFR) polymorphism on the clinical features and therapeutic effects in patients with migraine.

Methods

The data of 135 patients with migraine were collected from January 2021 to December 2021. The MTHFR C677T polymorphism was analyzed. The pain intensity was evaluated using a numerical rating scale (NRS) during treatment. The levels of folic acid, homocysteine (Hcy), vitamin B12, interleukin-2 (IL-2), IL-4, and ferritin, and changes of NRS were compared between folic acid and conventional treatment groups stratified by different genotypes of MTHFR in migraine patients.

Results

The levels of Hcy and ferritin in male patients were higher than that in female patients (P < 0.05); Compared with CC and CT genotype groups, the TT genotype group showed significantly higher Hcy levels (P < 0.05) and lower folic acid levels (P < 0.05); In both folic acid and conventional treatment groups, a significant decrease in NRS score was observed in different genotypes post-treatment (P < 0.05). Patients with TT genotype in the folic acid treatment group showed better therapeutic efficacy than conventional treatment group (P < 0.05). There is no significant difference in the therapeutic efficacy in other genotypes between the two groups (P > 0.05).

Conclusion

The MTHFR C677T genotyping may provide a new method to guide and optimize individualized medication for migraine patients.
The microbiota-gut- hippocampus axis
Authors: Salami Mahmoud , Soheili Masoud
Published: December 2022

Introduction

It is well known that the intestinal bacteria substantially affect physiological processes in many body organs. Especially, through a bidirectional communication called as gut-microbiota-brain axis, the gut microbiota deeply influences development and function of the nervous system. Hippocampus, as a part of medial temporal lobe, is known to be involved in cognition, emotion, and anxiety. Growing evidence indicates that the hippocampus is a target of the gut microbiota. We used a broad search linking the hippocampus with the gut microbiota and probiotics.

Methods

All experimental studies and clinical trials published until end of 2021 were reviewed. Influence of the gut microbiota on the behavioral, electrophysiological, biochemical and histological aspects of the hippocampus were evaluated in this review.

Results

The effect of disrupted gut microbiota and probiotic supplements on the microbiota-hippocampus link is also considered. Studies show that a healthy gut microbiota is necessary for normal hippocampus dependent learning and memory and synaptic plasticity. The known current mechanisms are production and modulation of neurotrophins, neurotransmitters and receptors, regulation of intracellular molecular processes, normalizing the inflammatory/anti-inflammatory and oxidative/antioxidant factors, and histological stability of the hippocampus. Activity of the hippocampal neuronal circuits as well as behavioral functions of the hippocampus positively respond to different mixtures of probiotic bacteria.

Discussion

Growing evidence from animal researches indicate a close association between the hippocampus with the gut microbiota and probiotic bacteria as well. However, human studies and clinical trials verifying such a link are scant. Since the most of papers on this topic have been published over the past 3 years, intensive future research awaits.
Prognostic significance of steroid response in pediatric acute lymphoblastic leukemia: The CCCG-ALL-2015 study
Authors: Chu Jinhua , Cai Huaju , Cai Jiaoyang , Bian Xinni , Cheng Yumei , Guan Xianmin , Chen Xiaoqian , Jiang Hua , Zhai Xiaowen , Fang Yongjun , Zhang Lei , Tian Xin , Zhou Fen , Wang Yaqin , Wang Lingzhen , Li Hong , Kwan Alex Leung Wing , Yang Minghua , Yang Hanfang , Zhan Aijun , Wang Ningling , Hu Shaoyan
Published: December 2022

Introduction

Whether steroid response is an independent risk factor for acute lymphoblastic leukemia (ALL) is controversial. This study aimed to investigate the relationship between response to dexamethasone and prognosis in children with ALL.

Methods

We analyzed the data of 5,161 children with ALL who received treatment in accordance with the Chinese Children’s Cancer Group ALL-2015 protocol between January 1, 2015, and December 31, 2018, in China. All patients received dexamethasone for 4 days as upfront window therapy. Based on the peripheral lymphoblast count on day 5, these patients were classified into the dexamethasone good response (DGR) and dexamethasone poor response (DPR) groups. A peripheral lymphoblast count ≥1× 109/L indicated poor response to dexamethasone.

Results

The age, white blood cell counts, prevalence of the BCR/ABL1 and TCF3/PBX1 fusion genes, and rates of recurrence in the central nervous system were higher in the DPR than in the DGR group (P<0.001). Compared to the DPR group, the DGR group had a lower recurrence rate (18.6% vs. 11%) and higher 6-year event-free survival (73% vs. 83%) and overall survival (86% vs. 92%) rates; nevertheless, subgroup analysis only showed significant difference in the intermediate-risk group (P<0.001).

Discussion

Response to dexamethasone was associated with an early treatment response in our study. In the intermediate-risk group, dexamethasone response added a prognostic value in addition to minimal residual disease, which may direct early intervention to reduce the relapse rate.
Comparison of chemotherapy regimens plus rituximab in adult Burkitt lymphoma: A single-arm meta-analysis
Authors: Lu Xiaoxuan , Liu Yu , Liu Ruyu , Liu Jiaxin , Yan Xiaojing , Qian Liren
Published: December 2022

Background and aim

Given the paucity of evidence-based treatment recommendations, the most appropriate first-line regimen for adult Burkitt lymphoma is currently undefined. We aimed to identify the optimal treatment regimen containing rituximab for adult Burkitt lymphoma patients.

Methods

The PubMed, Embase, Web of Science, and Cochrane databases were searched in December 2021 (10). We included all studies for the treatment of Burkitt lymphoma including rituximab. We excluded studies of patients aged ≤14 years old and those with sample numbers ≤10 patients. Random-effects models were used to compare different chemotherapy regimens regarding estimated 2-year overall survival (OS) rate, 2-year progression-free survival (PFS) rate, and overall response rate (ORR).

Results

A total of 17 studies were included in this meta-analysis and divided into four groups: CODOX-M/IVAC, DA-EPOCH, GMALL-B-ALL/NHL2002, and Hyper-CVAD. DA-EPOCH was associated with a significantly higher 2-year OS rate [0.95, 95% confidence interval (CI) 0.86–1.00]. There was no significant difference in the 2-year PFS rates (0.81, 95% CI 0.76–0.85) and ORR (0.90, 95% CI 0.87–0.94) between these four treatment regimens.

Conclusions

The meta-analysis indicates that DA-EPOCH could be more effective in providing curative treatment for adult Burkitt lymphoma patients, especially without CNS and BM involvement considering OS time. Due to the types of studies and the limited number of included studies, bias should be acknowledged and a randomized controlled trial (RCT) needs to be performed to further identify the optimal treatment regimen for such patients.
Advances in peptides encoded by non-coding RNAs: A cargo in exosome
Authors: Yang Jing , Liu Mengxiao , Fang Xidong , Zhang Huiyun , Ren Qian , Zheng Ya , Wang Yuping , Zhou Yongning
Published: December 2022

The metastasis of malignant tumors determines patient prognosis. This is the main reason for the poor prognosis of patients with cancer and the most challenging aspect of treating malignant tumors. Therefore, it is important to identify early tumor markers and molecules that can predict patient prognosis. However, there are currently no molecular markers with good clinical accuracy and specificity. Many non-coding RNA (ncRNAs)have been identified, which can regulate the process of tumor development at multiple levels. Interestingly, some ncRNAs are translated to produce functional peptides. Exosomes act as signal carriers, are encapsulated in nucleic acids and proteins, and play a messenger role in cell-to-cell communication. Recent studies have identified exosome peptides with potential diagnostic roles. This review aims to provide a theoretical basis for ncRNA-encoded peptides or proteins transported by exosomes and ultimately to provide ideas for further development of new diagnostic and prognostic cancer markers.
Minor histological components predict the recurrence of patients with resected stage I acinar- or papillary-predominant lung adenocarcinoma
Authors: Liu Wei , Zhang Qian , Zhang Tiantian , Li Li , Xu Chunhua
Published: December 2022

Objective

Invasive lung adenocarcinoma is composed of five different histological subgroups with diverse biological behavior and heterogeneous morphology, the acinar/papillary-predominant lung adenocarcinomas are the most common subgroups and recognized as an intermediate-grade group. In the real world, clinicians primarily consider predominant patterns and ignore the impact of minor components in the prognosis of lung adenocarcinoma. The study evaluated the clinicopathologic characteristics of the lepidic, solid, and micropapillary patterns as non-predominant components and whether the minimal patterns had prognostic value on acinar/papillary-predominant lung adenocarcinomas.

Methods

A total of 153 acinar/papillary-predominant lung adenocarcinoma patients with tumor size ≤4 cm were classified into four risk subgroups based on the presence of lepidic and micropapillary/solid components: MP/S−Lep+, MP/S+Lep+, MP/S−Lep−, and MP/S+Lep− groups. The Cox-proportional hazard regression model was used to assess disease-free survival (DFS).

Results

The risk subgroups based on the non-predominant patterns were associated with differentiation (P = 0.001), lymphovascular invasion (P = 0.001), and recurrence (P = 0.003). In univariate analysis, DFS was correlated with non-predominant components (P = 0.014), lymphovascular invasion (P = 0.001), carcinoembryonic antigen (CEA) (P = 0.001), and platelet-to-lymphocyte ratio (PLR) (P = 0.012). In the multivariate analysis, non-predominant components (P = 0.043) and PLR (P = 0.032) were independent prognostic factors for DFS. The 5-year survival rates of MP/S−Lep+, MP/S+Lep+, MP/S−Lep− and MP/S+Lep− subgroups were 93.1%,92.9%,73.1%,61.9%, respectively. The MP/S−Lep+ subgroup had the favorable prognosis than MP/S+Lep− subgroup with a statistically significant difference (P = 0.002). As minor components, the lepidic patterns were a protective factor, and the solid and micropapillary components were poor factors. The recurrence was related to the presence of non-predominant patterns rather than their proportion. Adjuvant chemotherapy did not significantly improve the prognosis of the MP/S+Lep- subgroup (P = 0.839).

Conclusions

Regardless of the proportion, the presence of micropapillary/solid components and the absence of lepidic patterns are aggressive factors of DFS in patients with resected stage I acinar- or papillary-predominant lung adenocarcinoma.
Frizzled receptors in melanomagenesis: From molecular interactions to target identification
Authors: Umar Sheikh A. , Dong Bo , Nihal Minakshi , Chang Hao
Published: December 2022

Frizzled (FZD) proteins are receptors for the WNT family ligands. Inherited human diseases and genetic experiments using knockout mice have revealed a central role of FZDs in multiple aspects of embryonic development and tissue homeostasis. Misregulated FZD signaling has also been found in many cancers. Recent studies on three out of the ten mammalian FZDs in melanoma have shown that they promote tumor cell proliferation and invasion, via the activation of the canonical WNT/β-catenin or non-canonical PCP signaling pathway. In this concise review, we summarize our current knowledge of individual FZDs in melanoma, discuss the involvement of both the canonical and non-canonical pathways, and describe ongoing efforts to target the FZD receptors for melanoma treatment.
A pyroptosis-related gene signature for prognostic and immunological evaluation in breast cancer
Authors: Zhong Yue , Peng Fu , Luo Xiaoru , Wang Xuan , Yang Bowen , Tang Xinglinzi , Xu Zheng , Ren Linlin , Wang Zhiyu , Peng Cheng , Wang Neng
Published: December 2022

Purpose

Pyroptosis exerts an undesirable impact on the clinical outcome of breast cancer. Since any single gene is insufficient to be an appropriate marker for pyroptosis, our aim is to develop a pyroptosis-related gene (PRG) signature to predict the survival status and immunological landscape for breast cancer patients.

Methods

The information of breast cancer patients was retrieved from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the gene expressions of this signature in breast cancer. Its prognostic value was evaluated by univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, receiver operating characteristics (ROCs), univariate/multivariate analysis, and nomogram. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to explore its potential biological function in breast cancer. The potential correlation between this signature and tumor immunity was revealed based on single sample gene set enrichment analysis (ssGSEA), ESTIMATE and CIBERSORT algorithms.

Results

A PRG signature containing GSDMC, GZMB, IL18, and TP63 was created in a TCGA training cohort and validated in two validation GEO cohorts GSE58812 and GSE37751. Compared with a human mammary epithelial cell line MCF-10A, the expression levels of GSDMC, GZMB and IL18 were upregulated, while TP63 was found with lower expression level in breast cancer cells SK-BR-3, BT-549, MCF-7, and MDA-MB-231 using RT-qPCR assay. Based on univariate and multivariate Cox models, ROC curve, nomogram as well as calibration curve, it was revealed that this signature with high-risk score could independently predict poor clinical outcomes in breast cancer. Enrichment analyses demonstrated that the involved mechanism was tightly linked to immune-related processes. SsGSEA, ESTIMATE and CIBERSORT algorithms further pointed out that the established model might exert an impact on immune cell abundance, immune cell types and immune-checkpoint markers. Furthermore, individuals with breast cancer responded differently to these therapeutic agents based on this signature.

Conclusions

Our data suggested that this PRG signature with high risk was tightly associated with impaired immune function, possibly resulting in an unfavorable outcome for breast cancer patients.