bluuebunny/crossref_metadata_2025 huggingface dataset:
Ambient Availability of Amino Acids, Proteins, and Iron Impacts Copper Resistance of Aspergillus fumigatus
Authors: Yap Annie , Talasz Heribert , Lindner Herbert , Würzner Reinhard , Haas Hubertus
Published: April 2022

The transition metals iron and copper are required by virtually all organisms but are toxic in excess. Acquisition of both metals and resistance to copper excess have previously been shown to be important for virulence of the most common airborne human mold pathogen, Aspergillus fumigatus. Here we demonstrate that the ambient availability of amino acids and proteins increases the copper resistance of A. fumigatus wild type and particularly of the ΔcrpA mutant that lacks export-mediated copper detoxification. The highest-protecting activity was found for L-histidine followed by L-asparagine, L-aspartate, L-serine, L-threonine, and L-tyrosine. Other amino acids and proteins also displayed significant but lower protection. The protecting activity of non-proteinogenic D-histidine, L-histidine-mediated growth inhibition in the absence of high-affinity copper uptake, determination of cellular metal contents, and expression analysis of copper-regulated genes suggested that histidine inhibits low-affinity but not high-affinity copper acquisition by extracellular copper complexation. An increase in the cellular copper content was found to be accompanied by an increase in the iron content, and, in agreement, iron starvation increased copper susceptibility, which underlines the importance of cellular metal balancing. Due to the role of iron and copper in nutritional immunity, these findings are likely to play an important role in the host niche.
The Role of Autophagy in the Mother-to-Child Transmission of Pregnant Women With a High Level of HBV DNA
Authors: Gao Hong , Xu Ling , Fan Zihao , Zhang Xiangying , Duan Zhongping , Ren Feng
Published: April 2022

Background

Mother-to-child transmission (MTCT) is the most common propagation mode of hepatitis B virus (HBV) transmission. Exploring the mechanisms of HBV MTCT is the key to protect infant from infection. In this study, we aim to clarify the important role of autophagy complicated in HBV MTCT.

Methods

A total of 169 placental samples were collected in this study, includes 144 HBV positive pregnant women and 25 normal pregnant women. In vitro, JEG-3 cells were treated with serum contained different HBV viral loads. Electron microscope was used to observed the number of autophagosome. RT-qPCR and western blotting were used to measure the expression level of autophagy relative genes and proteins respectively. Immunofluorescence was used to analyzed the expression of LC-3 of the frozen section of placental tissue.

Results

According to the number of autophagosomes and the expression level of autophagic genes mRNA and protein, autophagy was increased in HBV maternal placenta. Among the control, low viral load, medium viral load and high viral load groups, autophagy was significantly up-regulated with the increase of HBV viral loads. Also, autophagy was increased in the HBeAg positive pregnant women compared with their HBeAg negative counterparts. Also, autophagy in infant-infected group was up-regulated compared with infant-uninfected group. In vitro, choriocarcinoma JEG-3 cells were treated with the different HBV viral loads or different time incubation, the mRNA and protein of autophagy related genes was maximum expression in the medium viral load or treatment in a short period, but decreased in the high viral load treatment or with long-term HBV exposure.

Conclusion

Our study determines the high levels of viremia could be the cause of both increase autophagy activities and MTCT. Autophagy was significantly up-regulated in pregnant women with high viral load or HBeAg positive, which plays an important part in the HBV MTCT.
Long Noncoding RNA Expression Rofiles Elucidate the Potential Roles of lncRNA- XR_003496198 in Duck Hepatitis A Virus Type 1 Infection
Authors: Sui Nana , Zhang Ruihua , Jiang Yue , Yu Honglei , Xu Guige , Wang Jingyu , Zhu Yanli , Xie Zhijing , Hu Jiaqing , Jiang Shijin
Published: April 2022

Duck hepatitis A virus type 1 (DHAV-1) is a highly lethal virus that severely affects the duck industry worldwide. Long noncoding RNAs (lncRNAs) exert crucial roles in pathogen attacks. Here, we conducted deep transcriptome analysis to investigate the dynamic changes of host lncRNAs profiles in DHAV-1-infected duck embryo fibroblasts. We identified 16,589 lncRNAs in total and characterized their genomic features. Moreover, 772 and 616 differentially expressed lncRNAs (DELs) were screened at 12 and 24 h post-infection. Additionally, we predicted the DELs’ cis- and trans-target genes and constructed lncRNA-target genes regulatory networks. Functional annotation analyses indicated that the putative target genes of DELs participated in diverse vital biological processed, including immune responses, cellular metabolism, and autophagy. For example, we confirmed the dysregulation of pattern recognition receptors (TLR3, RIG-I, MDA5, LGP2, cGAS), signal transducers (STAT1), transcription factors (IRF7), immune response mediators (IL6, IL10, TRIM25, TRIM35, TRIM60, IFITM1, IFITM3, IFITM5), and autophagy-related genes (ULK1, ULK2, EIF4EBP2) using RT-qPCR. Finally, we confirmed that one DHAV-1 induced lncRNA-XR_003496198 is likely to inhibit DHAV-1 replication in DEFs. Our study comprehensively analyzed the lncRNA profiles upon DHAV-1 infection and screened the target genes involved in the innate immune response and autophagy signaling pathway, thereby revealing the essential roles of duck lncRNAs and broadening our understanding of host-virus interactions.
Towards the Integration of an Islet-Based Biosensor in Closed-Loop Therapies for Patients With Type 1 Diabetes
Authors: Olçomendy Loïc , Cassany Louis , Pirog Antoine , Franco Roberto , Puginier Emilie , Jaffredo Manon , Gucik-Derigny David , Ríos Héctor , Ferreira de Loza Alejandra , Gaitan Julien , Raoux Matthieu , Bornat Yannick , Catargi Bogdan , Lang Jochen , Henry David , Renaud Sylvie , Cieslak Jérôme
Published: April 2022

In diabetes mellitus (DM) treatment, Continuous Glucose Monitoring (CGM) linked with insulin delivery becomes the main strategy to improve therapeutic outcomes and quality of patients’ lives. However, Blood Glucose (BG) regulation with CGM is still hampered by limitations of algorithms and glucose sensors. Regarding sensor technology, current electrochemical glucose sensors do not capture the full spectrum of other physiological signals, i.e., lipids, amino acids or hormones, relaying the general body status. Regarding algorithms, variability between and within patients remains the main challenge for optimal BG regulation in closed-loop therapies. This work highlights the simulation benefits to test new sensing and control paradigms which address the previous shortcomings for Type 1 Diabetes (T1D) closed-loop therapies. The UVA/Padova T1DM Simulator is the core element here, which is a computer model of the human metabolic system based on glucose-insulin dynamics in T1D patients. That simulator is approved by the US Food and Drug Administration (FDA) as an alternative for pre-clinical testing of new devices and closed-loop algorithms. To overcome the limitation of standard glucose sensors, the concept of an islet-based biosensor, which could integrate multiple physiological signals through electrical activity measurement, is assessed here in a closed-loop insulin therapy. This investigation has been addressed by an interdisciplinary consortium, from endocrinology to biology, electrophysiology, bio-electronics and control theory. In parallel to the development of an islet-based closed-loop, it also investigates the benefits of robust control theory against the natural variability within a patient population. Using 4 meal scenarios, numerous simulation campaigns were conducted. The analysis of their results then introduces a discussion on the potential benefits of an Artificial Pancreas (AP) system associating the islet-based biosensor with robust algorithms.
Effect of Washed Microbiota Transplantation on Patients With Dyslipidemia in South China
Authors: Liang Fenfen , Lu Xinjian , Deng Zhiliang , Zhong Hao-Jie , Zhang Wei , Li Qing , Zhou Hong-Hao , Liou Yu-Ligh , He Xing-Xiang
Published: April 2022

Background and Aims

Although the manual crude fecal microbiota transplantation (FMT) reduces blood lipids in animal models of hyperlipidemia, its clinical effect on blood lipid metabolism in patients with hyperlipidemia and hypolipidemia remains unclear, especially in the Chinese population. It was reported that washed microbiota transplantation (WMT) was safer, more precise, and more quality-controllable than the crude FMT by manual. This study aimed to investigate the feasibility and effectiveness of WMT on lipid metabolism in the Chinese population.

Methods

Clinical data of patients with various indications who received WMT for 1–3 treatment procedures were collected. Changes in blood lipids before and after WMT, namely, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), homeostasis model assessment of insulin resistance (HOMA-IR), liver fat attenuation, and liver stiffness measurement, were compared.

Results

A total of 177 patients (40 cases of hyperlipidemia, 87 cases with normal blood lipids, and 50 cases of hypolipidemia) were enrolled in the First Affiliated Hospital of Guangdong Pharmaceutical University. WMT has a significant therapeutic effect in reducing blood lipid levels (TC and TG) in the short- and medium term in patients with hyperlipidemia (p <0.05). Hyper blood lipid decreased to normal in the short-term (35.14%; p <0.001), and LDL-C changed to normal in the medium term (33.33%; p = 0.013). In the hypolipidemia group, 36.36% and 47.06% changed to normal in the short-term (p = 0.006) and medium term (p = 0.005) of therapeutic effects based on blood lipid levels. In the normal blood lipid group and the low-risk group of atherosclerotic cardiovascular disease (ASCVD), the change was not statistically significant, indicating that WMT does not increase the risk of blood lipid and ASCVD in the long-term.

Conclusions

WMT treatment changes blood lipids in patients with hyperlipidemia and hypolipidemia without serious adverse events, with no risk for increasing blood lipids and ASCVD in the long-term. There were significant decreased TC, TG, and LDL-C levels in the medium term of WMT treatment for hyperlipidemia. Therefore, the regulation of gut microbiota by WMT may indicate a new clinical method for the treatment of dyslipidemia.
Growth Hormone Is Beneficial for Induction of Spermatogenesis in Adult Patients With Congenital Combined Pituitary Hormone Deficiency
Authors: Zhu Yiyi , Nie Min , Wang Xi , Huang Qibin , Yu Bingqing , Zhang Rui , Zhang Junyi , Sun Bang , Mao Jiangfeng , Wu Xueyan
Published: April 2022

Background

Gonadotropins are effective in inducing spermatogenesis in patients with congenital combined pituitary hormone deficiency (CCPHD). Data on recombinant human growth hormone(rhGH) adjuvant treatment to improve gonadotropin-induced spermatogenesis are limited.

Design and Setting

This retrospective study included 60 male patients with CCPHD on a relatively large case series in a single center from mainland China. Twenty-nine patients who received gonadotropin therapy alone were defined as the Gn group, while 31 patients treated with a combination of rhGH and gonadotropins were defined as GH/Gn group.

Results

Spermatogenesis rate was 96.77% (30/31) and 62.07% (18/29) in the GH/Gn and Gn group, respectively (P < 0.001). The time for initial sperm appearance in the GH/Gn group was shorter than in the Gn group (14 versus 23 months, P < 0.001). A higher level of serum testosterone was achieved in the GH/Gn group than in the Gn group (4.79 versus 3.38 ng/mL, P = 0.026). After adjustment for potential confounders, rhGH supplementation was an independent beneficial factor on spermatogenesis (HR = 2.294, 95% CI: 1.143-4.604, P = 0.019).

Conclusions

rhGH induces earlier spermatogenesis in patients with CCPHD, which encourages the co-treatment with rhGH and gonadotropins in CCPHD patients.
Animal Coloration in the Anthropocene
Authors: Koneru Manisha , Caro Tim
Published: April 2022

Natural habitats are increasingly affected by anthropogenically driven environmental changes resulting from habitat destruction, chemical and light pollution, and climate change. Organisms inhabiting such habitats are faced with novel disturbances that can alter their modes of signaling. Coloration is one such sensory modality whose production, perception and function is being affected by human-induced disturbances. Animals that acquire pigment derivatives through diet are adversely impacted by the introduction of chemical pollutants into their environments as well as by general loss of natural habitat due to urbanization or logging leading to declines in pigment sources. Those species that do manage to produce color-based signals and displays may face disruptions to their signaling medium in the form of light pollution and turbidity. Furthermore, forest fragmentation and the resulting breaks in canopy cover can expose animals to predation due to the influx of light into previously dark environments. Global climate warming has been decreasing snow cover in arctic regions, causing birds and mammals that undergo seasonal molts to appear conspicuous against a snowless background. Ectotherms that rely on color for thermoregulation are under pressure to change their appearances. Rapid changes in habitat type through severe fire events or coral bleaching also challenge animals to match their backgrounds. Through this review, we aim to describe the wide-ranging impacts of anthropogenic environmental changes on visual ecology and suggest directions for the use of coloration both as an indicator of ecological change and as a tool for conservation.
The Comprehensive Analysis Identified an Autophagy Signature for the Prognosis and the Immunotherapy Efficiency Prediction in Lung Adenocarcinoma
Authors: Li Xizhe , Dai Ziyu , Wu Xianning , Zhang Nan , Zhang Hao , Wang Zeyu , Zhang Xun , Liang Xisong , Luo Peng , Zhang Jian , Liu Zaoqu , Zhou Yanwu , Cheng Quan , Chang Ruimin
Published: April 2022

Background

Lung adenocarcinoma (LUAD) is a fatal malignancy in the world. Growing evidence demonstrated that autophagy-related genes regulated the immune cell infiltration and correlated with the prognosis of LUAD. However, the autophagy-based signature that can predict the prognosis and the efficiency of checkpoint immunotherapy in LUAD patients is yet to be discovered.

Methods

We used conventional autophagy-related genes to screen candidates for signature construction in TCGA cohort and 9 GEO datasets (tumor samples, n=2181; normal samples, n=419). An autophagy-based signature was constructed, its correlation with the prognosis and the immune infiltration of LUAD patients was explored. The prognostic value of the autophagy-based signature was validated in an independent cohort with 70 LUAD patients. Single-cell sequencing data was used to further characterize the various immunological patterns in tumors with different signature levels. Moreover, the predictive value of autophagy-based signature in PD-1 immunotherapy was explored in the IMvigor210 dataset. At last, the protective role of DRAM1 in LUAD was validated by in vitro experiments.

Results

After screening autophagy-related gene candidates, a signature composed by CCR2, ITGB1, and DRAM1 was established with the ATscore in each sample. Further analyses showed that the ATscore was significantly associated with immune cell infiltration and low ATscore indicated poor prognosis. Meanwhile, the prognostic value of ATscore was validated in our independent LUAD cohort. GSEA analyses and single-cell sequencing analyses revealed that ATscore was associated with the immunological status of LUAD tumors, and ATscore could predict the efficacy of PD-1 immunotherapy. Moreover, in vitro experiments demonstrated that the inhibition of DRAM1 suppressed the proliferation and migration capacity of LUAD cells.

Conclusion

Our study identified a new autophagy-based signature that can predict the prognosis of LUAD patients, and this ATscore has potential applicative value in the checkpoint therapy efficiency prediction.
The Yin and Yang of Pneumolysin During Pneumococcal Infection
Authors: Pereira Joana M. , Xu Shuying , Leong John M. , Sousa Sandra
Published: April 2022

Pneumolysin (PLY) is a pore-forming toxin produced by the human pathobiont Streptococcus pneumoniae, the major cause of pneumonia worldwide. PLY, a key pneumococcal virulence factor, can form transmembrane pores in host cells, disrupting plasma membrane integrity and deregulating cellular homeostasis. At lytic concentrations, PLY causes cell death. At sub-lytic concentrations, PLY triggers host cell survival pathways that cooperate to reseal the damaged plasma membrane and restore cell homeostasis. While PLY is generally considered a pivotal factor promoting S. pneumoniae colonization and survival, it is also a powerful trigger of the innate and adaptive host immune response against bacterial infection. The dichotomy of PLY as both a key bacterial virulence factor and a trigger for host immune modulation allows the toxin to display both “Yin” and “Yang” properties during infection, promoting disease by membrane perforation and activating inflammatory pathways, while also mitigating damage by triggering host cell repair and initiating anti-inflammatory responses. Due to its cytolytic activity and diverse immunomodulatory properties, PLY is integral to every stage of S. pneumoniae pathogenesis and may tip the balance towards either the pathogen or the host depending on the context of infection.
Ocean Futures for the World’s Largest Yellowfin Tuna Population Under the Combined Effects of Ocean Warming and Acidification
Authors: Nicol Simon , Lehodey Patrick , Senina Inna , Bromhead Don , Frommel Andrea Y. , Hampton John , Havenhand Jon , Margulies Daniel , Munday Philip L. , Scholey Vernon , Williamson Jane E. , Smith Neville
Published: April 2022

The impacts of climate change are expected to have profound effects on the fisheries of the Pacific Ocean, including its tuna fisheries, the largest globally. This study examined the combined effects of climate change on the yellowfin tuna population using the ecosystem model SEAPODYM. Yellowfin tuna fisheries in the Pacific contribute significantly to the economies and food security of Pacific Island Countries and Territories and Oceania. We use an ensemble of earth climate models to project yellowfin populations under a high greenhouse gas emissions (IPCC RCP8.5) scenario, which includes, the combined effects of a warming ocean, increasing acidification and changing ocean chemistry. Our results suggest that the acidification impact will be smaller in comparison to the ocean warming impact, even in the most extreme ensemble member scenario explored, but will have additional influences on yellowfin tuna population dynamics. An eastward shift in the distribution of yellowfin tuna was observed in the projections in the model ensemble in the absence of explicitly accounting for changes in acidification. The extent of this shift did not substantially differ when the three-acidification induced larval mortality scenarios were included in the ensemble; however, acidification was projected to weaken the magnitude of the increase in abundance in the eastern Pacific. Together with intensive fishing, these potential changes are likely to challenge the global fishing industry as well as the economies and food systems of many small Pacific Island Countries and Territories. The modelling framework applied in this study provides a tool for evaluating such effects and informing policy development.
Preliminary Estimation of Marine Recreational Fisheries (MRF) in the Time of COVID-19 Pandemic: The Marche Region Case Study (Adriatic Sea, Italy)
Authors: Bolognini Luca , Cevenini Fabio , Franza Valentina , Guicciardi Stefano , Petetta Andrea , Santangelo Laura , Scanu Martina , Grati Fabio
Published: April 2022

Marine Recreational Fishing (MRF) is a highly attended complex activity, extremely evident along the coastlines, and mainly practiced among riparian communities. For that reason, this activity plays an important role to effectively contribute to the collective well-being, both from the social and economic points of view. However, it may negatively affect the fish stocks and the marine environment in general, mainly due to the removal of biological resources. The growing need to evaluate the magnitude of marine recreational fishing is recognized worldwide, especially in the last decade, when inclusive fishing programs began to focus their attention on this fishing activity. Based on its unexpected evidence and its wider repercussion on social behavior, the COVID-19 pandemic is considered by the scientific community as one of the most unique opportunities to better understand the social phenomenon and their repercussion on the environment. In this work will be reported very preliminary results on the consistency of marine recreational fishing in the case study of the Marche region (Italy). Number of recreational fishers and fishing effort were estimated through a telephone survey conducted in the Italian side of the Northern Adriatic Sea (FAO GFCM Geographical Sub Area 17) by interviewing 580 households. The sampling strategy also included a recall survey, which was carried out every month on a list of recruited fishers. In this manner, additional information was collected, such as detailed fishing effort, catches, and expenditures. In addition, biological data of catches were estimated through several on-site surveys. The information collected from January and December 2020 was affected by the COVID-19 pandemic in terms of social restrictions and access to marine places, inevitably impacting on marine recreational fishing features, including the biological resources and the related economic aspects.
Early Comprehensive Kidney Care in Dialysis-Requiring Acute Kidney Injury Survivors: A Populational Study
Authors: Wu Chun-Yi , Liu Jia-Sin , Chen Cheng-Hsu , Huang Chun-Te , Yu Tung-Min , Chuang Ya-Wen , Huang Shih-Ting , Hsu Chih-Cheng , Wu Ming-Ju
Published: April 2022

Background

For patients with Acute Kidney Injury (AKI), a strong and graded relationship exists between AKI severity and mortality. One of the most severe entities of AKI is Dialysis-Requiring Acute Kidney Injury (D-AKI), which is associated with high rates of mortality and end-stage renal disease (ESRD). For this high-risk population group, there is a lack of evidence regarding optimal post-AKI care. We propose that post-AKI care through the combined efforts of the nephrologist and the multidisciplinary care team may improve outcomes. Our aim here is to study for survivors of dialysis-requiring acute kidney injury, the effects of implementing early comprehensive kidney care.

Methods

This is a retrospective longitudinal cohort study of Taiwanese through analyzing the National Health Insurance Research Database (NHIRD). We included patients with acute dialysis during hospitalization from January 1, 2015 to December 31, 2018. Propensity match was done at 1:1, including estimated glomerular filtration rate (eGFR) based on CKD-EPI which was performed due to large initial disparities between these two cohorts.

Results

After the propensity match, each cohort had 4,988 patients. The mean eGFR based on CKD-EPI was 27.5 ml/min/1.73 m2, and the mean follow-up period was 1.4 years.

The hazard ratio for chronic dialysis or ESRD was 0.55 (95% CI, 0.49–0.62; p < 0.001). The hazard ratio for all-cause mortality was 0.79 (95% CI, 0.57–0.88; p < 0.001). Both outcomes favored early comprehensive kidney care.

Conclusions

For survivors of dialysis-requiring acute kidney injury, early comprehensive kidney care significantly lowered risks of chronic dialysis and all-cause mortality.
Cytotoxic Effects of Alternariol, Alternariol Monomethyl-Ether, and Tenuazonic Acid and Their Relevant Combined Mixtures on Human Enterocytes and Hepatocytes
Authors: den Hollander Danica , Holvoet Celestien , Demeyere Kristel , De Zutter Noémie , Audenaert Kris , Meyer Evelyne , Croubels Siska
Published: April 2022

Alternariol (AOH), alternariol monomethyl-ether (AME), and tenuazonic acid (TeA) are major mycotoxins produced by fungi of the genus Alternaria and are common contaminants of food products such as fruits, vegetables, cereals and grains. Alternaria mycotoxins are known to cause relevant economic losses and to have a negative impact on human and animal health. EFSA stated in its scientific opinion that data on the toxicity of Alternaria mycotoxins in humans and livestock are generally lacking, precluding proper hazard characterization. This study aimed to fill some knowledge gaps by studying the in vitro cytotoxicity toward human intestinal epithelial cells (Caco-2) and hepatocytes (HepG2). Cytotoxic properties were assessed by flow cytometric analyses of remaining viable cells (i.e., propidium iodide negative) after mycotoxin exposure for 24–48 h versus solvent control. Treatment of cells with single doses of AOH, AME, and TeA resulted in a dose-dependent loss of cell viability for both cell lines. Half maximal effective concentrations (EC50) of the different mycotoxins were comparable for the two cell lines. On HepG2 cells, EC50 values varying between 8 and 16, 4 and 5, and 40 and 95 μg/mL were calculated for AOH, AME, and TeA, respectively. On Caco-2 cells, EC50 values of 19 μg/mL and varying between 6 and 23, and 60 and 90 μg/mL were calculated for AOH, AME, and TeA, respectively. A general relative cytotoxicity ranking of about 1 = 1 >>> 3 was obtained for AOH, AME, and TeA, respectively. Treatment of both cell lines with combined binary and ternary mixtures of AOH, AME, and TeA in a 1:1:3 ratio, also showed a dose-dependent decrease in cell viability. For both cell lines, the binary combination of especially AME and TeA (1:3 ratio) but also of AOH and AME (1:1 ratio) significantly increased the cytotoxicity compared to the single compound toxicity, although mainly at the highest concentrations tested. The ternary combinations of AOH, AME, and TeA induced only a slight increase in cytotoxicity compared to the single mycotoxins, again at the highest concentrations tested.
Messengers From the Gut: Gut Microbiota-Derived Metabolites on Host Regulation
Authors: Li Chenyu , Liang Yaquan , Qiao Yuan
Published: April 2022

The human gut is the natural habitat for trillions of microorganisms, known as the gut microbiota, which play indispensable roles in maintaining host health. Defining the underlying mechanistic basis of the gut microbiota-host interactions has important implications for treating microbiota-associated diseases. At the fundamental level, the gut microbiota encodes a myriad of microbial enzymes that can modify various dietary precursors and host metabolites and synthesize, de novo, unique microbiota-derived metabolites that traverse from the host gut into the blood circulation. These gut microbiota-derived metabolites serve as key effector molecules to elicit host responses. In this review, we summarize recent studies in the understanding of the major classes of gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs) and peptidoglycan fragments (PGNs) on their regulatory effects on host functions. Elucidation of the structures and biological activities of such gut microbiota-derived metabolites in the host represents an exciting and critical area of research.
Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline
Authors: Grasso Patricia
Published: April 2022

In this review, the current understanding of leptin’s role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic “harmony” of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.
Advanced Brain-Age in Psychotic Psychopathology: Evidence for Transdiagnostic Neurodevelopmental Origins
Authors: Demro Caroline , Shen Chen , Hendrickson Timothy J. , Arend Jessica L. , Disner Seth G. , Sponheim Scott R.
Published: April 2022

Schizophrenia is characterized by abnormal brain structure such as global reductions in gray matter volume. Machine learning models trained to estimate the age of brains from structural neuroimaging data consistently show advanced brain-age to be associated with schizophrenia. Yet, it is unclear whether advanced brain-age is specific to schizophrenia compared to other psychotic disorders, and whether evidence that brain structure is “older” than chronological age actually reflects neurodevelopmental rather than atrophic processes. It is also unknown whether advanced brain-age is associated with genetic liability for psychosis carried by biological relatives of people with schizophrenia. We used the Brain-Age Regression Analysis and Computation Utility Software (BARACUS) prediction model and calculated the residualized brain-age gap of 332 adults (163 individuals with psychotic disorders: 105 schizophrenia, 17 schizoaffective disorder, 41 bipolar I disorder with psychotic features; 103 first-degree biological relatives; 66 controls). The model estimated advanced brain-ages for people with psychosis in comparison to controls and relatives, with no differences among psychotic disorders or between relatives and controls. Specifically, the model revealed an enlarged brain-age gap for schizophrenia and bipolar disorder with psychotic features. Advanced brain-age was associated with lower cognitive and general functioning in the full sample. Among relatives, cognitive performance and schizotypal symptoms were related to brain-age gap, suggesting that advanced brain-age is associated with the subtle expressions associated with psychosis. Exploratory longitudinal analyses suggested that brain aging was not accelerated in individuals with a psychotic disorder. In sum, we found that people with psychotic disorders, irrespective of specific diagnosis or illness severity, show indications of non-progressive, advanced brain-age. These findings support a transdiagnostic, neurodevelopmental formulation of structural brain abnormalities in psychotic psychopathology.
Astroglia in the Vulnerability to and Maintenance of Stress-Mediated Neuropathology and Depression
Authors: Miguel-Hidalgo José Javier
Published: April 2022

Significant stress exposure and psychiatric depression are associated with morphological, biochemical, and physiological disturbances of astrocytes in specific brain regions relevant to the pathophysiology of those disorders, suggesting that astrocytes are involved in the mechanisms underlying the vulnerability to or maintenance of stress-related neuropathology and depression. To understand those mechanisms a variety of studies have probed the effect of various modalities of stress exposure on the metabolism, gene expression and plasticity of astrocytes. These studies have uncovered the participation of various cellular pathways, such as those for intracellular calcium regulation, neuroimmune responses, extracellular ionic regulation, gap junctions-based cellular communication, and regulation of neurotransmitter and gliotransmitter release and uptake. More recently epigenetic modifications resulting from exposure to chronic forms of stress or to early life adversity have been suggested to affect not only neuronal mechanisms but also gene expression and physiology of astrocytes and other glial cells. However, much remains to be learned to understand the specific role of those and other modifications in the astroglial contribution to the vulnerability to and maintenance of stress-related disorders and depression, and for leveraging that knowledge to achieve more effective psychiatric therapies.
Potent Bioactive Compounds From Seaweed Waste to Combat Cancer Through Bioinformatics Investigation
Authors: Bharadwaj Kaushik Kumar , Ahmad Iqrar , Pati Siddhartha , Ghosh Arabinda , Sarkar Tanmay , Rabha Bijuli , Patel Harun , Baishya Debabrat , Edinur Hisham Atan , Abdul Kari Zulhisyam , Ahmad Mohd Zain Muhammad Rajaei , Wan Rosli Wan Ishak
Published: April 2022

The seaweed industries generate considerable amounts of waste that must be appropriately managed. This biomass from marine waste is a rich source of high-value bioactive compounds. Thus, this waste can be adequately utilized by recovering the compounds for therapeutic purposes. Histone deacetylases (HDACs) are key epigenetic regulators established as one of the most promising targets for cancer chemotherapy. In the present study, our objective is to find the HDAC 2 inhibitor. We performed top-down in silico methodologies to identify potential HDAC 2 inhibitors by screening compounds from edible seaweed waste. One hundred ninety-three (n = 193) compounds from edible seaweeds were initially screened and filtered with drug-likeness properties using SwissADME. After that, the filtered compounds were followed to further evaluate their binding potential with HDAC 2 protein by using Glide high throughput virtual screening (HTVS), standard precision (SP), extra precision (XP), and quantum polarized ligand docking (QPLD). One compound with higher negative binding energy was selected, and to validate the binding mode and stability of the complex, molecular dynamics (MD) simulations using Desmond were performed. The complex-binding free energy calculation was performed using molecular mechanics-generalized born surface area (MM-GBSA) calculation. Post-MD simulation analyses such as PCA, DCCM, and free energy landscape were also evaluated. The quantum mechanical and electronic properties of the potential bioactive compounds were assessed using the density functional theory (DFT) study. These findings support the use of marine resources like edible seaweed waste for cancer drug development by using its bioactive compounds. The obtained results encourage further in vitro and in vivo research. Our in silico findings show that the compound has a high binding affinity for the catalytic site of the HDAC 2 protein and has drug-likeness properties, and can be utilized in drug development against cancer.
Impact of Adjuvant Chemotherapy on Variant Histology of Upper Tract Urothelial Carcinoma: A Propensity Score-Matched Cohort Analysis
Authors: Lo Chi-Wen , Li Wei-Ming , Ke Hung-Lung , Chang Yi-Huei , Wu Hsi-Chin , Chen I-Hsuan Alan , Lin Jen-Tai , Huang Chao-Yuan , Chen Chung-Hsin , Tseng Jen-Shu , Lin Wun-Rong , Jiang Yuan-Hong , Lee Yu-Khun , Tsai Chung-You , Chung Shiu-Dong , Hsueh Thomas Y. , Chiu Allen W. , Jou Yeong-Chin , Cheong Ian-Seng , Chen Yung-Tai , Chen Jih-Sheng , Chiang Bing-Juin , Yu Chih-Chin , Lin Wei Yu , Wu Chia-Chang , Chen Chuan-Shu , Weng Han-Yu , Tsai Yao-Chou
Published: April 2022

Background

The advantage of adjuvant chemotherapy for upper urinary tract urothelial cancer (UTUC) has been reported, whereas its impact on upper tract cancer with variant histology remains unclear. We aimed to answer the abovementioned question with our real-world data.

Design, Setting, and Participants

Patients who underwent radical nephroureterectomy (RNU) and were confirmed to have variant UTUC were retrospectively evaluated for eligibility of analysis. In the Taiwan UTUC Collaboration database, we identified 245 patients with variant UTUC among 3,109 patients with UTUC who underwent RNU after excluding patients with missing clinicopathological information.

Intervention

Those patients with variant UTUC were grouped based on their history of receiving adjuvant chemotherapy or not.

Outcome Measurements and Statistical Analysis

Propensity score matching was used to reduce the treatment assignment bias. Multivariable Cox regression model was used for the analysis of overall, cancer-specific, and disease-free survival.

Results and Limitations

For the patients with variant UTUC who underwent adjuvant chemotherapy compared with those without chemotherapy, survival benefit was identified in overall survival in univariate analysis (hazard ratio (HR), 0.527; 95% confidence interval (CI), 0.285–0.973; p = 0.041). In addition, in multivariate analysis, patients with adjuvant chemotherapy demonstrated significant survival benefits in cancer-specific survival (OS; HR, 0.454; CI, 0.208–0.988; p = 0.047), and disease-free survival (DFS; HR, 0.324; 95% CI, 0.155–0.677; (p = 0.003). The main limitations of the current study were its retrospective design and limited case number.

Conclusions

Adjuvant chemotherapy following RNU significantly improved cancer-related survivals in patients with UTUC with variant histology.
Significance of Nerve Plane for Inferior Mesenteric Plexus Preservation in Laparoscopic Rectal Cancer Surgery
Authors: Li Kai , Zeng Junjie , Pang Pengcheng , Cheng Hua , He Xiaobo , Cao Fengyu , Luo Qiang , Tong Shilun , Zheng Yongbin
Published: April 2022

Background

Station 253 node dissection with high ligation of the inferior mesenteric artery (IMA) is difficult to perform without damage to the surrounding autonomic nerve plexuses. This study aimed to investigate the significance of the nerve plane for inferior mesenteric plexus (IMP) preservation in laparoscopic rectal cancer surgery.

Methods

A total of 56 consecutive rectal patients underwent laparoscopic en bloc station 253 node dissection with high ligation of the IMA. Station 253 nodes were divided into the extra- and intra-nerve plane station 253 nodes for further H&E staining and immunohistochemical analysis. Based on IMP nerve plane-based evidence and histopathological results, a novel nerve-sparing technique, IMP nerve plane orientation, was proposed and performed on 68 rectal cancer patients. Urinary and sexual functions in all patients were evaluated at 6 months postoperatively.

Results

Lymph node metastasis was not found, but abundant nerve bundles containing gangliocytes were observed in extra-nerve plane station 253 nodes. The nerve plane was identified intraoperatively and then confirmed by both postoperative gross specimen evaluation and histopathological analysis. The novel nerve-sparing technique (IMP nerve plane orientation) was successfully performed with no postoperative complications, and the operated patients had improved postoperative urinary and sexual functions.

Conclusion

The nerve plane is helpful for IMP preservation and station 253 node dissection. This novel nerve-sparing technique of nerve plane orientation is technically feasible and safe, which could result in faster recovery of urinary and sexual functions.
Prognostic and Clinical Significance of COX-2 Overexpression in Laryngeal Cancer: A Meta-Analysis
Authors: Du Jingwei , Feng Jun , Luo Deyan , Peng Lijuan
Published: April 2022

Objective

Several studies were conducted to explore the clinical significance of cyclooxygenase-2 (COX-2) overexpression in laryngeal cancer. However, the associations between COX-2 overexpression and clinicopathological characteristics of laryngeal cancer patients remained unclear. Here, we performed a meta-analysis to eva-TY -40luate the role of COX-2 overexpression in the risk, clinical progression, and progno\sis of laryngeal cancer.

Methods

The eligible literature was obtained from PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. Odds ratio (OR), risk ratio (RR), and 95% confidence interval (CI) were calculated to assess the strength of the associations, and I2 statistics were used to evaluate heterogeneity among studies. Publication bias was detected with Begg’s test and Egger’s test.

Results

A total of 47 eligible articles were included for the meta-analysis after screening. COX-2 expression levels in the laryngeal cancer patients were significantly higher than those in the normal controls (OR = 11.62, 95% CI: 6.96–19.40, P < 0.05). The pooled results also showed that there were significant correlations between COX-2 overexpression and clinicopathological characteristics (tumor stage, OR = 3.26, 95% CI: 2.13–4.98, P < 0.05; lymph node metastasis, in Asians, OR = 2.35, 95% CI: 1.53–3.60, P < 0.05; recurrence, OR = 10.71, 95% CI: 3.54–32.38, P < 0.05; T stage, in Asians, OR = 2.52, 95% CI: 1.66–3.83, P < 0.05). In addition, significant correlations between COX-2 overexpression and overall survival of laryngeal cancer were found both in Asians and in Caucasians (total, HR = 1.73, 95% CI: 1.23–2.24, P < 0.05; survival in Asians, HR = 2.59, 95% CI: 1.27–3.92, P < 0.05; survival in Caucasians, HR = 1.59, 95% CI: 1.03–2.14, P < 0.05).

Conclusions

The meta-analysis results suggested that COX-2 overexpression was significantly associated with the increased risk, worse clinicopathological progression, and poorer prognosis of laryngeal cancer.
Machine Learning Models for Classifying High- and Low-Grade Gliomas: A Systematic Review and Quality of Reporting Analysis
Authors: Bahar Ryan C. , Merkaj Sara , Cassinelli Petersen Gabriel I. , Tillmanns Niklas , Subramanian Harry , Brim Waverly Rose , Zeevi Tal , Staib Lawrence , Kazarian Eve , Lin MingDe , Bousabarah Khaled , Huttner Anita J. , Pala Andrej , Payabvash Seyedmehdi , Ivanidze Jana , Cui Jin , Malhotra Ajay , Aboian Mariam S.
Published: April 2022

Objectives

To systematically review, assess the reporting quality of, and discuss improvement opportunities for studies describing machine learning (ML) models for glioma grade prediction.

Methods

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy (PRISMA-DTA) statement. A systematic search was performed in September 2020, and repeated in January 2021, on four databases: Embase, Medline, CENTRAL, and Web of Science Core Collection. Publications were screened in Covidence, and reporting quality was measured against the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement. Descriptive statistics were calculated using GraphPad Prism 9.

Results

The search identified 11,727 candidate articles with 1,135 articles undergoing full text review and 85 included in analysis. 67 (79%) articles were published between 2018-2021. The mean prediction accuracy of the best performing model in each study was 0.89 ± 0.09. The most common algorithm for conventional machine learning studies was Support Vector Machine (mean accuracy: 0.90 ± 0.07) and for deep learning studies was Convolutional Neural Network (mean accuracy: 0.91 ± 0.10). Only one study used both a large training dataset (n>200) and external validation (accuracy: 0.72) for their model. The mean adherence rate to TRIPOD was 44.5% ± 11.1%, with poor reporting adherence for model performance (0%), abstracts (0%), and titles (0%).

Conclusions

The application of ML to glioma grade prediction has grown substantially, with ML model studies reporting high predictive accuracies but lacking essential metrics and characteristics for assessing model performance. Several domains, including generalizability and reproducibility, warrant further attention to enable translation into clinical practice.

Systematic Review Registration

PROSPERO, identifier CRD42020209938.
Association Between Recombinant Growth Hormone Therapy and All-Cause Mortality and Cancer Risk in Childhood: Systematic Review and Meta-Analysis
Authors: He Mengyang , Deng Xiangling , Wang Xuan , Wan Yuxiang , Huang Jinchang , Zhang Zhixin , Niu Wenquan
Published: April 2022

Objectives

The safety of recombinant human growth hormone (rhGH) treatment in childhood and the role of rhGH therapy in promoting tumorigenesis and progression have been the subject of debate for decades. We aimed to systematically assess the relationship between rhGH therapy in children and adolescents and clinical outcomes, including all-cause mortality, cancer mortality, cancer incidence, and risk of the second neoplasm.

Methods

Literature retrieval, study selection, and data extraction were completed independently and in duplicate. Effect-size estimates are expressed as standardized mortality ratios (SMRs), standardized incidence ratio (SIR), and relative risk (RR) with a 95% CI.

Results

Data from 24 articles, involving 254,776 persons, were meta-analyzed. Overall analyses revealed the association of rhGH therapy was not statistically significant with all-cause mortality (SMR = 1.28; 95% CI: 0.58–2.84; P = 0.547; I2 = 99.2%; Tau2 = 2.154) and cancer mortality (SMR = 2.59; 95% CI: 0.55–12.09; P = 0.228; I2 = 96.7%; Tau2 = 2.361) and also cancer incidence (SIR = 1.54; 95% CI: 0.68–3.47; P = 0.229; I2 = 97.5%; Tau2 = 2.287), yet statistical significance was observed for second neoplasm (RR = 1.77; 95% CI: 1.33–2.35; P = 0.001; I2 = 26.7%; Tau2 = 0.055). Differences in the geographic region, gender, treatment duration, mean rhGH dose, overall rhGH exposure dose, and initial disease accounted for heterogeneity in the subgroup analyses.

Conclusion

Our findings indicate that the rhGH therapy is not related to all-cause mortality and cancer mortality and cancer incidence, yet it seems to trigger a second tumor risk. Future prospective studies are needed to confirm our findings and answer the more challenging question regarding the optimal dose of rhGH therapy in children and adolescents.
What Can We Learn From a Human-Rights Based Approach to Disability for Public and Patient Involvement in Research?
Authors: Browne Jacqui , Dorris Emma R.
Published: April 2022

Public and Patient Involvement can align both the research process and its outcomes with the values, needs and expectations of society. By fostering the design of inclusive, engaged, and sustainable practices, research and research integrity can be improved. Devolving power to involve patients and relevant publics in deliberative decision making can produce better research outcomes. Disabled people are often categorized as “Hard to Reach.” There is a varied and complex ecosystem of societal challenges of living with a disability that reinforce this. However, if researchers are to meet their obligations under the UN Convention on the Rights of Persons with Disabilities, disabled people should be included in public and patient involvement for all research in which they have a stake. In this article we argue that a better understanding of rights-based approaches and the social model of disability within the wider research community can help to remove barriers to research involvement for disabled persons. We focus on articles 3, 4, and 9 of the Convention and discuss how the principles of participation, accessibility, and equality of opportunity can be applied to research involvement, and how their adoption can facilitate truly meaningful PPI in disability research.