bluuebunny/crossref_metadata_2025 huggingface dataset:
Autophagy Blockage Reduces the Incidence of Pancreatic Ductal Adenocarcinoma in the Context of Mutant Trp53
Authors: Mainz Laura , Sarhan Mohamed A. F. E. , Roth Sabine , Sauer Ursula , Maurus Katja , Hartmann Elena M. , Seibert Helen-Desiree , Rosenwald Andreas , Diefenbacher Markus E. , Rosenfeldt Mathias T.
Published: March 2022

Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53R172H) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.
Whole-Exome Sequencing Identifies a Novel CPT2 Mutation in a Pedigree With Gout
Authors: Guo Yong , Jin Jing , Zhou Zhenni , Chen Yihui , Sun Li , Zhang Chunwu , Xia Xiaoru
Published: March 2022

Background: Gout is a common inflammatory arthritis, and its exact pathogenesis remains unclear. Multiple studies have demonstrated that genetic factors play important roles in the development of gout. This study aims to investigate the genetic basis of gout in a three-generation pedigree of affected individuals.

Methods: Whole-exome sequencing (WES), comprehensive variant analyses, and co-segregation testing were performed. The effects of candidate variants on protein localization and cellular expression were analyzed, as were interactions with gout-related genes.

Results: After comprehensive bioinformatic analysis, Sanger sequencing validation, and pedigree co-segregation analysis, we identified a rare heterozygous missense variant (c.1891C > T, p.R631C) in CPT2. Although no associated changes in localization were observed, the fluorescence intensity of p.R631C mutants was obviously reduced in comparison to the wild-type protein, suggesting that protein degradation is induced by the mutant. Furthermore, our results also indicate that the c.1891C > T variant influences the ability of CPT2 to bind UCP2.

Conclusion: This study identified a rare CPT2 mutation in a large Chinese pedigree with gout. Functional studies were used to define the effect of this mutant. This study provides novel insight into the genetic etiology of gout.
Recent Update on Retinoic Acid-Driven Initiation of Spermatogonial Differentiation
Authors: Bhattacharya Indrashis , Sharma Partigya , Purohit Shriya , Kothiyal Sachin , Das Moitreyi , Banerjee Arnab
Published: March 2022

Germ cells (Gc) propagate the genetic information to subsequent generations. Diploid (2n) Gc get transformed to specialized haploid (n) gametes by mitotic and meiotic divisions in adult gonads. Retinoic acid (RA), an active derivative of vitamin A (retinol), plays a critical role in organ morphogenesis and regulates the meiotic onset in developing Gc. Unlike ovaries, fetal testes express an RA-degrading enzyme CYP26B1, and thereby, male Gc fail to enter into meiosis and instead get arrested at G0/G1 stage, termed as gonocytes/pro-spermatogonia by embryonic (E) 13.5 days. These gonocytes are transformed into spermatogonial stem/progenitor cells after birth (1–3 days of neonatal age). During post-natal testicular maturation, the differentiating spermatogonia enter into the meiotic prophase under the influence RA, independent of gonadotropic (both FSH and LH) support. The first pulse of RA ensures the transition of undifferentiated type A spermatogonia to differentiated A1 spermatogonia and upregulates STRA8 expression in Gc. Whereas, the second pulse of RA induces the meiotic prophase by augmenting MEIOSIN expression in differentiated spermatogonia B. This opinion article briefly reviews our current understanding on the RA-driven spermatogonial differentiation in murine testes.
Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy
Authors: Gage Meghan , Gard Megan , Thippeswamy Thimmasettappa
Published: March 2022

Glial scars have been observed following stab lesions in the spinal cord and brain but not observed and characterized in chemoconvulsant-induced epilepsy models. Epilepsy is a disorder characterized by spontaneous recurrent seizures and can be modeled in rodents. Diisopropylfluorophosphate (DFP) exposure, like other real-world organophosphate nerve agents (OPNAs) used in chemical warfare scenarios, can lead to the development of status epilepticus (SE). We have previously demonstrated that DFP-induced SE promotes epileptogenesis which is characterized by the development of spontaneous recurrent seizures (SRS), gliosis, and neurodegeneration. In this study, we report classical glial scars developed in the piriform cortex, but not in the hippocampus, by 8 days post-exposure. We challenged both male and female rats with 4–5 mg/kg DFP (s.c.) followed immediately by 2 mg/kg atropine sulfate (i.m.) and 25 mg/kg pralidoxime (i.m.) and one hour later by midazolam (i.m). Glial scars were present in the piriform cortex/amygdala region in 73% of the DFP treated animals. No scars were found in controls. Scars were characterized by a massive clustering of reactive microglia surrounded by hypertrophic reactive astrocytes. The core of the scars was filled with a significant increase of IBA1 and CD68 positive cells and a significant reduction in NeuN positive cells compared to the periphery of the scars. There was a significantly higher density of reactive GFAP, complement 3 (C3), and inducible nitric oxide synthase (iNOS) positive cells at the periphery of the scar compared to similar areas in controls. We found a significant increase in chondroitin sulfate proteoglycans (CS-56) in the periphery of the scars compared to a similar region in control brains. However, there was no change in TGF-β1 or TGF-β2 positive cells in or around the scars in DFP-exposed animals compared to controls. In contrast to stab-induced scars, we did not find fibroblasts (Thy1.1) in the scar core or periphery. There were sex differences with respect to the density of iNOS, CD68, NeuN, GFAP, C3 and CS-56 positive cells. This is the first report of cortical glial scars in rodents with systemic chemoconvulsant-induced SE. Further investigation could help to elucidate the mechanisms of scar development and mitigation strategies.
Electrochemical Sensing of Nitrite Ions Using Modified Electrode by Poly 1,8-Diaminonaphthalene/Functionalized Multi-Walled Carbon Nanotubes
Authors: Salhi Ouissal , Ez-zine Tarik , Oularbi Larbi , El Rhazi Mama
Published: March 2022

A novel electrochemical sensor based on conducting polymer and multi-walled carbon nanotubes was reported for the detection of nitrite ions (NO2−). The hybrid material poly 1,8-Diaminonaphthalene (poly 1,8-DAN)/functionalized multi-walled carbon nanotubes (f-MWCNT) was prepared by using a simple electrochemical approach which is based on the deposition of functionalized multi-walled carbon nanotubes (f-MWCNT) on the surface of the electrode followed by the electropolymerization of 1,8-DAN using cyclic voltammetry. The morphology and the electro-catalytic properties of the obtained electrodes were investigated with Fourier Transform Infrared Spectroscopy (FTIR), Transmission Electron Microscopy (TEM), Cyclic Voltammetry (CV), and Electrochemical Impedance Spectroscopy (EIS) showing an improvement of the electronic transfer due to the synergic effect between the proprieties of poly 1,8-DAN and f-MWCNT. Under the optimum experimental conditions, the poly 1,8-DAN/f-MWCNT/CPE exhibited excellent electro-catalytic activity towards nitrite detection. The nitrite anodic peak potential decreased by 210 mV compared to the bare carbon paste electrode. The calibration plot of nitrite detection was linear in the range of concentration from 300 to 6500 nM with a low detection limit of 75 nM.
Microbial Community Composition in Explanted Cystic Fibrosis and Control Donor Lungs
Authors: Einarsson Gisli G. , Vanaudenaerde Bart M. , Spence Christopher D. , Lee Andrew J. , Boon Mieke , Verleden Geert M. , Elborn J. Stuart , Dupont Lieven J. , Van Raemdonck Dirk , Gilpin Deirdre F. , Vos Robin , Verleden Stijn E. , Tunney Michael M.
Published: March 2022

To date, investigations of the microbiota in the lungs of people with Cystic Fibrosis (PWCF) have primarily focused on microbial community composition in luminal mucus, with fewer studies observing the microbiota in tissue samples from explanted lung tissue. Here, we analysed both tissue and airway luminal mucus samples extracted from whole explanted lungs of PWCF and unused donor lungs. We determined if the lung microbiota in end-stage CF varied within and between patients, was spatially heterogeneous and related to localized structural damage. Microbial community composition was determined by Illumina MiSeq sequencing and related to the CF-Computed Tomography (CT) score and features of end-stage lung disease on micro-CT. Ninety-eight CF tissue (n=11 patients), 20 CF luminal mucus (n=8 patients) and 33 donor tissue (n=4 patients) samples were analysed. Additionally, we compared 20 paired CF tissue and luminal mucus samples that enabled a direct “geographical” comparison of the microbiota in these two niches. Significant differences in microbial communities were apparent between the 3 groups. However, overlap between the three groups, particularly between CF and donor tissue and CF tissue and CF luminal mucus was also observed. Microbial diversity was lower in CF luminal mucus compared to CF tissue, with dominance higher in luminal mucus. For both CF and donor tissue, intra- and inter-patient variability in ecological parameters was observed. No relationships were observed between ecological parameters and CF-CT score, or features of end-stage lung disease. The end-stage CF lung is characterised by a low diversity microbiota, differing within and between individuals. No clear relationship was observed between regional microbiota variation and structural lung damage.
Diagnosis and Management of Bloodstream Infections With Rapid, Multiplexed Molecular Assays
Authors: Dunbar Sherry A. , Gardner Christopher , Das Shubhagata
Published: March 2022

Bloodstream infection is a major health concern, responsible for considerable morbidity and mortality across the globe. Prompt identification of the responsible pathogen in the early stages of the disease allows clinicians to implement appropriate antibiotic therapy in a timelier manner. Rapid treatment with the correct antibiotic not only improves the chances of patient survival, but also significantly reduces the length of hospital stay and associated healthcare costs. Although culture has been the gold standard and most common method for diagnosis of bloodstream pathogens, it is being enhanced or supplanted with more advanced methods, including molecular tests that can reduce the turnaround time from several days to a few hours. In this article, we describe two rapid, molecular bloodstream infection panels that identify the most common pathogens and associated genetic determinants of antibiotic resistance – the Luminex® VERIGENE® Gram-Positive Blood Culture Test and the VERIGENE® Gram-Negative Blood Culture Test. We conducted a search on PubMed to retrieve articles describing the performance and impact of these tests in the clinical setting. From a total of 48 articles retrieved, we selected 15 for inclusion in this review based on the type and size of the study and so there would be minimum of three articles describing performance and three articles describing the impact post-implementation for each assay. Here we provide a comprehensive review of these publications illustrating the performance and clinical utility of these assays, demonstrating how genotypic tests can benefit diagnostic and antimicrobial stewardship efforts.
Exploring Potential Links Between Co-occurring Coastal Terrestrial and Marine Heatwaves in Australia
Authors: Pathmeswaran Charuni , Sen Gupta Alex , Perkins-Kirkpatrick Sarah E. , Hart Melissa Anne
Published: March 2022

Despite numerous studies examining terrestrial or marine heatwaves independently, little work has investigated potential associations between these two types of extreme events. Examination of a limited number of past events suggests that certain co-occurring terrestrial and marine heatwaves have common drivers. Co-occurring events may also interact via local land-sea interactions, thereby altering the likelihood of these events. This study explores possible links between adjacent coastal marine and terrestrial heatwaves around Australia using observation and reanalysis data. We find a significant increase in the number of terrestrial heatwave days in the presence of an adjacent co-occurring marine heatwave along the coastal belt of Australia. In most regions, this increase persists at least 150 km inland. This suggests that processes operating beyond the narrow coastal belt are important in most regions. We also show that synoptic conditions driving a terrestrial heatwave in three locations around Australia are conducive for warming the ocean, which would increase the likelihood of a marine heatwave occurring. However, ocean state must also be conducive to reach MHW conditions. Our findings suggest that co-occurring terrestrial and marine heatwaves co-occur more frequently than chance would dictate, and that large scale synoptics may be conducive to both coastal terrestrial and marine heatwaves.
Diagnostic Value of 11C-PIB PET/MR in Cardiac Amyloidosis
Authors: Bi Xiao , Xu Baixuan , Liu Jiajin , Wang Guanyun , An Jing , Zhang Xiaojun , Wang Ruimin , Dong Wei , Guan Zhiwei
Published: March 2022

Background

The thioflavin T derivative, 11C-Pittsburgh-B (PIB), is used for Alzheimer's disease imaging because it specifically binds to β-amyloid protein deposits in the brain. The aim of this study was to estimate the diagnostic value of combined 11C-PIB positron emission tomography/magnetic resonance (PET/MR) in cardiac amyloidosis (CA).

Methods

We enrolled 23 heart failure patients with suspected CA based on echocardiographic and electrocardiograph findings. All patients underwent cardiac 11C-PIB PET/MR and non-cardiac biopsy within one week. We also enrolled eight healthy volunteers that underwent cardiac 11C-PIB PET/MR as a control group. The cardiac magnetic resonance (CMR) protocol included cine imaging, late gadolinium enhancement (LGE), and native and post-contrast T1 mapping. Extracellular volume (ECV) was measured using pre- and post-contrast T1 mapping images. LVEF, IVSD, LVPW, LVmass, LVESV, LVEDV, native T1 value, ECV, and maximum uptake of myocardial tissue-to-blood background ratio (TBR) values were obtained from PET/MR images in all patients and healthy subjects.

Results

Thirteen out of twenty-three heart failure patients were clinically diagnosed with CA. The remaining 10 patients were CA-negative (non-CA patient group). Twelve of the thirteen CA patients showed diffuse transmural LGE patterns, whereas LGE was either absent or patchy in the non-CA patients. The diagnostic sensitivity and specificity of TBRmax were 92.3 and 100%, respectively, at a cut-off value of 1.09. Several CMR imaging parameters (LVEF, IVSD, LVmass, LVEDV, LVESV, LVPW, native T1 value and ECV) and TBR showed significant differences between CA patients, non-CA patients, and healthy controls (P < 0.05). Native T1 mapping values positively correlated with TBRmax values in CA and non-CA patients (r = 0.38, P = 0.0004).

Conclusions

11C-PIB PET/MRI is a valuable tool for the accurate and non-invasive diagnosis of CA because it distinguishes CA patients from non-CA patients and healthy subjects with high specificity and sensitivity. Moreover, native T1 mapping values positively correlated with TBRmax values in CA and non-CA patients. In the future, larger cohort studies are necessary to confirm our findings.
Fibroblast Growth Factor 21 Predicts Short-Term Prognosis in Patients With Acute Heart Failure: A Prospective Cohort Study
Authors: Wu Guihai , Wu Shenglin , Yan Jingyi , Gao Shanshan , Zhu Jinxiu , Yue Minghui , Li Zexin , Tan Xuerui
Published: March 2022

Background

Recent studies of fibroblast growth factor 21 (FGF21), first recognized as a regulator of glucose and lipid metabolism, have found that the level of in serum FGF21 is associated with the prognosis of many cardiovascular diseases, but its relationship to acute heart failure (AHF) patients remains unknown. Our study aimed to investigate whether circulating FGF21 could predict the short-term prognosis of AHF patients.

Methods

Four hundred and two AHF patients and 19 healthy controls were recruited into the prospective cohort study, and blood samples of participants were collected, in tubes without anticoagulant, within the first 24 h after hospital admission. Serum FGF21 levels were detected by enzyme-linked immunosorbent assay (ELISA). All patients were followed-up at least 6 months after discharge. The primary endpoint was all-cause death, and secondary endpoint was a composite endpoint of death and heart failure readmission. Mortality and composite end point events were analyzed using Kaplan-Meier curves. ROC curves compared the difference between the FGF21 and NT-proBNP in predicting 3- and 6-months mortality. Time-to-event data were evaluated using Kaplan-Meier estimation and Cox proportional hazards models.

Results

In the present study, the serum FGF21 concentrations were significantly higher in the 402 AHF patients enrolled, compared with the 19 healthy controls (p < 0.001). The average age was 70 (±12) years, and 58% were males. Participants were divided into two groups according to the median FGF21 level (262 pg/ml): a high FGF21 group (n = 201, FGF21 ≥ 262 pg/ml) and low FGF21 group (n = 201, FGF21 <262 pg/ml). FGF21 was positively correlated with NT-proBNP, BUN, AST, creatinine and cholesterol, and negatively correlated with ALB and HDL. After a median follow-up of 193 days, the high FGF21 group had higher mortality and composite endpoint events compared with the low FGF21 group (HR: 3.91, 95% CI 2.21–6.92, p <0.001), even after adjusting for NT-proBNP (HR: 3.17, 95% CI 1.72–5.81, p < 0.001). ROC analysis shows that FGF21 was better than NT-proBNP in predicting death at both 3 (AUC, 0.77 vs. 0.63, p < 0.001) and 6 months (AUC, 0.78 vs. 0.66).

Conclusion

High baseline FGF21 levels are associated with adverse clinical outcomes in AHF patients. Serum FGF21 might be a potential predictive biomarker of AHF patients.
Case Report: Residual Atrial Shunt Lesions in Aging Adults With Congenital Heart Disease: An Underestimated Risk of Stroke?
Authors: Schneider Matthias , Dannenberg Varius , Opgen-Rhein Bernd , Berger Felix , Pieske Burkert , Gabriel Harald , Boldt Leif-Hendrik
Published: March 2022

We report two cases of paradoxical cerebral embolism in adults with congenital heart disease (ACHD) with residual atrial shunt lesions, a 59 year-old male patient with partial detachment of a surgical ASD closure patch, and a 57 year-old male patient with Ebstein’s anomaly and a large patent foramen ovale. Considering these mechanisms and the increasing incidence of venous thrombosis with age, a higher prevalence of paradoxical embolism in ACHD patients with residual atrial shunts may be suspected. Regular follow-up of patients with ACHD remains important throughout life even in seemingly stable lesions.
The Role of in silico Research in Developing Nanoparticle-Based Therapeutics
Authors: Jayasinghe Migara Kavishka , Lee Chang Yu , Tran Trinh T. T. , Tan Rachel , Chew Sarah Min , Yeo Brendon Zhi Jie , Loh Wen Xiu , Pirisinu Marco , Le Minh T. N.
Published: March 2022

Nanoparticles (NPs) hold great potential as therapeutics, particularly in the realm of drug delivery. They are effective at functional cargo delivery and offer a great degree of amenability that can be used to offset toxic side effects or to target drugs to specific regions in the body. However, there are many challenges associated with the development of NP-based drug formulations that hamper their successful clinical translation. Arguably, the most significant barrier in the way of efficacious NP-based drug delivery systems is the tedious and time-consuming nature of NP formulation—a process that needs to account for downstream effects, such as the onset of potential toxicity or immunogenicity, in vivo biodistribution and overall pharmacokinetic profiles, all while maintaining desirable therapeutic outcomes. Computational and AI-based approaches have shown promise in alleviating some of these restrictions. Via predictive modeling and deep learning, in silico approaches have shown the ability to accurately model NP-membrane interactions and cellular uptake based on minimal data, such as the physicochemical characteristics of a given NP. More importantly, machine learning allows computational models to predict how specific changes could be made to the physicochemical characteristics of a NP to improve functional aspects, such as drug retention or endocytosis. On a larger scale, they are also able to predict the in vivo pharmacokinetics of NP-encapsulated drugs, predicting aspects such as circulatory half-life, toxicity, and biodistribution. However, the convergence of nanomedicine and computational approaches is still in its infancy and limited in its applicability. The interactions between NPs, the encapsulated drug and the body form an intricate network of interactions that cannot be modeled with absolute certainty. Despite this, rapid advancements in the area promise to deliver increasingly powerful tools capable of accelerating the development of advanced nanoscale therapeutics. Here, we describe computational approaches that have been utilized in the field of nanomedicine, focusing on approaches for NP design and engineering.
Automated Seismo-Volcanic Event Detection Applied to Stromboli (Italy)
Authors: Fenner Darius , Rümpker Georg , Li Wei , Chakraborty Megha , Faber Johannes , Köhler Jonas , Stöcker Horst , Srivastava Nishtha
Published: March 2022

Many active volcanoes exhibit Strombolian activity, which is typically characterized by relatively frequent mild volcanic explosions and also by rare and much more destructive major explosions and paroxysms. Detailed analyses of past major and minor events can help to understand the eruptive behavior of volcanoes and the underlying physical and chemical processes. Catalogs of these eruptions and, specifically, seismo-volcanic events may be generated using continuous seismic recordings at stations in the proximity of volcanoes. However, in many cases, the analysis of the recordings relies heavily on the manual picking of events by human experts. Recently developed Machine Learning-based approaches require large training data sets which may not be available a priori. Here, we propose an alternative user-friendly, time-saving, automated approach labelled as: the Adaptive-Window Volcanic Event Selection Analysis Module (AWESAM). This strategy of creating seismo-volcanic event catalogs consists of three main steps: 1) identification of potential volcanic events based on squared ground-velocity amplitudes, an adaptive MaxFilter, and a prominence threshold. 2) catalog consolidation by comparing and verifying the initial detections based on recordings from two different seismic stations. 3) identification and exclusion of signals from regional tectonic earthquakes. The strength of the python package is the reliable detection of very small and frequent events as well as major explosions and paroxysms. Here, it is applied to publicly accessible continuous seismic recordings from two almost equidistant stations at Stromboli volcano in Italy. We tested AWESAM by comparison with a hand-picked catalog and found that around 95% of the seismo-volcanic events with a signal-to-noise ratio above three are detected. In a first application, we derive a new amplitude-frequency relationship from over 290.000 seismo-volcanic events at Stromboli during 2019–2020 which were detected by AWESAM. The module allows for a straightforward generalization and application to other volcanoes with frequent Strombolian activity worldwide. Furthermore, this module can be implemented for volcanoes with rarer explosions.
Comparative Cardiovascular Outcomes of SGLT2 Inhibitors in Type 2 Diabetes Mellitus: A Network Meta-Analysis of Randomized Controlled Trials
Authors: Jiang Yu , Yang Pingping , Fu Linghua , Sun Lizhe , Shen Wen , Wu Qinghua
Published: March 2022

Background

A network meta-analysis of randomized controlled trials (RCTs) was conducted to explore the cardiovascular outcomes of all the kind and dosages of sodium-glucose cotransport-2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients.

Method and Result

The Cochrane Library, PubMed, and Embase databases were systematically searched for studies to compare the therapeutic effects of different SGLT2 inhibitors in T2DM patients. The effect measurements estimate chosen were odds ratios (ORs) and their corresponding 95% confidence interval (CI). Forty-seven RCTs involving a total of 70574 participants were eligible for direct and indirect comparisons. In direct comparison, treatment with dapagliflozin 5mg showed significantly lower risk of all-cause mortality compared with treatment with dapagliflozin 2.5mg (OR 0.09, 95% CI 0.01-0.70). According to NMA, interestingly, empagliflozin 10mg/25mg, and canagliflozin 100mg was associated with significantly lower risks of all-cause mortality compared with placebo (OR of 0.70, 95% CI 0.58-0.85; 0.69, 95% CI 0.57-0.84; and 0.83, 95% CI 0.73-0.95, respectively). Compared with placebo, dapagliflozin 10mg, empagliflozin 10mg and 25mg displayed the lower risks for cardiovascular events (OR 0.78, 95% CI 0.44-1.00; OR 0.47, 95% CI 0.22-0.93; and 0.43, 95% CI 0.24-0.74, respectively) by direct comparison. Moreover, canagliflozin 100/300mg showed significantly higher risks of cardiovascular events compared with empagliflozin 10mg (OR of 4.83, 95% CI 1.14-20.46 and 5.31, 95% CI 1.26-22.34, respectively) and empagliflozin 25mg (4.23, 95% CI 1.13-15.83 and 4.65, 95% CI 1.25-17.27, respectively) according to NMA. There were non-significant differences among all interventions in volume depletion in traditional pairwise meta-analysis. While in NMA, canagliflozin 100/300mg were associated with significantly increased risks of volume depletion compared with placebo (OR of 1.47, 95% CI 1.08-1.99 and 2.19, 95% CI 1.66-2.90, respectively).

Conclusion

In the limitations of the NMA, this study showed that empagliflozin might be better than other SGLT2 inhibitors with low risks of all-cause mortality and cardiovascular events in patients with T2DM suggesting the need for ad hoc RCTs.
Perirenal Fat Thickness: A Surrogate Marker for Metabolic Syndrome in Chinese Newly Diagnosed Type 2 Diabetes
Authors: Guo Xiu Li , Tu Mei , Chen Yang , Wang Wei
Published: March 2022

Objective

Increasing evidence suggested that perirenal fat thickness (PrFT) was associated with metabolic risk factors. This study aimed to assess the association between PrFT and metabolic syndrome (MetS) in Chinese newly diagnosed type 2 diabetes (T2DM), further evaluating the ability of PrFT in identifying MetS.

Method

A total of 445 Chinese newly diagnosed T2DM were enrolled in this study from January to June 2021. Demographic and anthropometric information were collected. PrFT was evaluated by CT scan on Revolution VCT 256. MetS was based on the Chinese Diabetes Society definition. Receiver operating characteristic (ROC) curve was conducted to assess the optimal cutoff value of PrFT in identifying MetS.

Results

Overall, the prevalence of MetS was 57.5% (95% CI: 54.0–64.0%) in men and 58.9% (95% CI: 52.3–65.5%) in women separately. The correlation analysis showed that PrFT was significantly correlated with metabolic risk factors like body mass index, waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, uric acid, and insulin resistance. PrFT was also shown to be independently associated with MetS after adjustment for other confounders. The odds ratios (ORs, 95% CI) were 1.15 (1.03–1.38) in men and 1.31 (1.08–1.96) in women (P <0.05). The ROC curves showed a good predictive value of PrFT for MetS. The areas under the curve of PrFT identifying MetS were 0.895 (95% CI: 0.852–0.939) in men and 0.910 (95% CI: 0.876–0.953) in women (P <0.001). The optimal cutoff values of PrFT were 14.6 mm (sensitivity: 83.8%, specificity: 89.6%) for men and 13.1 mm (sensitivity: 87.6%, specificity: 91.1%) for women.

Conclusions

PrFT was significantly associated with MetS and showed a powerful predictive value for it, which suggested that PrFT can be an applicable surrogate marker for MetS in Chinese newly diagnosed T2DM.

Clinical Trial Registration

This study was registered in clinicaltrials.gov (ChiCTR2100052032).
The Influence of the Corona Virus Pandemic on Sustainable Development Goal 13 and United Nations Framework Convention on Climate Change Processes
Authors: Filho Walter Leal , Hickmann Thomas , Nagy Gustavo J. , Pinho Patricia , Sharifi Ayyoob , Minhas Aprajita , Islam M Rezaul , Djalanti Riyanti , García Vinuesa Antonio , Abubakar Ismaila Rimi
Published: March 2022

Apart from many social and economic problems worldwide, the COVID-19 pandemic has also led to sudden halt in face-to-face climate-related meetings. Moreover, it has also negatively influenced the works related to the preparations for the sixth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC) and organizing the 26th Conference of the Parties of the UN Framework Convention on Climate Change (UNFCCC), namely COP26 to be held in Glasgow, which was postponed to November 2021. This article presents a global study undertaken among UNFCCC contact points and other climate experts, to ascertain the impacts of the pandemic on the implementation of SDG13 and UNFCCC processes. The methodological approach entails an bibliometric analysis, online survey, and authors’ expert judgment. Results of the bibliometric analysis show that the most common terms associated with this theme are COVID-19, climate change, CO2, energy, “pandemic-related,” and “adaptation-related.” In addition, the survey revealed some difficulties associated with online participation in the processes from many developing countries. The study concluded that there is negative impact of COVID-19 pandemic on the UNFCCC process, more minor government priorities regarding climate action, loss of traction of the process, and a challenge to achieve the Paris Agreement, with less significant support from the respondents from less developed countries. The findings suggest that urgent action is needed, to make up for the lost time, and place climate issues more prominently on the global agenda.
A Synoptic Framework for Forecasting the Urban Rainfall Effect Using Composite and K-Means Cluster Analyses
Authors: McLeod Jordan , Shepherd Marshall
Published: March 2022

Observational and numerical modeling studies continue to affirm the existence of the “urban rainfall effect” (URE), or a discernible anomaly in warm season precipitation due to urbanization. However, the literature has been lacking a progression towards the predictability of the URE. Atlanta, Georgia has consistently appeared in the literature because of its well-studied urban rainfall anomalies. Using the Multi-sensor Precipitation Estimates (MPE) dataset and the ERA-Interim reanalysis dataset, an 18-year period (2002–2019) is examined. Three similar but distinct methods are used to define urban rainfall days (URDs), or periods when the precipitation in the urbanized areas of Atlanta are greater than the surrounding rural areas. A combination of compositing, wind rose, and k-means cluster analyses are employed to extract the synoptic framework supportive of the URE in Atlanta, Georgia. The synoptic-scale compositing analysis reveals that there are a consistent set of meteorological ingredients that are needed to produce an URD, including weaker-than-average southwesterly-to-northwesterly flow at 700 hPa, copious amounts of moisture throughout the tropospheric column, and a background low-level convergent flow. Composite atmospheric soundings reveal that there is enhanced moisture throughout the tropospheric column on URDs, leading to marginal instability that favors localized convection across the Atlanta metropolitan area. The study also provides clarity on how often the URE is present (roughly 8% of the time) during warm season days across the Atlanta metropolitan area. Taken together, this synoptic framework will aid in the forecasting of the URE in Atlanta and can be easily applied to other cities.
Highly Sensitive Fluorescent Biosensor Based on Acetylcholinesterase and Carbon Dots–Graphene Oxide Quenching Test for Analytical and Commercial Organophosphate Pesticide Detection
Authors: Gaviria Maria I. , Barrientos Kaory , Arango Juan Pablo , Cano Juan B. , Peñuela Gustavo A.
Published: March 2022

Graphical Abstract
Review and Synthesis of Estimation Strategies to Meet Small Area Needs in Forest Inventory
Authors: Dettmann Garret T. , Radtke Philip J. , Coulston John W. , Green P. Corey , Wilson Barry T. , Moisen Gretchen G.
Published: March 2022

Small area estimation is a growing area of research for making inferences over geographic, demographic, or temporal domains smaller than those in which a particular survey data set was originally intended to be used. We aimed to review a body of literature to summarize the breadth and depth of small area estimation and related estimation strategies in forest inventory and management to-date, as well as the current state of terminology, methods, concerns, data sources, research findings, challenges, and opportunities for future work relevant to forestry and forest inventory research. Estimation methodologies explored include direct, indirect, and composite estimation within design-based and model-based inference bases. A variety of estimation methods in forestry have been applied to extensive multi-resource inventory systems like national forest inventories to increase the precision of estimates on small domains or subsets of the overall populations of interest. To avoid instability and large variances associated with small sample sizes when working with small area domains, forest inventory data are often supplemented with information from auxiliary sources, especially from remote sensing platforms and other geospatial, map-based products. Results from many studies show gains in precision compared to direct estimates based only on field inventory data. Gains in precision have been demonstrated in both project-level applications and national forest inventory systems. Potential gains are possible over varying geographic and temporal scales, with the degree of success in reducing variance also dependent on the types of auxiliary information, scale, strength of model relationships, and methodological alternatives, leaving considerable opportunity for future research and growth in small area applications for forest inventory.
Experimental Evolution Reveals Redox State Modulates Mycobacterial Pathogenicity
Authors: Jiang Zheng , Zhuang Zengfang , Mi Kaixia
Published: March 2022

Understanding how Mycobacterium tuberculosis has evolved into a professional pathogen is helpful in studying its pathogenesis and for designing vaccines. We investigated how the evolutionary adaptation of M. smegmatis mc251 to an important clinical stressor H2O2 allows bacteria to undergo coordinated genetic mutations, resulting in increased pathogenicity. Whole-genome sequencing identified a mutation site in the fur gene, which caused increased expression of katG. Using a Wayne dormancy model, mc251 showed a growth advantage over its parental strain mc2155 in recovering from dormancy under anaerobic conditions. Meanwhile, the high level of KatG in mc251 was accompanied by a low level of ATP, which meant that mc251 is at a low respiratory level. Additionally, the redox-related protein Rv1996 showed different phenotypes in different specific redox states in M. smegmatis mc2155 and mc251, M. bovis BCG, and M. tuberculosis mc27000. In conclusion, our study shows that the same gene presents different phenotypes under different physiological conditions. This may partly explain why M. smegmatis and M. tuberculosis have similar virulence factors and signaling transduction systems such as two-component systems and sigma factors, but due to the different redox states in the corresponding bacteria, M. smegmatis is a nonpathogen, while M. tuberculosis is a pathogen. As mc251 overcomes its shortcomings of rapid removal, it can potentially be developed as a vaccine vector.
A Polymorphism in the BDNF Gene (rs11030101) is Associated With Negative Symptoms in Chinese Han Patients With Schizophrenia
Authors: Ping Junjiao , Zhang Jie , Wan Jing , Huang Caiying , Luo Jiali , Du Baoguo , Jiang Tingyun
Published: March 2022

Objective: This study aimed to investigate the association between brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element binding protein (CREB) gene polymorphisms and schizophrenia.

Methods: This study used a case-control design, and diagnoses were made based on the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. One hundred and thirty-four patients with schizophrenia were recruited from the Third People’s Hospital of Zhongshan City from January 2018 to April 2020. Sixty-four healthy controls were recruited from the same region. Genotypes at the BDNF gene single nucleotide polymorphisms rs11030101, rs2030324, and rs6265 and the CREB gene single nucleotide polymorphisms rs6740584 and rs2551640 were determined using a MassARRAY mass spectrometer. Linkage disequilibrium and haplotype analyses were performed, and genotype and allele frequencies were compared between groups. The positive and negative symptom scale (PANSS) was used to evaluate the association between the BDNF and CREB gene polymorphisms and schizophrenic symptoms.

Results: There was no significant difference in genotype or allele frequencies for rs11030101, rs2030324, rs6265, rs6740584, or rs2551640 between schizophrenic patients and controls (p > 0.05). In addition, there were no significant differences in rs11030101, rs2030324, rs6265, rs6740584, or rs2551640 genotype frequencies between the two groups in the dominant, recessive, or over-dominant models (p > 0.05). Three loci in the BDNF gene and two loci in the CREB gene were in a state of strong linkage disequilibrium. The frequency of haplotype AAC (rs11030101/rs2030324/rs626), composed of three loci in the BDNF gene, was significantly increased in schizophrenic patients compared with control subjects. There were significant differences in the subscores of PANSSS for negative symptoms, in patients with different rs11030101 genotypes of the BDNF gene (p < 0.05). There was also significant differences in the PANSS scores for the general symptom G12 (judgment and lack of insight) in patients with different rs6265 genotypes of the BDNF gene (p < 0.05).

Conclusion: The BDNF gene rs11030101/rs2030324/rs6265 AAC haplotype was potentially associated with an increased risk of schizophrenia. In addition, genotypes at the rs11030101 and rs6265 loci may affect the negative symptoms and general symptoms of schizophrenic patients, respectively.
Identification of Potential Diagnostic and Prognostic Biomarkers for Gastric Cancer Based on Bioinformatic Analysis
Authors: Niu Xiaoji , Ren Liman , Hu Aiyan , Zhang Shuhui , Qi Hongjun
Published: March 2022

Background: Gastric cancer (GC) is one of the most prevalent cancers all over the world. The molecular mechanisms of GC remain unclear and not well understood. GC cases are majorly diagnosed at the late stage, resulting in a poor prognosis. Advances in molecular biology techniques allow us to get a better understanding of precise molecular mechanisms and enable us to identify the key genes in the carcinogenesis and progression of GC.

Methods: The present study used datasets from the GEO database to screen differentially expressed genes (DEGs) between GC and normal gastric tissues. GO and KEGG enrichments were utilized to analyze the function of DEGs. The STRING database and Cytoscape software were applied to generate protein–protein network and find hub genes. The expression levels of hub genes were evaluated using data from the TCGA database. Survival analysis was conducted to evaluate the prognostic value of hub genes. The GEPIA database was involved to correlate key gene expressions with the pathological stage. Also, ROC curves were constructed to assess the diagnostic value of key genes.

Results: A total of 607 DEGs were identified using three GEO datasets. GO analysis showed that the DEGs were mainly enriched in extracellular structure and matrix organization, collagen fibril organization, extracellular matrix (ECM), and integrin binding. KEGG enrichment was mainly enriched in protein digestion and absorption, ECM-receptor interaction, and focal adhesion. Fifteen genes were identified as hub genes, one of which was excluded for no significant expression between tumor and normal tissues. COL1A1, COL5A2, P4HA3, and SPARC showed high values in prognosis and diagnosis of GC.

Conclusion: We suggest COL1A1, COL5A2, P4HA3, and SPARC as biomarkers for the diagnosis and prognosis of GC.
The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes
Authors: Sun Jianxuan , Zhong Xingyu , Fu Xiaoyu , Miller Heather , Lee Pamela , Yu Bing , Liu Chaohong
Published: March 2022

Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.
Poxvirus MVA Expressing SARS-CoV-2 S Protein Induces Robust Immunity and Protects Rhesus Macaques From SARS-CoV-2
Authors: Mooij Petra , García-Arriaza Juan , Pérez Patricia , Lázaro-Frías Adrian , Verstrepen Babs E. , Böszörményi Kinga P. , Mortier Daniella , Fagrouch Zahra , Kiemenyi-Kayere Gwendoline , Niphuis Henk , Acar Roja Fidel , Meijer Lisette , Stammes Marieke A. , Kondova Ivanela , Verschoor Ernst J. , GeurtsvanKessel Corine H. , de Bruin Erwin , Sikkema Reina S. , Luczkowiak Joanna , Delgado Rafael , Montenegro Dolores , Puentes Eugenia , Rodríguez Esteban , Bogers Willy M. J. M. , Koopman Gerrit , Esteban Mariano
Published: March 2022

Novel safe, immunogenic, and effective vaccines are needed to control the COVID-19 pandemic, caused by SARS-CoV-2. Here, we describe the safety, robust immunogenicity, and potent efficacy elicited in rhesus macaques by a modified vaccinia virus Ankara (MVA) vector expressing a full-length SARS-CoV-2 spike (S) protein (MVA-S). MVA-S vaccination was well tolerated and induced S and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against SARS-CoV-2 and several variants of concern. S-specific IFNγ, but not IL-4, -producing cells were also elicited. After SARS-CoV-2 challenge, vaccinated animals showed a significant strong reduction of virus loads in bronchoalveolar lavages (BAL) and decreased levels in throat and nasal mucosa. Remarkably, MVA-S also protected macaques from fever and infection-induced cytokine storm. Computed tomography and histological examination of the lungs showed reduced lung pathology in MVA-S-vaccinated animals. These findings favor the use of MVA-S as a potential vaccine for SARS-CoV-2 in clinical trials.
MVA-CoV2-S Vaccine Candidate Neutralizes Distinct Variants of Concern and Protects Against SARS-CoV-2 Infection in Hamsters
Authors: Boudewijns Robbert , Pérez Patricia , Lázaro-Frías Adrián , Van Looveren Dominique , Vercruysse Thomas , Thibaut Hendrik Jan , Weynand Birgit , Coelmont Lotte , Neyts Johan , Astorgano David , Montenegro Dolores , Puentes Eugenia , Rodríguez Esteban , Dallmeier Kai , Esteban Mariano , García-Arriaza Juan
Published: March 2022

To control the coronavirus disease 2019 (COVID-19) pandemic and the emergence of different variants of concern (VoCs), novel vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed. In this study, we report the potent immunogenicity and efficacy induced in hamsters by a vaccine candidate based on a modified vaccinia virus Ankara (MVA) vector expressing a human codon optimized full-length SARS-CoV-2 spike (S) protein (MVA-S). Immunization with one or two doses of MVA-S elicited high titers of S- and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against parental SARS-CoV-2 and VoC alpha, beta, gamma, delta, and omicron. After SARS-CoV-2 challenge, MVA-S-vaccinated hamsters showed a significantly strong reduction of viral RNA and infectious virus in the lungs compared to the MVA-WT control group. Moreover, a marked reduction in lung histopathology was also observed in MVA-S-vaccinated hamsters. These results favor the use of MVA-S as a potential vaccine candidate for SARS-CoV-2 in clinical trials.
Immune Cell Landscaping Reveals Distinct Immune Signatures of Inflammatory Bowel Disease
Authors: Bai Xiaowu , Liu Weixin , Chen Hongxia , Zuo Tao , Wu Xiaojian
Published: March 2022

Determining how the profile of immune cells varies with their disease subtypes and across lesion locations is critical for understanding the pathogenesis in inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). To that end, we herein combined the IBD TaMMA framework and the CIBERSORT pipeline to deconvolute the large amount of RNA-seq data from patients with IBD (both CD and UC were included) and healthy human controls across 28 cohorts (a total of 3,852 samples) while accommodating data heterogeneity across cohorts, to define the immune cell landscape of IBD. Our study uncovered that both absolute quantities of innate and adaptive immune cell populations were elevated in most intestinal regions of IBD patients, yet disease-specific (CD versus UC) and intestinal location (ileum, colon, and rectum)-specific features. In the ileum, the increase in innate immune cells was more pronounced in CD than UC. In contrast, innate and adaptive immune cells were elevated more drastically in the UC than CD in the rectum. Such revelation of immune signatures across the highly variable IBD phenotypes (in both disease subtypes and intestinal regions) underpins differential immune-pathophysiological mechanisms in IBD pathogenesis and therefore serves as a resource for the development of future targeted studies.