bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural products in drug discovery and development: Synthesis and medicinal perspective of leonurine
Authors: Li Zhaoyi , Chen Keyuan , Rose Peter , Zhu Yi Zhun
Published: October 2022

Natural products, those molecules derived from nature, have been used by humans for thousands of years to treat ailments and diseases. More recently, these compounds have inspired chemists to use natural products as structural templates in the development of new drug molecules. One such compound is leonurine, a molecule isolated and characterized in the tissues of Herb leonuri. This molecule has received attention from scientists in recent years due to its potent anti-oxidant, anti-apoptotic, and anti-inflammatory properties. More recently researchers have shown leonurine to be useful in the treatment of cardiovascular and nervous system diseases. Like other natural products such as paclitaxel and artemisinin, the historical development of leonurine as a therapeutic is very interesting. Therefore, this review provided an overview of natural product discovery, through to the development of a potential new drug. Content will summarize known plant sources, the pathway used in the synthesis of leonurine, and descriptions of leonurine’s pharmacological properties in mammalian systems.
A universal coating strategy for inhibiting the growth of bacteria on materials surfaces
Authors: Zhang Jie , Wang Min , Hu Liwei , Zhang Qiang , Chen Enni , Wang Zhongchao , Shi Yidong , Tan Lin , Xiao Shimeng
Published: October 2022

The development of a versatile antibacterial coating, irrespective of material characteristics, is greatly attractive but still a challenge. In this work, mussel-inspired dopamine-modified sodium alginate (SA-DA) was successfully synthesized as the adhesion layer, and antibacterial coatings on three types of substrates, namely cotton fabric, aluminum sheet, and polyurethane membrane, were constructed through the layer-by-layer (LbL) deposition of polyhexamethylene guanidine and sodium alginate. Among the coated materials, the coated cotton fabric was systematically characterized, and the results showed that it still exhibited ideal hydrophilicity, and its liquid absorption capacity increased with an increase in the coating layers. The growth of Escherichia coli and Staphylococcus aureus was notably inhibited on the coated cotton fabric, and 10 coating bilayers achieved 100% inhibition of bacterial growth within 10 min. Furthermore, an ideal antibacterial ability maintained after 10 cycles of antibacterial trials or 50 washing or soaping cycles. In vitro evaluation of the hemostatic effect indicated that the coated cotton fabric could promote blood clotting by concentrating the components of blood and activating the platelets, and no significant hemolysis and cytotoxicity were observed in the coated cotton fabric. Moreover, the coated aluminum and polyurethane film also displayed an obvious antibacterial effect, which proved that the constructed coating could successfully adhere to the metal and polymer surfaces. Therefore, this work provided a proper way for the progress of a current antibacterial coating tactics for different substrate surfaces.
Predictive value of the presence of Prevotella and the ratio of Porphyromonas gingivalis to Prevotella in saliva for esophageal squamous cell carcinoma
Authors: Chen Xiaohui , Xian Bohong , Wei Junmin , Chen Yixiang , Yang Dongyang , Lai Xiaorong , Liu Lifang , Wu Yinghong , Lin Xiayi , Deng Yu , Zhang Huabin , Liu Wanwei , Qiao Guibin , Li Zijun
Published: October 2022

Background

Imbalance of oral salivary microbiota has been linked to the pathogenesis of a variety of systemic diseases, and oral bacterial species have been shown to be useful biomarkers for systemic diseases.This study aimed to characterize the alterations of oral microbiota in patients with esophageal squamous cell carcinoma (ESCC) and to evaluate the diagnostic performance of oral microbial biomarkers for ESCC.

Methods

The relative abundance of flora in saliva samples was analyzed by 16S rDNA sequencing, and differences in the species present in samples from ESCC patients and healthy controls (HCs) were identified by analyzing species diversity and performing LEfSe analysis. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic performance of the characteristic bacteria individually and in combination.

Results

Differences in bacterial diversity indexes were observed for the saliva of ESCC patients versus HCs (P<0.05), but principal coordinate analysis did not detect a significant difference in the composition of oral microbiota between ESCC patients and HCs (P>0.05). LEfSe analysis showed that Leptotrichia, Porphyromonas (Pg), Streptococcus, Rothia, Lactobacillus and Peptostreptococcus were more abundant in ESCC patient saliva than in HC saliva, whereas Haemophilus, Alloprevotella (All), Prevotella_7, Prevotella (Pre), Prevotella_6, Pasteurellaceae and Pasteurellales were significantly less abundant in ESCC patient saliva (P<0.05). From ROC curve analysis, Pg could detect ESCC with an area under the ROC curve (AUC) of 0.599, sensitivity of 62.2%, and specificity of 70%, whereas the ratio of Pg/Pre had an AUC of 0.791, sensitivity of 93.3%, and specificity of 62.3%. Moreover, the combination of the Pg/Pre and Pg/All ratios showed further improved diagnostic performance for ESCC (AUC=0.826) and even good sensitivity and specificity for the diagnosis of early ESCC (68.2% and 86%, respectively; AUC=0.786).

Conclusion

This study shows that Pg in saliva can be used as a characteristic marker of ESCC, and the ratios of Pg/Pre and Pg/All offered significantly improved diagnostic performance, especially for early ESCC.
Embodiment enables non-predictive ways of coping with self-caused sensory stimuli
Authors: Garner James , Egbert Matthew D.
Published: October 2022

Living systems process sensory data to facilitate adaptive behavior. A given sensor can be stimulated as the result of internally driven activity, or by purely external (environmental) sources. It is clear that these inputs are processed differently—have you ever tried tickling yourself? Self-caused stimuli have been shown to be attenuated compared to externally caused stimuli. A classical explanation of this effect is that when the brain sends a signal that would result in motor activity, it uses a copy of that signal to predict the sensory consequences of the resulting motor activity. The predicted sensory input is then subtracted from the actual sensory input, resulting in attenuation of the stimuli. To critically evaluate the utility of this predictive approach for coping with self-caused stimuli, and investigate when non-predictive solutions may be viable, we implement a computational model of a simple embodied system with self-caused sensorimotor dynamics, and use a genetic algorithm to explore the solutions possible in this model. We find that in this simple system the solutions that emerge modify their behavior to shape or avoid self-caused sensory inputs, rather than predicting these self-caused inputs and filtering them out. In some cases, solutions take advantage of the presence of these self-caused inputs. The existence of these non-predictive solutions demonstrates that embodiment provides possibilities for coping with self-caused sensory interference without the need for an internal, predictive model.
Unfreezing autonomous vehicles with game theory, proxemics, and trust
Authors: Camara Fanta , Fox Charles
Published: October 2022

Recent years have witnessed the rapid deployment of robotic systems in public places such as roads, pavements, workplaces and care homes. Robot navigation in environments with static objects is largely solved, but navigating around humans in dynamic environments remains an active research question for autonomous vehicles (AVs). To navigate in human social spaces, self-driving cars and other robots must also show social intelligence. This involves predicting and planning around pedestrians, understanding their personal space, and establishing trust with them. Most current AVs, for legal and safety reasons, consider pedestrians to be obstacles, so these AVs always stop for or replan to drive around them. But this highly safe nature may lead pedestrians to take advantage over them and slow their progress, even to a complete halt. We provide a review of our recent research on predicting and controlling human–AV interactions, which combines game theory, proxemics and trust, and unifies these fields via quantitative, probabilistic models and robot controllers, to solve this “freezing robot” problem.
Association of non-alcoholic fatty liver disease with left ventricular changes in treatment-naive patients with uncomplicated hypertension
Authors: Catena Cristiana , Brosolo Gabriele , Da Porto Andrea , Donnini Debora , Bulfone Luca , Vacca Antonio , Soardo Giorgio , Sechi Leonardo A.
Published: October 2022

Background and aims

Cardiac structural and functional changes have been demonstrated in patients with non-alcoholic fatty liver disease (NAFLD). Because of the frequent association of NAFLD with hypertension, we aimed to examine the relationship of liver steatosis with left ventricular (LV) changes in patients with hypertension.

Materials and methods

In a cross-sectional study, we included 360 untreated, essential hypertensive patients who were free of major cardiovascular and renal complications. Liver steatosis was assessed by three different biochemical scores (NAFLD Liver Fat Score, LFS; Fatty Liver Index, FLI; Hepatic Steatosis Index, HSI). Echocardiography was performed with standard B-mode and tissue-Doppler imaging.

Results

LV hypertrophy was present in 19.4% and LV diastolic dysfunction in 49.2% of patients who had significantly higher body mass index (BMI), blood pressure (BP), and homeostatic model assessment (HOMA) index and higher frequency of the metabolic syndrome and liver steatosis that was defined by presence of 2 or more positive scores. LV mass index increased progressively across patients who had none, 1, or 2 or more liver steatosis scores, with associated progressive worsening of LV diastolic function. LV mass index was significantly and positively correlated with age, BMI, BP, HOMA-index, LFS, and HSI. Logistic regression analysis showed that age, BP, and liver steatosis scores independently predicted LV hypertrophy and diastolic dysfunction. Liver steatosis independently predicted LV dysfunction but not LV hypertrophy even after inclusion in analysis of the HOMA-index.

Conclusion

NAFLD is associated with LV hypertrophy and diastolic dysfunction in untreated patients with hypertension. In hypertension, NAFLD could contribute to LV diastolic dysfunction with mechanisms unrelated to insulin resistance.
Antithrombotic therapy in peripheral arterial disease
Authors: Espinola-Klein Christine , Weißer Gerhard , Schmitt Volker , Schwaderlapp Melanie , Munzel Thomas
Published: October 2022

Background

Patients with peripheral arterial disease (PAD) are at increased risk for major adverse cardiovascular events (MACE) such as cardiovascular death, myocardial infarction, and stroke as well as major adverse limb events (MALE) such as amputation and acute limb ischemia. Therefore, prevention of thrombotic events is crucial to improve the prognosis of PAD patients. This review article concludes current evidence and guideline recommendations about antithrombotic therapy in PAD patients.

Antithrombotic therapy is highly effective to reduce MACE and MALE events in PAD patients. Recently, the concept of dual pathway inhibition (low-dose rivaroxaban plus acetylic salicylic acid (ASA) has been tested in the COMPASS and VOYAGER-PAD trial. Compared to ASA alone dual pathway inhibition was superior to prevent MACE and MALE. After peripheral revascularization, in particular the risk for acute limb ischemia was reduced. In contrast, the risk for major bleeding is increased. Therefore, current guidelines recommend the combination of low-dose rivaroxaban and ASA in PAD patients with low bleeding risk. In patients with high bleeding risk, a single antiplatelet drug (preferable clopidogrel) is indicated. In patients with atherosclerotic vascular disease and indication for oral anticoagulation, no additional antiplatelet drug is necessary, as this would increase the risk of bleeding without improving the prognosis.

Conclusion

Antithrombotic treatment reduces MACE and MALE and is recommended in all patients with PAD. Individual bleeding risk should always be considered based on the current data situation and an individual benefit-risk assessment must be carried out.
Independent association of PCSK9 with platelet reactivity in subjects without statin or antiplatelet agents
Authors: Wang Shuai , Fu Di , Liu Huixing , Peng Daoquan
Published: October 2022

Background and aims

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels could predict cardiovascular event in patients with well-controlled LDL-C levels, suggesting an LDL-independent mechanism of PCSK9 on the cardiovascular system. Accumulating evidence suggests PCSK9 might be associated with increased platelet reactivity. This study aimed to assess the relationship between PCSK9 levels and platelet reactivity in subjects not taking statins or antiplatelet agents.

Methods

A cross-sectional study was conducted to investigate the independent contribution of PCSK9 to platelet activity by controlling for the potential confounding factors. The study population included 89 subjects from a health examination centre who underwent routine annual health check-ups or had an examination before a selective operation. Subjects taking statins or antiplatelet agents were excluded. Adenosine diphosphate (ADP)-induced platelet aggregation was determined by PL-11 platelet analyzer using impedance aggregometry and plasma PCSK9 levels were determined using an ELISA. Serum Lipid profile was assessed by measuring the concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG), with low-density lipoprotein cholesterol (LDL-C) being directly measured using enzymatic techniques. The association between PCSK9 and platelet reactivity was investigated.

Results

The study subjects were composed of 53 males and 36 females with an average age of 55 (±11) years old. The univariate correlation analysis showed significant correlation between ADP-induced maximal aggregation rate (MAR) and PCSK9 (r = 0.55, p < 0.001) as well as TC (r = 0.23, p = 0.028), LDL-C (r = 0.27, p < 0.001), and PLT (r = 0.31, p = 0.005). Being male (41.2% vs. 46.6, p = 0.04) and smoking (37.4 vs. 46.2%, p = 0.016) were associated with lower ADP-induced MAR than being female and non-smoking. However, there is no correlation between PCSK9 and AA-induced platelet maximal aggregation rate (r = 0.17, p = 0.12). Multiple regression analysis suggested that PCSK9 contributed independently to ADP-induced maximal aggregation rate (β = 0.08, p = 0.004) after controlling for the effect of TC, LDL-C, PLT, being male, and smoking.

Conclusions

PCSK9 is positively associated with platelet reactivity, which may partly account for the beneficial effect of PCSK9 inhibition in reducing the risk of major adverse cardiovascular events after acute coronary syndrome (ACS).
Clinical perspectives on the use of the GIP/GLP-1 receptor agonist tirzepatide for the treatment of type-2 diabetes and obesity
Authors: Gallwitz Baptist
Published: October 2022

Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1RA) are already established in the treatment of type 2 diabetes (T2D). The development of novel dual- or triple-receptor agonists that bind to the receptors not only for GLP-1 but also to the receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon is intended to address different metabolic pathways for carbohydrate, lipid, and protein metabolism simultaneously. Dual- and triple-receptor agonists acting via different receptors and postreceptor pathways seem attractive in view of potentially additive or synergistic effects in the treatment of T2D and obesity. Recently, the first approval for a dual-receptor agonist marks an important step in this development. The GIP/GLP-1-receptor agonist tirzepatide was approved for the treatment of T2D by the Food and Drug Administration (FDA) in the USA for once-weekly subcutaneous injections in May 2022 and has just received a positive opinion from the European Medicines Agency (EMA). Tirzepatide dose-dependently leads to clinically significant reductions in glycemic parameters and body weight and has been shown to have stronger effects in reducing these parameters than standard antidiabetic therapy. This article summarizes the current clinical study program and the respective outcomes and highlights further potential indications for tirzepatide in the treatment of obesity and potentially other comorbidities of T2D.
Preoperative red cell distribution width is associated with postoperative lymphovascular invasion in prostate cancer patients treated with radical prostatectomy: A retrospective study
Authors: Wang Fangming , Liang Jing , Yang Feiya , Liu Fei , Han Sujun , Xing Nianzeng
Published: October 2022

Purpose

To investigate the relationship between baseline clinicopathological and laboratory variables especially hematological parameters and lymphovascular invasion (LVI) in patients who underwent radical prostatectomy (RP).

Methods

We retrospectively evaluated 348 prostate cancer (PCa) patients who underwent RP in our center between May 2018 and June 2021. We divided them into non-LVI and LVI groups based on LVI status, and compared clinicopathological characteristics between non-LVI and LVI groups. Clinicopathological parameters including age, body mass index (BMI), history of hypertension and diabetes mellitus, neoadjuvant hormonal therapy (NHT), pathological stage T (pT) and lymph node status (pN), ISUP (international society of urological pathology) grade, positive surgical margin (PSM) rate, and hematological parameters containing prostate-specific antigen (PSA), whole blood parameters and inflammatory indexes were collected. The association between the clinicopathological parameters and the presence of LVI was identified by multivariate logistic regression analysis.

Results

The pathological results of the RP specimen consisted of 53 (15.2%) patients with LVI and 295 (84.8%) cases without LVI. The level of PSA, percentages of advanced pT and grade, pN1, and PSM were significantly higher in the LVI group when compared with the non-LVI counterpart (p<0.001, p<0.001, p<0.001, p<0.001, p=0.007, respectively). Among the whole blood parameters, only red cell distribution width (RDW) was significantly different (41.2 ± 2.5 vs. 42.1 ± 3.1, p=0.035). Multivariate regression analysis demonstrated that RDW and NHT were negatively correlated with the presence of LVI (OR = 0.870, p=0.024; OR = 0.410, p=0.025), while PSA, ISUP, and pT were positively correlated with the presence of LVI (OR=1.013, p=0.005; OR =1.589, p=0.001; OR=1.655, p=0.008) after adjusting for confounding factors.

Conclusions

RDW rather than other whole blood parameters was independently and negatively associated with the presence of LVI in PCa patients, suggesting that RDW might play an essential role in PCa invasion.
Silent pheochromocytoma and paraganglioma: Systematic review and proposed definitions for standardized terminology
Authors: Constantinescu Georgiana , Preda Cristina , Constantinescu Victor , Siepmann Timo , Bornstein Stefan R. , Lenders Jacques W. M. , Eisenhofer Graeme , Pamporaki Christina
Published: October 2022

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with heterogeneous clinical presentations and potential lethal outcomes. The diagnosis is based on clinical suspicion, biochemical testing, imaging and histopathological confirmation. Increasingly widespread use of imaging studies and surveillance of patients at risk of PPGL due to a hereditary background or a previous tumor is leading to the diagnosis of these tumors at an early stage. This has resulted in an increasing use of the term “silent” PPGL. This term and other variants are now commonly found in the literature without any clear or unified definition. Among the various terms, “clinically silent” is often used to describe the lack of signs and symptoms associated with catecholamine excess. Confusion arises when these and other terms are used to define the tumors according to their ability to synthesize and/or release catecholamines in relation to biochemical test results. In such cases the term “silent” and other variants are often inappropriately and misleadingly used. In the present analysis we provide an overview of the literature and propose standardized terminology in an attempt at harmonization to facilitate scientific communication.
Lack of placental neurosteroid alters cortical development and female somatosensory function
Authors: Bakalar Dana , O’Reilly Jiaqi J. , Lacaille Helene , Salzbank Jacquelyn , Ellegood Jacob , Lerch Jason P. , Sasaki Toru , Imamura Yuka , Hashimoto-Torii Kazue , Vacher Claire-Marie , Penn Anna A.
Published: October 2022

Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of neurodevelopmental processesviapositive allosteric modulation of the GABAAreceptor (GABAA-R). Using a mouse model (plKO) in which the gene encoding the ALLO synthesis enzyme is specifically deleted in trophoblasts, we previously showed that placental ALLO insufficiency alters cerebellar white matter development and leads to male-specific autistic-like behavior. We now demonstrate that the lack of placental ALLO causes female-predominant alterations of cortical development and function. Placental ALLO insufficiency disrupts cell proliferation in the primary somatosensory cortex (S1) in a sex-linked manner. Early changes are seen in plKO embryos of both sexes, but persist primarily in female offspring after birth. Adolescent plKO females show significant reduction in pyramidal neuron density, as well as somatosensory behavioral deficits as compared with plKO males and control littermates. Assessment of layer-specific markers in human postmortem cortices suggests that preterm infants may also have female-biased abnormalities in cortical layer specification as compared with term infants. This study establishes a novel and fundamental link between placental function and sex-linked long-term neurological outcomes, emphasizing the importance of the growing field of neuroplacentology.
Evaluating energy efficiency from the perspective of clean energy and carbon emission
Authors: Chen Bin , Dai Yao , Ye Junhao , Xu Huan , Huang Yanlu , Bie Pei
Published: October 2022

Improving energy efficiency and optimizing energy structure is the key to achieving the “dual carbon” goal and high-quality development. This paper calculates the energy efficiency of 30 provinces in China between 2000 and 2017 using the DEA method. The study found that in China, the energy efficiency is higher in East China than in West China, in South China than in North China, and in the coastal areas than in the interior. Moreover, the efficiency gap between clean fuel and fossil fuel is widening. Taking total power consumption as energy input and measuring carbon emissions using regional grid base line emission factor can accurately measure China’s clean energy efficiency. The conclusions of the study provide important references for promoting China’s energy transformation and the development of the green economy.
Visualization analysis of research on climate innovation on CiteSpace
Authors: Cheng Zhice , Xie Yuchen , Wen Huwei
Published: October 2022

Climate change has brought great challenges to global sustainability, but only few research achievements in innovation for climate change mitigation and adaptation have been reported. This study aims to identify the current research status and trends in climate innovation via CiteSpace visual analysis. We searched for published papers (up to 2021) in the core repository of Web of Science by using the theme of innovation for climate change mitigation and adaptation. Using the collected articles, we conducted co-authorship analysis, co-citation analysis, and keyword co-occurrence analysis and found that the main contributors are from America, England, and China. Moreover, climate innovation has an interdisciplinary knowledge source, and its main research frontier focuses on the design of policies for energy efficiency improvement and new energy technologies. These results point out some directions for further research on climate innovation and outline the knowledge structure in this field, thereby addressing the lack of studies on such topic. By analyzing the lineage of research developments, it is found that energy technology and energy efficiency would be the main research hotspots in climate innovation in the future, and relevant policies also need to strengthen incentives for research in this area. This study is particularly helpful for those researchers who are interested in climate innovation and can subsequently contribute to the long-term development of various research directions in this field, to the formulation of climate change mitigation and adaptation policies, and to the sustainable development of human society.
Evolutionary game analysis of clean heating governance in rural areas of Northern China
Authors: Liu Wenlong , Li Yunfeng , Zhu Weiping
Published: October 2022

The attainment of clean heating in the rural areas of northern China is of great significance for environmental governance and the realization of the dual carbon goal. Based on the evolutionary game theory, this study constructs a three-party evolutionary game model of the central government, local government, and farmers, introduces key parameters, such as the local government’s governance strength, central government’s inspection strength, and two levels of government subsidy strength, into the model, systematically deduces different possible strategy combinations of the three parties, and analyzes the possible scenarios and stability conditions of each scenario. Finally, the study numerically simulates each scenario and analyzes the influence of the key parameters on the strategies of the three parties. The study conclusions are as follows. 1) The system is optimized in Scenario 6 (1,1,0). 2) The strategy of the local government has a decisive influence on farmers, and the central government’s inspector strength has a weak effect on farmers. 3) The cost of clean heating over coal-fired heating has a significant effect on farm households but not on the two levels of government. 4) The low perception that farmers hold regarding the benefits of the indoor environment weakens the government’s subsidy effect. This study provides effective practical guidance and policy references for governments to promote clean heating in rural areas.
Sources, spectral characteristics, and fluxes of dissolved organic matter in coastal groundwater and river water in western Guangdong, China
Authors: Wang Chao , Hu Xuanyu , Liu Yilin , Jin Guangzhe
Published: October 2022

Groundwater discharge and river runoff are two important ways for allochthonous dissolved organic matter (DOM) to enter the ocean, but they vary spatially. Currently, the source, composition, and efflux of groundwater and riverine dissolved organic matter to the tropical northern South China Sea remain poorly understood, preventing an accurate estimate of coastal carbon budgets. In July 2021, nine groundwater and six river water samples were collected along the coast of western Guangdong and were characterized using dissolved organic carbon (DOC) analysis, UV-visible, and fluorescence spectroscopy techniques. Atypical absorption spectra were strongly observed in groundwaters, which were mainly attributed to the high-level nitrates. An exponential-Gaussian equation showed that the average contribution of nitrate to total groundwater absorbances was up to 36% at ∼ 300 nm. Groundwater showed lower levels of DOC, colored dissolved organic matter (CDOM), and fluorescent dissolved organic matter (FDOM) as compared to river water, whereas the humic-like components dominated both groundwater and river water FDOM pools. Higher values of spectral slope S350–400, fluorescence index, biological index, and the ratio of two humic-like fluorescence jointly reveal that groundwater DOM mainly originated from microbial activities, whereas the river water DOM had considerable contribution from terrestrial soil. High precipitation, natural or agricultural land types, and a lack of seawater intrusion are expected to cause low levels of groundwater DOM in western Guangdong. Among 52 rivers from across the globe, high watershed productivity and precipitation may lead to high–moderate DOM levels in river water in western Guangdong. The DOM fluxes via fresh groundwater discharge in western Guangdong are comparable in magnitude to those by river runoff, accounting for 16%–18% of the Pearl River DOM fluxes. Based on the slopes of linear correlations between CDOM and DOC obtained in groundwater samples and 52 rivers, as well as the data on water fluxes and DOC levels, the global CDOM fluxes via groundwater discharge and river runoff are estimated to be 3.5–12.2 × 1012 m2 yr−1 and 4.3 ± 0.3 × 1014 m2 yr−1, respectively, highlighting the importance of considering groundwater discharge and river runoff in coastal carbon budgets.
An overview of online resources for intra-species detection of gene duplications
Authors: Zhang Xi , Smith David Roy
Published: October 2022

Gene duplication plays an important role in evolutionary mechanism, which can act as a new source of genetic material in genome evolution. However, detecting duplicate genes from genomic data can be challenging. Various bioinformatics resources have been developed to identify duplicate genes from single and/or multiple species. Here, we summarize the metrics used to measure sequence identity among gene duplicates within species, compare several computational approaches that have been used to predict gene duplicates, and review recent advancements of a Basic Local Alignment Search Tool (BLAST)-based web tool and database, allowing future researchers to easily identify intra-species gene duplications. This article is a quick reference guide for research tools used for detecting gene duplicates.
Allelic diversity of the pharmacogene CYP2D6 in New Zealand Māori and Pacific peoples
Authors: Hitchman Leonie M. , Faatoese Allamanda , Merriman Tony R. , Miller Allison L. , Liau Yusmiati , Graham Oscar E. E. , Kee Ping Siu , Pearson John F. , Fakahau Tony , Cameron Vicky A. , Kennedy Martin A. , Maggo Simran D. S.
Published: October 2022

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Māori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.
Identification of senescence-associated long non-coding RNAs to predict prognosis and immune microenvironment in patients with hepatocellular carcinoma
Authors: Gao Chengzhi , Zhou Guangming , Cheng Min , Feng Lan , Cao Pengbo , Zhou Gangqiao
Published: October 2022

Background: Cellular senescence plays a complicated and vital role in cancer development because of its divergent effects on tumorigenicity. However, the long non-coding RNAs (lncRNAs) associated with tumor senescence and their prognostic value in hepatocellular carcinoma (HCC) remain unexplored.

Methods: The trans-cancer oncogene-induced senescence (OIS) signature was determined by gene set variation analysis (GSVA) in the cancer genome atlas (TCGA) dataset. The OIS-related lncRNAs were identified by correlation analyses. Cox regression analyses were used to screen lncRNAs associated with prognosis, and an optimal predictive model was created by regression analysis of the least absolute shrinkage and selection operator (LASSO). The performance of the model was evaluated by Kaplan-Meier survival analyses, nomograms, stratified survival analyses, and receiver operating characteristic curve (ROC) analyses. Gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) were carried out to explore the functional relevance and immune cell infiltration, respectively.

Results: Firstly, we examined the pan-cancer OIS signature, and found several types of cancer with OIS strongly associated with the survival of patients, including HCC. Subsequently, based on the OIS signature, we identified 76 OIS-related lncRNAs with prognostic values in HCC. We then established an optimal prognostic model based on 11 (including NRAV, AC015908.3, MIR100HG, AL365203.2, AC009005.1, SNHG3, LINC01138, AC090192.2, AC008622.2, AL139423.1, and AC026356.1) of these lncRNAs by LASSO-Cox regression analysis. It was then confirmed that the risk score was an independent and potential risk indicator for overall survival (OS) (HR [95% CI] = 4.90 [2.74–8.70], p < 0.001), which outperforms those traditional clinicopathological factors. Furthermore, patients with higher risk scores also showed more advanced levels of a proinflammatory senescence-associated secretory phenotype (SASP), higher infiltration of regulatory T (Treg) cells and lower infiltration of naïve B cells, suggesting the regulatory effects of OIS on immune microenvironment. Additionally, we identified NRAV as a representative OIS-related lncRNA, which is over-expressed in HCC tumors mainly driven by DNA hypomethylation.

Conclusion: Based on 11 OIS-related lncRNAs, we established a promising prognostic predictor for HCC patients, and highlighted the potential immune microenvironment-modulatory roles of OIS in HCC, providing a broad molecular perspective of tumor senescence.
Sex-specific association between alcohol consumption and liver cirrhosis: An updated systematic review and meta-analysis
Authors: Llamosas-Falcón Laura , Probst Charlotte , Buckley Charlotte , Jiang Huan , Lasserre Aurélie M. , Puka Klajdi , Tran Alexander , Rehm Jürgen
Published: October 2022

Different studies have shown that females develop liver diseases at lower levels of alcohol consumption than males. Our aim was to quantify the dose-response relationship between alcohol consumption and the risk of liver cirrhosis by sex and identify the differences between females and males. A systematic review was conducted using PubMed/Medline and Embase to identify longitudinal and case-control studies that analyzed the relationship between the level of alcohol use and liver cirrhosis (LC) incidence, and mortality (ICD-8 and ICD-9 codes 571 and ICD-10 codes K70, K73, K74). Pooled relative risks (RR) were calculated by random effects models. Restricted cubic splines were used to model the dose-response relationship. A total of 24 studies were included in the analysis. There were collectively 2,112,476 females and 924,853 males, and a total of 4,301 and 4,231 cases of LC for females and males, respectively. We identified a non-linear dose-response relationship. Females showed a higher risk for LC compared to males with the same amount of alcohol consumed daily. For instance, drinking 40 g/day showed RRs of 9.35 (95% CI 7.64-11.45) in females and 2.82 (95% CI 2.53-3.14) in males, while drinking 80 g/day presented RRs of 23.32 (95% CI 18.24-29.82) in females and 7.93 (95% CI 7.12-8.83) in males. Additional analyses showed that a higher risk for females was found for morbidity and for mortality. Understanding the influence of sex on the association of alcohol consumption and the risk of LC is needed to develop recommendations and clinical guidelines for prevention and treatment.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022299680, identifier CRD42022299680.
Effect of calorie-restriction and rapamycin on autophagy and the severity of caerulein-induced experimental acute pancreatitis in mice
Authors: Sharma Manish Kumar , Priyam Kumari , Kumar Punit , Garg Pramod Kumar , Roy Tara Sankar , Jacob Tony George
Published: October 2022

Background

Impaired autophagy contributes to development of acute pancreatitis (AP). We studied the effect of inducing autophagy by calorie-restriction and rapamycin, separately, in the caerulein-induced model of severe AP.

Methods

Adult, male, Swiss albino mice were given eight, hourly, intraperitoneal injections of caerulein (Ce) (50µg/Kg/dose). The interventions were calorie restriction (CR) and rapamycin (2mg/Kg). Mice were sacrificed at the 9th hour. Pancreas was harvested for histopathology and immunoblotting. Amylase activity and the levels of cytokines were measured in plasma.

Results

The histopathological score and amylase activity were significantly lower in calorie-restricted caerulein-induced AP (CRCeAP) in comparison to animals that had unrestricted access to chow. In the CRCeAP group, levels of IL-6 and GM-CSF in plasma were lower and the expression of LC3II and Beclin-1 were higher. On transmission electron-microscopy, the area occupied by autophagic vacuoles was higher in CRCeAP. The expression of caspase-8 and caspase-9 was also higher in CRCeAP. In rapamycin with caerulein-induced AP (Rapa+CeAP), the histopathological score and amylase activity were significantly lower than caerulein-induced AP (CeAP). In Rapa+CeAP, the expression of LC3II and Beclin-1 were higher, whereas; SQSTM1 was decreased. The number of autophagic vacuoles in Rapa+CeAP group was fewer. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were lower in Rapa+CeAP. Caspase-3 increased and high mobility group box 1 (HMGB1) decreased in Rapa+CeAP.

Conclusion

Calorie-restriction and rapamycin can individually decrease the severity of injury in the caerulein-induced model of severe AP.
Case Report: Anlotinib combined with PD-1 inhibitor and sequential GA regimen or FOLFIRINOX Chemotherapy in treatment of KRAS G12V mutated pancreatic ductal adenocarcinoma with liver metastasis: A case and literature review
Authors: Wang Yunpeng , Wang Bofang , Xiang Lin , Deng Junge , Xu Bo , He Puyi , Pu Weigao , Wang Haiyun , Fan Yong , Chen Hao
Published: October 2022

There is a high mortality rate associated with pancreatic cancer, and the incidence has been rising globally in recent decades. When patients are diagnosed, there is little chance that surgery will be beneficial. Systemic chemotherapy is the currently accepted treatment option for patients with metastatic advanced pancreatic cancer. However, a very limited survival improvement is possible with chemotherapy for advanced pancreatic cancer, and chemotherapy resistance plays a significant role in poor prognosis. Despite the fact that targeting growth factor receptor inhibitors such as anti-vascular endothelial growth factor (VEGFR) antibodies significantly improves survival in pancreatic cancer, only a very small number of patients benefit from the treatment. As emerging drugs, immune checkpoint inhibitors (ICIs) have demonstrated significant therapeutic effects in several tumor types, but monotherapy is not effective in pancreatic cancer. In the first-line treatment of solid tumors, combination therapy may result in remarkable outcomes. Here in, we have reported a younger patient with pancreatic ductal adenocarcinoma with liver metastasis (PDACLM) who had a long-term partial response and good tolerance to the combination of anlotinib and programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. Gene analysis suggested only one mutation in the Kirsten rat sarcoma viral oncogene (KRAS) G12V gene. Consequently, there is some hope for patients with pancreatic cancer, especially for KRAS G12V gene mutated patients. Upon reviewing the literature, this patient’s combination therapy is the first to have been reported.
Type of mRNA COVID-19 vaccine and immunomodulatory treatment influence humoral immunogenicity in patients with inflammatory rheumatic diseases
Authors: Raptis Catherine E. , Berger Christoph T. , Ciurea Adrian , Andrey Diego O. , Polysopoulos Christos , Lescuyer Pierre , Maletic Tanja , Riek Myriam , Scherer Almut , von Loga Isabell , Safford Judith , Lauper Kim , Möller Burkhard , Vuilleumier Nicolas , Finckh Axel , Rubbert-Roth Andrea
Published: October 2022

Patients with inflammatory rheumatic diseases (IRD) are at increased risk for worse COVID-19 outcomes. Identifying whether mRNA vaccines differ in immunogenicity and examining the effects of immunomodulatory treatments may support COVID-19 vaccination strategies. We aimed to conduct a long-term, model-based comparison of the humoral immunogenicity following BNT162b2 and mRNA-1273 vaccination in a cohort of IRD patients. Patients from the Swiss IRD cohort (SCQM), who assented to mRNA COVID-19 vaccination were recruited between 3/2021-9/2021. Blood samples at baseline, 4, 12, and 24 weeks post second vaccine dose were tested for anti-SARS-CoV-2 spike IgG (anti-S1). We examined differences in antibody levels depending on the vaccine and treatment at baseline while adjusting for age, disease, and past SARS-CoV-2 infection. 565 IRD patients provided eligible samples. Among monotherapies, rituximab, abatacept, JAKi, and TNFi had the highest odds of reduced anti-S1 responses compared to no medication. Patients on specific combination therapies showed significantly lower antibody responses than those on monotherapy. Irrespective of the disease, treatment, and past SARS-CoV-2 infection, the odds of higher antibody levels at 4, 12, and 24 weeks post second vaccine dose were, respectively, 3.4, 3.8, and 3.8 times higher with mRNA-1273 versus BNT162b2 (p < 0.0001). With every year of age, the odds ratio of higher peak humoral immunogenicity following mRNA-1273 versus BNT162b2 increased by 5% (p < 0.001), indicating a particular benefit for elderly patients. Our results suggest that in IRD patients, two-dose vaccination with mRNA-1273 versus BNT162b2 results in higher anti-S1 levels, even more so in elderly patients.
Porcine cGAS-STING signaling induced autophagy inhibits STING downstream IFN and apoptosis
Authors: Xia Nengwen , Zheng Wanglong , Jiang Sen , Cao Qi , Luo Jia , Zhang Jiajia , Xu Yulin , Sun Shaohua , Zhang Kaili , Chen Nanhua , Meurens François , Zhu Jianzhong
Published: October 2022

The innate immune DNA sensing cGAS-STING signaling pathway has been widely recognized for inducing interferons (IFNs) and subsequent antiviral state. In addition to IFN, the cGAS-STING pathway also elicits other cell autonomous immunity events including autophagy and apoptosis. However, the downstream signaling events of this DNA sensing pathway in livestock have not been well defined. Here, we systematically analyzed the porcine STING (pSTING) induced IFN, autophagy and apoptosis, revealed the distinct dynamics of three STING downstream events, and established the IFN independent inductions of autophagy and apoptosis. Further, we investigated the regulation of autophagy on pSTING induced IFN and apoptosis. Following TBK1-IRF3-IFN activation, STING induced Atg5/Atg16L1 dependent autophagy through LIR motifs. In turn, the autophagy likely promoted the pSTING degradation, inhibited both IFN production and apoptosis, and thus restored the cell homeostasis. Therefore, this study sheds lights on the molecular mechanisms of innate immunity in pigs.
Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape
Authors: Wang Zide , Zhong Hanlin , Liang Xiaohong , Ni Shilei
Published: October 2022

Tumor-associated macrophages (TAMs) can directly clear tumor cells and enhance the phagocytic ability of immune cells. An abundance of TAMs at the site of the glioblastoma tumor indicates that TAM-targeting immunotherapy could represent a potential form of treatment for this aggressive cancer. Herein, we discuss: i) the dynamic role of TAMs in glioblastoma; ii) describe the formation of the immunosuppressive tumor microenvironment; iii) summarize the latest clinical trial data that reveal how TAM function can be regulated in favor tumor eradication; and lastly, iv) evaluate the implications of existing and novel translational approaches for treating glioblastoma in clinical practice.
Olfactory receptors in macrophages and inflammation
Authors: Orecchioni Marco , Matsunami Hiroaki , Ley Klaus
Published: October 2022

Olfactory receptors (ORs) that bind odorous ligands are the largest family of G-protein-coupled receptors. In the olfactory epithelium, approximately 400 and 1,100 members are expressed in humans and mice, respectively. Growing evidence suggests the extranasal functions of ORs. Here, we review OR expression and function in macrophages, specialized innate immune cells involved in the detection, phagocytosis, and destruction of cellular debris and pathogens as well as the initiation of inflammatory responses. RNA sequencing data in mice suggest that up to 580 ORs may be expressed in macrophages. Macrophage OR expression is increased after treatment with the Toll-like receptor 4 ligand lipopolysaccharide, which also induces the transcription of inflammasome components. Triggering human OR6A2 or its mouse orthologue Olfr2 with their cognate ligand octanal induces inflammasome assembly and the secretion of IL-1β, which exacerbates atherosclerosis. Octanal is positively correlated with blood lipids like low-density lipoprotein –cholesterol in humans. Another OR, Olfr78, is activated by lactate, which promotes the generation of tumor-associated macrophages that dampen the immune response and promote tumor progression. Olfactory receptors in macrophages are a rich source of untapped opportunity for modulating inflammation. It is not known which of the many ORs expressed in macrophages promote or modulate inflammation. Progress in this area also requires deorphanizing more ORs and determining the sources of their ligands.