bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue Doppler derived biphasic velocities during the pre and post-ejection phases: patterns, concordance and hemodynamic significance in health and disease
Authors: Omar Alaa Mabrouk Salem , Botero Diana Maria Ronderos , Caraballo Javier Arreaza , Kim Ga Hee , Khachatoorian Yeraz , Kliewer Jaclyn , Rahman Mohamed Ahmed Abdel , Rifaie Osama , Bella Jonathan N. , Argulian Edgar , Contreras Johanna
Published: July 2022

Background

Pre-(PRE) and post-ejection (POE) velocities by mitral annular tissue Doppler (TD) are biphasic and may be related to myocardial deformations. We investigated the predominance and concordance of TD-PRE and POE velocities and their effect on myocardial functions in controls and in heart failure (HF) patients.

Methods

Retrospectively, 84 HF patients [57.6 years, 28(33%) females, NYHA: 2.3 ± 0.6, EF: 55 ± 15%, 52(62%) preserved EF, and 32(38%) reduced EF], 42 normal young controls, and 26 asymptomatic age matched controls were included. Echocardiography was done and from mitral annular tissue Doppler recordings, the biphasic PRE and POE velocity signals were identified and compared between groups.

Results

While controls had almost always predominantly positive PRE and negative POE, HF had more negative PRE and positive POE. Moreover, almost all controls exhibited normal concordance (positive PRE and negative POE). HF exhibited more abnormal concordance which was significantly associated with worse NYHA, and parameters of diastolic and systolic functions. Opposite PRE and POE velocities correlated significantly in all groups (PREp vs POEn: young:r = 0.52, p < 0.001, age controls:r = 0.79, p < 0.001, HFpEF: r = 0.56, p < 0.001, HFrEF: r = 0.42, p = 0.018; PREn vs POEp: young: r = 0.25,p = 0.1, age controls: r = 0.42, p = 0.04, HFpEF: r = 0.43, p = 0.004, HFrEF: r = 0.61, p < 0.001) and the ratios PRE-P/N and POE-N/P correlated significantly with E/e’ in HF only.

Conclusions

In physiological state, TD signals are predominantly positive during PRE and negative during POE. Opposite PRE and POE velocities corelate, representing the PRE-generation and POE-reversal of shortening–stretch relationships, the attenuation of which in HF may be related to elevated LV filling pressures. In HF, partially or completely reversed concordance of PRE and POE is associated with progressive worsening of clinical and hemodynamic profiles.
Fucoidan-derived carbon dots against Enterococcus faecalis biofilm and infected dentinal tubules for the treatment of persistent endodontic infections
Authors: Tang Shang , Zhang Hui , Mei Li , Dou Keke , Jiang Yuying , Sun Zhanyi , Wang Shuai , Hasanin Mohamed Sayed , Deng Jing , Zhou Qihui
Published: July 2022

Enterococcus faecalis (E. faecalis) biofilm-associated persistent endodontic infections (PEIs) are one of the most common tooth lesions, causing chronic periapical periodontitis, root resorption, and even tooth loss. Clinical root canal disinfectants have the risk of damaging soft tissues (e.g., mucosa and tongue) and teeth in the oral cavity, unsatisfactory to the therapy of PEIs. Nanomaterials with remarkable antibacterial properties and good biocompatibility have been developed as a promising strategy for removing pathogenic bacteria and related biofilm. Herein, carbon dots (CDs) derived from fucoidan (FD) are prepared through a one-pot hydrothermal method for the treatment of PEIs. The prepared FDCDs (7.15 nm) with sulfate groups and fluorescence property are well dispersed and stable in water. Further, it is found that in vitro FDCDs display excellent inhibiting effects on E. faecalis and its biofilm by inducing the formation of intracellular and extracellular reactive oxygen species and altering bacterial permeability. Importantly, the FDCDs penetrated the root canals and dentinal tubules, removing located E. faecalis biofilm. Moreover, the cellular assays show that the developed FDCDs have satisfactory cytocompatibility and promote macrophage recruitment. Thus, the developed FDCDs hold great potential for the management of PEIs.

Graphical Abstract
Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis
Authors: Hua Tong , Yang Mei , Song Honghao , Kong Erliang , Deng Mengqiu , Li Yongchang , Li Jian , Liu Zhixiao , Fu Hailong , Wang Yue , Yuan Hongbin
Published: July 2022

Background

Chronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model.

Methods

C57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms.

Results

Huc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy.

Conclusion

Huc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis.

Graphical Abstract
Van-mediated self-aggregating photothermal agents combined with multifunctional magnetic nickel oxide nanoparticles for precise elimination of bacterial infections
Authors: Du Ting , Cao Jiangli , Xiao Zehui , Liu Jiaqi , Wei Lifei , Li Chunqiao , Jiao Jingbo , Song Zhiyong , Liu Jifeng , Du Xinjun , Wang Shuo
Published: July 2022

Building a novel and efficient photothermal antibacterial nanoplatform is a promising strategy for precise bacterial elimination. Herein, a nanocomposite NiO NPs@AuNPs@Van (NAV) for selective MRSA removal was constructed by electrostatic self-assembly of highly photothermal magnetic NiO NPs and vancomycin (Van)-modified gold nanoparticles (AuNPs). In the presence of MRSA and under NIR irradiation, Van-mediated AuNPs can self-aggregate on MRSA surface, generating photothermal effect in situ and killing 99.6% MRSA in conjunction with magnetic NiO NPs. Additionally, the photothermal efficiency can be improved by magnetic enrichment due to the excellent magnetism of NAV, thereby enhancing the bactericidal effect at a lower experimental dose. In vitro antibacterial experiments and full-thickness skin wound healing test demonstrated that this combination therapy could effectively accelerate wound healing in MRSA-infected mice, increase collagen coverage, reduce IL-6 and TNF-α content, and upregulate VEGF expression. Biological safety experiments confirmed that NAV has good biocompatibility in vivo and in vitro. Overall, this work reveals a new type of nanocomposite with enhanced photothermal antibacterial activity as a potential nano-antibacterial agent for treating bacteria-infected wounds.
IGF2 reduces meiotic defects in oocytes from obese mice and improves embryonic developmental competency
Authors: Wan Yanling , Muhammad Tahir , Huang Tao , Lv Yue , Sha Qianqian , Yang Shuang , Lu Gang , Chan Wai-yee , Ma Jinlong , Liu Hongbin
Published: July 2022

Background

Maternal obesity is a global issue that has devastating effects across the reproductive spectrum such as meiotic defects in oocytes, consequently worsening pregnancy outcomes. Different studies have shown that such types of meiotic defects originated from the oocytes of obese mothers. Thus, there is an urgent need to develop strategies to reduce the incidence of obesity-related oocyte defects that adversely affect pregnancy outcomes. Multiple growth factors have been identified as directly associated with female reproduction; however, the impact of various growth factors on female fertility in response to obesity remains poorly understood.

Methods

The immature GV-stage oocytes from HFD female mice were collected and cultured in vitro in two different groups (HFD oocytes with and without 50 nM IGF2), however; the oocytes from ND mice were used as a positive control. HFD oocytes treated with or without IGF2 were further used to observe the meiotic structure using different analysis including, the spindle and chromosomal analysis, reactive oxygen species levels, mitochondrial functional activities, and early apoptotic index using immunofluorescence. Additionally, the embryonic developmental competency and embryos quality of IGF2-treated zygotes were also determined.

Results

In our findings, we observed significantly reduced contents of insulin-like growth factor 2 (IGF2) in the serum and oocytes of obese mice. Our data indicated supplementation of IGF2 in a culture medium improves the blastocyst formation: from 46% in the HFD group to 61% in the HFD + IGF2-treatment group (50 nM IGF2). Moreover, adding IGF2 to the culture medium reduces the reactive oxygen species index and alleviates the frequency of spindle/chromosome defects. We found increased mitochondrial functional activity in oocytes from obese mice after treating the oocytes with IGF2: observed elevated level of adenosine triphosphate, increased mitochondrial distribution, higher mitochondrial membrane potentials, and reduced mitochondrial ultrastructure defects. Furthermore, IGF2 administration also increases the overall protein synthesis and decreases the apoptotic index in oocytes from obese mice.

Conclusions

Collectively, our findings are strongly in favor of adding IGF2 in culture medium to overcome obesity-related meiotic structural-developmental defects by helping ameliorate the known sub-optimal culturing conditions that are currently standard with assisted reproduction technologies.
A loss-of-function variant in SSFA2 causes male infertility with globozoospermia and failed oocyte activation
Authors: Huang Gelin , Zhang Xueguang , Yao Guanping , Huang Lin , Wu Sixian , Li Xiaoliang , Guo Juncen , Wen Yuting , Wang Yan , Shang Lijun , Li Na , Xu Wenming
Published: July 2022

Globozoospermia (OMIM: 102530) is a rare type of teratozoospermia (< 0.1%). The etiology of globozoospermia is complicated and has not been fully revealed. Here, we report an infertile patient with globozoospermia. Variational analysis revealed a homozygous missense variant in theSSFA2gene (NM_001130445.3: c.3671G > A; p.R1224Q) in the patient. This variant significantly reduced the protein expression of SSFA2. Immunofluorescence staining showed positive SSFA2 expression in the acrosome of human sperm. Liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) and Coimmunoprecipitation (Co-IP) analyses identified that GSTM3 and Actin interact with SSFA2. Further investigation revealed that for the patient, regular intracytoplasmic sperm injection (ICSI) treatment had a poor prognosis. However, Artificial oocyte activation (AOA) by a calcium ionophore (A23187) after ICSI successfully rescued the oocyte activation failure for the patient with theSSFA2variant, and the couple achieved a live birth. This study revealed that SSFA2 plays an important role in acrosome formation, and the homozygous c.3671G > A loss-of-function variant inSSFA2caused globozoospermia.SSFA2may represent a new gene in the genetic diagnosis of globozoospermia, especially the successful outcome of AOA-ICSI treatment for couples, which has potential value for clinicians in their treatment regimen selections.
Environmental and practice factors associated with children’s device-measured physical activity and sedentary time in early childhood education and care centres: a systematic review
Authors: Martin Anne , Brophy Rachel , Clarke Joanne , Hall Charlotte J. S. , Jago Russell , Kipping Ruth , Reid Tom , Rigby Benjamin , Taylor Hilary , White James , Simpson Sharon A.
Published: July 2022

Background

Early childhood education and care (ECEC) settings offer a potentially cost-effective and sustainable solution for ensuring children have opportunities to meet physical activity (PA) and sedentary time (ST) guidelines. This paper systematically reviewed the association between childcare environment and practice and children’s PA and ST.

Methods

Three electronic databases were searched, and citation tracking of eligible studies performed between June–July 2020 (updated March 2022). Studies were eligible when (i) participants attended ECEC settings, (ii) they reported the association between use of outdoor space, including factors of time, availability, play, size and equipment, and children’s device-measured PA and ST, and (iii) where applicable, they compared the exposure to use of indoor space. Risk of bias was assessed using the Critical Appraisal Skills Program (CASP) tools. A synthesis was performed using effect direct plots and charts to visualise effect sizes.

Results

Of 1617 reports screened, 29 studies met the inclusion criteria. Studies provided data on outdoor versus indoor time (n = 9; 960 children), outdoor versus indoor play (n = 3; 1104 children), outdoor play space (n = 19; 9596 children), outdoor space use external to ECEC (n = 2; 1148 children), and portable (n = 7; 2408 children) and fixed (n = 7; 2451 children) outdoor equipment. Time spent outdoors versus indoors was associated with increased moderate-to-vigorous PA (MVPA), light PA (LPA) and total PA, while the association with ST was inconclusive. The mean (standard deviation) levels of outdoor MVPA (4.0 ± 3.2 to 18.6 ± 5.6 min/h) and LPA (9.9 ± 2.6 to 30.8 ± 11.8 min/h) were low, and ST high (30.0 ± 6.5 to 46.1 ± 4.3 min/h). MVPA levels doubled when children played outdoors versus indoors. Outdoor play space, and outdoor portable equipment, were associated with increased MVPA. A dose-response relationship for outdoor play area size was observed, demonstrating increased MVPA with areas ≥505m2 (5436 ft2), but no further increases when areas were > 900m2 (9688 ft2). No studies reported on injuries in outdoor settings.

Conclusions

ECEC policies and practices should promote not only outdoor time but also the availability of resources such as portable play equipment and sufficient size of outdoor play areas that enable children to be physically active for sustained periods while outdoors.

Systematic review registration

International prospective register of systematic reviews (PROSPERO) Registration Number: CRD42020189886.
Identification of ENO1 as a prognostic biomarker and molecular target among ENOs in bladder cancer
Authors: Huang Zhengnan , Yan Yilin , Wang Tengjiao , Wang Zeyi , Cai Jinming , Cao Xiangqian , Yang Chenkai , Zhang Fang , Wu Gang , Shen Bing
Published: July 2022

Background

Enolase is an essential enzyme in the process of glycolysis and has been implicated in cancer progression. Though dysregulation of ENOs has been reported in multiple cancers, their prognostic value and specific role in bladder cancer (BLCA) remain unclear.

Methods

Multiple databases were employed to examine the expression of ENOs in BLCA. The expression of ENO1 was also validated in BLCA cell lines and tissue samples by western blotting and immunohistochemistry. Kaplan–Meier analysis, ROC curve, univariate and multivariate Cox regression were performed to evaluate the predictive capability of the ENO1. Gene ontology (GO) and Gene Set Enrichment Analyses (GSEA) analysis were employed to perform the biological processes enrichment. Function experiments were performed to explore the biological role of ENO1 in BLCA. The correlation of ENO1 with immune cell infiltration was explored by CIBERSORT.

Results

By analyzing three ENO isoforms in multiple databases, we identified that ENO1 was the only significantly upregulated gene in BLCA. High expression level of ENO1 was further confirmed in BLCA tissue samples. Aberrant ENO1 overexpression was associated with clinicopathological characteristics and unfavorable prognosis. Functional studies demonstrated that ENO1 depletion inhibited cancer cell aggressiveness. Furthermore, the expression level of ENO1 was correlated with the infiltration levels of immune cells and immune-related functions.

Conclusions

Taken together, our results indicated that ENO1 might serve as a promising prognostic biomarker for prognosticating prognosis associated with the tumor immune microenvironment, suggesting that ENO1 could be a potential immune-related target against BLCA.
Molecular mimicry between tumor associated antigens and microbiota-derived epitopes
Authors: Ragone Concetta , Manolio Carmen , Mauriello Angela , Cavalluzzo Beatrice , Buonaguro Franco M. , Tornesello Maria Lina , Tagliamonte Maria , Buonaguro Luigi
Published: July 2022

Background

The gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, progression and response to treatments, such as immunotherapies, has been extensively described. Here we offer a new perspective, proposing a role for the microbiota based on the molecular mimicry of tumor associated antigens by microbiome-associated antigens.

Methods

In the present study we looked for homology between published TAAs and non-self microbiota-derived epitopes. Blast search for sequence homology was combined with extensive bioinformatics analyses.

Results

Several evidences for homology between TAAs and microbiota-derived antigens have been found. Strikingly, three cases of 100% homology between the paired sequences has been identified. The predicted average affinity to HLA molecules of microbiota-derived antigens is very high (< 100 nM). The structural conformation of the microbiota-derived epitopes is, in general, highly similar to the corresponding TAA. In some cases, it is identical and contact areas with both HLA and TCR chains are indistinguishable. Moreover, the spatial conformation of TCR-facing residues can be identical in paired TAA and microbiota-derived epitopes, with exactly the same values of planar as well as dihedral angles.

Conclusions

The data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteroidetes phyla, which together account for 90% of gut microbiota. Cross-reacting CD8+ T cell responses are very likely induced. Therefore, the anti-microbiota T cell memory may turn out to be an anti-cancer T cell memory, able to control the growth of a cancer developed during the lifetime if the expressed TAA is similar to the microbiota epitope. This may ultimately represent a relevant selective advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy.
Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain
Authors: Peng Zhuang , Peng Sha , Lin Kangguang , Zhao Bin , Wei Lai , Tuo Qinhui , Liao Duanfang , Yuan Tifei , Shi Zhe
Published: July 2022

Background

Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect.

Methods

In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain–blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated.

Results

We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response.

Conclusions

Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.
NOX2-mediated reactive oxygen species are double-edged swords in focal cerebral ischemia in mice
Authors: Yingze Ye , Zhihong Jian , Tong Jin , Yina Li , Zhi Zeng , Xu Zhang , Xiaoxing Xiong , Lijuan Gu
Published: July 2022

Background

Reactive oxygen species (ROS) often promote acute brain injury after stroke, but their roles in the recovery phase have not been well studied. We tested the hypothesis that ROS activity mediated by NADPH oxidase 2 (NOX2) contributes to acute brain injury but promotes functional recovery during the delayed phase, which is linked with neuroinflammation, autophagy, angiogenesis, and the PI3K/Akt signaling pathway.

Methods

We used the NOX2 inhibitor apocynin to study the role of NOX2 in brain injury and functional recovery in a middle cerebral artery occlusion (MCAO) stroke mouse model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7, 10 and 14 after reperfusion. In addition, dynamic NOX2-induced ROS levels were measured by dihydroethidium (DHE) staining. Autophagy, inflammasomes, and angiogenesis were measured by immunofluorescence staining and western blotting. RNA sequencing was performed, and bioinformatics technology was used to analyze differentially expressed genes (DEGs), as well as the enrichment of biological functions and signaling pathways in ischemia penumbra at 7 days after reperfusion. Then, Akt pathway-related proteins were further evaluated by western blotting.

Results

Our results showed that apocynin injection attenuated infarct size and mortality 3 days after stroke but promoted mortality and blocked functional recovery from 5 to 14 days after stroke. DHE staining showed that ROS levels were increased at 3 days after reperfusion and then gradually declined in WT mice, and these levels were significantly reduced by the NOX2 inhibitor apocynin. RNA-Seq analysis indicated that apocynin activated the immune response under hypoxic conditions. The immunofluorescence and western blot results demonstrated that apocynin inhibited the NLRP3 inflammasome and promoted angiogenesis at 3 days but promoted the NLRP3 inflammasome and inhibited angiogenesis at 7 and 14 days after stroke, which was mediated by regulating autophagy activation. Furthermore, RNA-Seq and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that apocynin injection resulted in PI3K–Akt signaling pathway enrichment after 7 days of MCAO. We then used an animal model to show that apocynin decreased the protein levels of phosphorylated PI3K and Akt and NF-κB p65, confirming that the PI3K–Akt–NF-κB pathway is involved in apocynin-mediated activation of inflammation and inhibition of angiogenesis.

Conclusions

NOX2-induced ROS production is a double-edged sword that exacerbates brain injury in the acute phase but promotes functional recovery. This effect appears to be achieved by inhibiting NLRP3 inflammasome activation and promoting angiogenesis via autophagy activation.
PPP2R5D promotes hepatitis C virus infection by binding to viral NS5B and enhancing viral RNA replication
Authors: Anwar Muhammad Ikram , Li Ni , Zhou Qing , Chen Mingxiao , Hu Chengguang , Wu Tao , Chen Haihang , Li Yi-Ping , Zhou Yuanping
Published: July 2022

Background

Hepatitis C virus (HCV) infection increased the risk of hepatocellular carcinoma. Identification of host factors required for HCV infection will help to unveil the HCV pathogenesis. Adaptive mutations that enable the replication of HCV infectious clones could provide hints that the mutation-carrying viral protein may specifically interact with some cellular factors essential for the HCV life cycle. Previously, we identified D559G mutation in HCV NS5B (RNA dependent RNA polymerase) important for replication of different genotype clones. Here, we searched for the factors that potentially interacted with NS5B and investigated its roles in HCV infection.

Methods

Wild-type-NS5B and D559G-NS5B of HCV genotype 2a clone, J6cc, were ectopically expressed in hepatoma Huh7.5 cells, and NS5B-binding proteins were pulled down and identified by mass spectrometry. The necessity and mode of action of the selected cellular protein for HCV infection were explored by experiments including gene knockout or knockdown, complementation, co-immunoprecipitation (Co-IP), colocalization, virus infection and replication, and enzymatic activity, etc.

Results

Mass spectrometry identified a number of cellular proteins, of which protein phosphatase 2 regulatory subunit B’delta (PPP2R5D, the PP2A regulatory B subunit) was one of D559G-NS5B-pulled down proteins and selected for further investigation. Co-IP confirmed that PPP2R5D specifically interacted with HCV NS5B but not HCV Core and NS3 proteins, and D559G slightly enhanced the interaction. NS5B also colocalized with PPP2R5D in the endoplasmic reticulum. Knockdown and knockout of PPP2R5D decreased and abrogated HCV infection in Huh7.5 cells, respectively, while transient and stable expression of PPP2R5D in PPP2R5D-knockout cells restored HCV infection to a level close to that in wild-type Huh7.5 cells. Replicon assay revealed that PPP2R5D promoted HCV replication, but the phosphatase activity and catalytic subunit of PP2A were not affected by NS5B.

Conclusions

PPP2R5D interactes with HCV NS5B and is required for HCV infection in cultured hepatoma cells through facilitating HCV replication.
Association between haemoglobin A1c and all-cause and cause-specific mortality in middle-aged and older Koreans: a prospective cohort study
Authors: Song Bo Mi , Lee Jung Hyun , Woo Hae Dong , Cho Mi Jin , Kim Sung Soo
Published: July 2022

Background

This study aimed to examine associations between haemoglobin A1c (HbA1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans.

Methods

Using 16 years of follow-up data from the Korean Genome and Epidemiology Study, we analysed 9294 individuals aged 40–69 years with no history of cardiovascular disease (CVD) or cancer. Participants were divided into a known diabetes group and five groups categorized by HbA1c levels (< 5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥ 6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA1c levels were calculated using a conventional and a time-dependent Cox proportional hazards model. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell counts.

Results

During a median follow-up period of 15.7 years, there were 944 deaths, including 185 deaths from CVD, 359 from cancer, and 125 from all external causes. Compared with participants with HbA1c levels of 5.5–5.9%, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels < 5.0%, 5.0–5.4%, 6.0–6.4%, and ≥ 6.5% and participants with known diabetes were 1.84 (1.35–2.51), 1.13 (0.95–1.34), 1.30 (1.04–1.62), 1.37 (0.97–1.93), and 2.03 (1.70–2.44), respectively. The risk of cancer mortality was significantly increased in HbA1c < 5.0% (HR, 2.21; 95% CI 1.42–3.44) and known diabetes (HR, 1.60; 95% CI 1.18–2.15). When we performed diverse subgroup analyses, low HbA1c levels at baseline were strongly associated with mortality in participants with liver diseases.

Conclusions

We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions.

Graphical abstract
Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis
Authors: Zhang Wenlong , He Xin , Yin Haoli , Cao Wenmin , Lin Tingsheng , Chen Wei , Diao Wenli , Ding Meng , Hu Hao , Mo Wenjing , Zhang Qing , Guo Hongqian
Published: July 2022

Background

Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies.

Methods

Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1.

Results

Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo.

Conclusions

This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.
The association of age at menarche and adult height with mammographic density in the International Consortium of Mammographic Density
Authors: Ward Sarah V. , Burton Anya , Tamimi Rulla M. , Pereira Ana , Garmendia Maria Luisa , Pollan Marina , Boyd Norman , dos-Santos-Silva Isabel , Maskarinec Gertraud , Perez-Gomez Beatriz , Vachon Celine , Miao Hui , Lajous Martín , López-Ridaura Ruy , Bertrand Kimberly , Kwong Ava , Ursin Giske , Lee Eunjung , Ma Huiyan , Vinnicombe Sarah , Moss Sue , Allen Steve , Ndumia Rose , Vinayak Sudhir , Teo Soo-Hwang , Mariapun Shivaani , Peplonska Beata , Bukowska-Damska Agnieszka , Nagata Chisato , Hopper John , Giles Graham , Ozmen Vahit , Aribal Mustafa Erkin , Schüz Joachim , Van Gils Carla H. , Wanders Johanna O. P. , Sirous Reza , Sirous Mehri , Hipwell John , Kim Jisun , Lee Jong Won , Dickens Caroline , Hartman Mikael , Chia Kee-Seng , Scott Christopher , Chiarelli Anna M. , Linton Linda , Flugelman Anath Arzee , Salem Dorria , Kamal Rasha , McCormack Valerie , Stone Jennifer
Published: July 2022

Background

Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk.

Methods

Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche.

Results

In pooled analyses, later age at menarche was associated with higher per cent density (β√PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (β√DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β√DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β√PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups.

Conclusions

In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.
Clinical risk factors for admission with Pseudomonas and multidrug-resistant Pseudomonas community-acquired pneumonia
Authors: Idigo Adeniyi J. , Wells J. Michael , Brown Matthew L. , Wiener Howard W. , Griffin Russell L. , Cutter Gary , Shrestha Sadeep , Lee Rachael A.
Published: July 2022

Background

Microbial etiology for community-acquired pneumonia (CAP) is evolving with pathogens known for high CAP mortality e.g., Pseudomonas species. Chronic obstructive pulmonary disease (COPD) patients are at risk for hospitalization for CAP. Understanding regional patterns and risk factors for multidrug-resistant (MDR) Pseudomonas acquisition has implications for antimicrobial stewardship.

Objectives

To evaluate the regional epidemiology of MDR Pseudomonas CAP and its association with COPD.

Methods

We queried the electronic medical records of the University of Alabama at Birmingham Healthcare System to identify patients hospitalized for CAP with Pseudomonas positive respiratory samples between 01/01/2013–12/31/2019. Log binomial regression models were used to examine associations between COPD diagnosis and risk of Pseudomonas/MDR Pseudomonas CAP.

Results

Cohort consisted of 913 culture positive CAP cases aged 59-year (IQR:48–68), 61% (560) male, 60% (547) white, 65% (580) current/past smokers, and 42% (384) COPD. Prevalence of Pseudomonas CAP in culture positive CAP was 18% (167), MDR Pseudomonas CAP in Pseudomonas CAP was 22% (36), and yearly incidence of MDR Pseudomonas CAP was stable (p = 0.169). COPD was associated with Pseudomonas CAP (RR 1.39; 95% CI 1.01, 1.91; p = 0.041) but not with MDR Pseudomonas CAP (0.71; 95% CI 0.35, 1.45; p = 0.349). Stroke (RR 2.64; 95% CI 1.51, 4.61; p = 0.0006) and use of supplemental oxygen (RR 2.31; 95% CI 1.30, 4.12; p = 0.005) were associated with MDR Pseudomonas CAP.

Conclusion

Incidence of MDR Pseudomonas CAP was stable over time. COPD was associated with Pseudomonas CAP but not with MDR Pseudomonas CAP. Larger cohort studies are needed to confirm findings.
Effects of the substitution of cow’s milk with soymilk on the micronutrients, microbial, and sensory qualities of yoghurt
Authors: Otolowo Dupe T. , Omosebi Omolola M. , Araoye Kudirat T. , Ernest Temiloluwa E. , Osundahunsi Oluwatooyin F.
Published: July 2022

The consumption of imported dairy products is high especially in developing countries including Nigeria where little or no milk is produced locally which makes the products expensive, out of reach to common consumers and also inconvenient for lactose intolerance and vegans. Soymilk, as plant-based milk was substituted for cow’s milk in parts and in whole for the production of yoghurt and the effect of substitution was evaluated on the minerals, vitamins, microbial, and sensory properties of the products using the established methods. Significant differences (p < 0.05) exits among the yoghurt samples in the micronutrient contents. The soymilk substitution produced yoghurts with trace/macro mineral contents’ range of 0.14–28.50 mg/100 g and vitamin contents (ranged 0.02–0.43 mg/100 g) that were of comparable range of values with the yoghurt made with 100% cow’s milk (0.21–29.60 mg/100 g minerals and 0.05–0.58 mg/100 g vitamins). Generally, no significant difference (p < 0.05) was observed in most of the sensory attributes evaluated (range 8.00–8.01) in the entire samples (except in the 100% soymilk yoghurt). The microbial analysis proved the safety of the entire products for consumption. These showed the positive effect of substituting soymilk for cow’s milk at all the levels used, thus, the lactose intolerance and vegans can find alternative to dairy yoghurt in the 100% soymilk substitution and enjoy the functional health benefits of yoghurt. Also, the total dependence on importation of dairy milk and cost of production of composited milk yoghurt could be reduced to improve the nation’s economy and make the product economically accessible to common man.

Graphical abstract
Nutritional management and maize variety combination effectively control Striga asiatica in southern Africa
Authors: Mutsvanga Simbarashe , Gasura Edmore , Setimela Peter S. , Nyakurwa Cacious S. , Mabasa Stanford
Published: July 2022

Maize (Zea mays L.) is an important staple food crop in sub-Saharan Africa (SSA) and contributes significantly to food security. Due to Striga, maize yield loss is estimated between 20 and 80% forcing some farmers to abandon their land therefore threatening food security. Many strategies have been applied to combat Striga infested fields to improve maize yields but alternative feasible approaches are still required. This study aimed at determining effects of phosphorus (P) and maize variety on Striga asiatica germination and attachment. A factorial experiment of eight P levels (0, 10, 20, 30, 40, 50, 60 and 70 kg ha−1), six maize varieties and Striga (inoculated and non-inoculated) in a 4 × 24 α-lattice design with three replications was set in a glasshouse at the University of Zimbabwe. A similar experiment was set under laboratory conditions using agar gel plates to determine S. asiatica germination using a complete randomized design with three replications. Adding P (at 40 kg ha−1) to soil infected with Striga, significantly (p < 0.05) reduced Striga counts and haustorial root attachments in all varieties with CV4 and R201 supporting lowest numbers. P also significantly (p < 0.05) improved plant height, chlorophyll content, leaf, cob, total biomasses and grain yield across all maize genotypes. Cultivar CV4 produced the highest grain yield under Striga attack. Furthermore, cultivars CV4 and CV1 had significantly (p < 0.05) lowest Striga seed maximum germination distance and percentages at zero P. Application of P reduced Striga germination, attachments and emergence in all varieties and increased tolerance of maize varieties.
Farmers’ perceptions of climate change, long-term variability and trends in rainfall in Apac district, northern Uganda
Authors: Atube Francis , Malinga Geoffrey M. , Nyeko Martine , Okello Daniel M. , Mugonola Basil , Omony George William , Okello-Uma Ipolto
Published: July 2022

Background

Climate change poses severe threats to smallholder farmers' agricultural livelihoods and food security in Sub Saharan Africa. Understanding long-term rainfall trends of variability and extremes at local scales and perceptions regarding long-term changes in climate variables is important in planning appropriate adaptation measures to climate change. This paper examines the perception of farmers in Apac district regarding long-term changes in climate variables and analyzes the trend of occurrence in seasonal and annual rainfall in Apac district, northern Uganda. A cross-sectional survey design was employed to collect data on farmers' perceptions regarding long-term changes in climate from 260 randomly selected smallholder farmers’ households across two sub-counties in Apac district by administering semi-structured questionnaires in February 2018. Monthly rainfall data sets from the Uganda Meteorological Authority (UMA) for the period 1980 to 2019 for Apac district were also used to analyze trends of occurrences in seasonal and annual rainfall in the study area. The non-parametric Sequential Mann–Kendall (SMK) tests were employed at a 5% significance level to detect mean seasonal rainfall trends and abrupt change points.

Results

The majority of the respondents (87%) perceived a decrease in precipitation over the past 39 years. The plot of forward regression u(ti) values and backward regression u’(ti) values showed interactions indicating rainfall trends, rainfall lower and upper limits and abrupt change points in the different cropping seasons. Analysis of historical series of mean monthly and annual rainfall showed an abrupt change in rainfall in March, April, May (MAM) season in 1982. Although the September, October and November (SON) season did not show a significant abrupt change, there was a significant (p < 0.05) increase in rainfall above the upper limit from 1994 to date.

Conclusion

The mean seasonal rainfall for MAM and SON cropping seasons in Apac district were highly variable from different time points within the past 39 years (1980–2019), while June, July, and August (JJA) did not realize a significant change in rainfall within the same study period that the two cropping seasons (MAM and SON) in the district experienced remarkable variations in rainfall. This, therefore, provides a basis for the government to strengthen the provision of an effective climate tailored agricultural advisory service to aid farmers’ adaptation planning at the local level and to assist smallholder farmers and land-use managers in developing effective adaptation management strategies to the effects of climate change.
Petrophysical inversion based on f-s-r amplitude-variation-with-offset linearization and canonical correlation analysis
Authors: Grana Dario , Russell Brian , Mukerji Tapan
Published: July 2022

The prediction of petrophysical properties, such as porosity and rock-fluid volumes, from partially stacked seismic data typically requires a rock-physics model that often is lithology dependent and difficult to calibrate. We adopt canonical correlation analysis (CCA) to infer the underlying relation between petrophysical properties and elastic attributes estimated from seismic data. We develop a two-step inversion approach: first, we predict elastic properties from partially stacked seismic data using a Bayesian linear inverse method based on an amplitude-variation-with-offset (AVO) linearization in terms of fluid, rigidity, and density factors, and then we predict petrophysical properties from the estimated AVO attributes using CCA. The novelty of our approach is the application of CCA to the fluid and rigidity factors, which avoids the calibration of an explicit rock-physics model by automatically deriving a linear relation in the lower dimensional space of the canonical variables. The parameterization of the linearization in terms of fluid, rigidity, and density factors maximizes the correlation with respect to the petrophysical properties of interest. Furthermore, the probabilistic approach is extended to the petrophysical inversion using Bayesian linear theory and the posterior distribution of petrophysical properties conditioned by seismic data is computed by combining the probability distributions obtained from seismic and petrophysical inversion to propagate the uncertainty from the seismic to the petrophysical domain. The inversion is validated on a synthetic case that finds high accuracy of our formulation. A case study with synthetic and real partially stacked seismic data also is presented and compared to a traditional inversion with an explicit rock-physics model.
Fast spatial structure constrained 3D prestack inversion based on the Sylvester equation
Authors: Yang Yaming , Yin Xingyao , Li Kun
Published: July 2022

Structurally constrained inversion (SCI) is a multitrace processing technology that can effectively reduce the complexity of prestack seismic inversion caused by complex geology such as faults and steeply dipping structures. Nevertheless, several factors limit its wide application in 3D prestack inversion, the most significant of which is the high computational cost. In addition, the existing SCI is mostly applied in 2D profiles, which can only consider structural features in one direction, making it challenging to ensure spatial continuity. We have developed a fast spatial structure constrained inversion for 3D prestack seismic data. First, based on the conventional SCI, we develop a new way to describe the spatial structural characteristics of the stratum by estimating the dip angles along two perpendicular directions. Second, we introduce the spatial structure constraints through the Hadamard product operator and construct a computationally well-behaved objective function with spatial structural constrained. Using our matrix operators, which are symbols representing the multiplication of 2D and 3D matrices, the minimization of the objective function can be simplified to solve a specific Sylvester equation. Moreover, we justify the rationality of our operator symbols and derive a fast algorithm for solving 3D problems with the Sylvester equation. Finally, the stability and computational efficiency of our method are compared with the 2D SCI algorithm on the 3D overthrust model and field prestack seismic data.