bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of KRAS splice variants in cancer biology
Authors: Nuevo-Tapioles Cristina , Philips Mark R.
Published: November 2022

The three mammalian RAS genes (HRAS, NRAS and KRAS) encode four proteins that play central roles in cancer biology. Among them, KRAS is mutated more frequently in human cancer than any other oncogene. The pre-mRNA of KRAS is alternatively spliced to give rise to two products, KRAS4A and KRAS4B, which differ in the membrane targeting sequences at their respective C-termini. Notably, both KRAS4A and KRAS4B are oncogenic when KRAS is constitutively activated by mutation in exon 2 or 3. Whereas KRAS4B is the most studied oncoprotein, KRAS4A is understudied and until recently considered relatively unimportant. Emerging work has confirmed expression of KRAS4A in cancer and found non-overlapping functions of the splice variants. The most clearly demonstrated of these is direct regulation of hexokinase 1 by KRAS4A, suggesting that the metabolic vulnerabilities of KRAS-mutant tumors may be determined in part by the relative expression of the splice variants. The aim of this review is to address the most relevant characteristics and differential functions of the KRAS splice variants as they relate to cancer onset and progression.
Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating protein: The present and the future
Authors: Zhang Yihao , Zhang Huarui , Chan Daniel Wing Ho , Ma Yuan , Lu Aiping , Yu Sifan , Zhang Baoting , Zhang Ge
Published: November 2022

Aptamers are short, single-stranded DNA or RNA oligonucleotide sequences that can bind specific targets. The molecular weight of aptamers (<20 kDa) is lower than the renal filtration threshold (30∼50 kDa), resulting in very short half-lives in vivo, which limit their druggability. The development of long-lasting modification approaches for aptamers can help address the druggability bottleneck of aptamers. This review summarized two distinct kinds of long-lasting modification approaches for aptamers, including macromolecular modification and low-molecular-weight modification. Though it is a current approach to extend the half-life of aptamers, the macromolecular modification approach could limit the space for the dosage increases, thus causing potential compliance concerns due to large molecular weight. As for the other modification approach, the low-molecular-weight modification approach, which uses low molecular weight coupling agents (LMWCAs) to modify aptamers, could greatly increase the proportion of aptamer moiety. However, some LMWCAs could bind to other proteins, causing a decrease in the drug amounts in blood circulation. Given these issues, the outlook for the next generation of long-lasting modification approaches was proposed at the end, including improving the administration method to increase dosage for aptamer drugs modified by macromolecule and developing Artificial intelligence (AI)-based strategies for optimization of LMWCAs.
What programs the size of animal cells?
Authors: Liu Shixuan , Tan Ceryl , Tyers Mike , Zetterberg Anders , Kafri Ran
Published: November 2022

The human body is programmed with definite quantities, magnitudes, and proportions. At the microscopic level, such definite sizes manifest in individual cells - different cell types are characterized by distinct cell sizes whereas cells of the same type are highly uniform in size. How do cells in a population maintain uniformity in cell size, and how are changes in target size programmed? A convergence of recent and historical studies suggest - just as a thermostat maintains room temperature - the size of proliferating animal cells is similarly maintained by homeostatic mechanisms. In this review, we first summarize old and new literature on the existence of cell size checkpoints, then discuss additional advances in the study of size homeostasis that involve feedback regulation of cellular growth rate. We further discuss recent progress on the molecules that underlie cell size checkpoints and mechanisms that specify target size setpoints. Lastly, we discuss a less-well explored teleological question: why does cell size matter and what is the functional importance of cell size control?
Age-dependent increase of cytoskeletal components in sensory axons in human skin
Authors: Metzner Klara , Darawsha Omar , Wang Mengzhe , Gaur Nayana , Cheng Yiming , Rödiger Annekathrin , Frahm Christiane , Witte Otto W. , Perocchi Fabiana , Axer Hubertus , Grosskreutz Julian , Brill Monika S.
Published: November 2022

Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases.
Recovery of carbon fiber-reinforced polymer waste using dimethylacetamide base on the resin swelling principle
Authors: Li Zixin , Xing Mingfei , Zhao Li , Li Zhan , Wang Yaping
Published: November 2022

The mechanical recycling method of the carbon fiber-reinforced polymer (CFRP) has the advantages of simple process, less pollution and low cost, but only low utilization value of carbon fibers in powder or short fibers form can be obtained. To reduce the length and strength loss of the recycled carbon fibers, a novel and cost-effective dimethylacetamide (DMAC) swelling technique was developed to achieve rapid delamination of the CFRP laminates under mild conditions (120°C–160°C, 1 h). The corresponding swelling ratios and mass-loss rates of cured epoxy resin (CEP) were about 121.39%–157.39% and 0–0.69%, respectively. Excessive swelling of CEP in DMAC resulted in the cracking of the resin matrix between the adjacent carbon fiber layers. Thus the CFRP laminates were delaminated into soft single carbon fiber layers, which showed excellent cutting performance and reinforcing properties. The delamination products were cut into thin strips of different sizes and vacuum bag molded into new CFRP laminates. The flexural strength and tensile strength of the newly produced CFRP laminates were about 76.38%–90.98% and 94.61%–98.54% of the original CFRP laminates, respectively. More importantly, the chemical compositions of DMAC and CEP were unchanged during the physical swelling process. No organic pollutants (caused by resin degradation) were generated. And the used DMAC can be easily recycled by filtration. Therefore, this study provides a strategy for low-cost and high-valued recycling of CFRP waste.
Community-based approaches to support the anchoring of climate-smart agriculture in Tanzania
Authors: Pamuk Haki , van Asseldonk Marcel , Wattel Cor , Ng'ang'a Stanley Karanja , Hella Joseph Philip , Ruben Ruerd
Published: November 2022

We assess the impact of community-based approaches to promote adoption of integrated climate smart agriculture (CSA) practices based on soybean cultivation combined with mulching, intercropping, crop rotation, manure application and rhizobium inoculation methods. We use quasi-experimental data of farmers participating in Farmer Field Business Schools (FFBS) and Village Savings and Loan Associations (VSLAs) in Iringa region of Tanzania. Farmers received technical training and financial support for the initial adoption of soybean production, and women's empowerment supported household's continuous involvement in CSA practices. We find a positive effect for farmers participating in the trainings provided by the FFBSs and receiving microfinance services from VLSA members on the adoption rates of several CSA practices, and this effect became more pronounced for households with higher scores on women empowerment. Farm-level improvement in soybean production and market-level incentives for soybean sales should also strengthen household income, consumption and nutrition levels to maintain CSA practices. Community-based platforms create critical external conditions for introducing CSA practices, but women's empowerment is indispensable for intrinsic incentives for anchoring their adoption.
High efficient solar photocatalytic carbon nanoparticles
Authors: Flores-Oña Diego , Fullana Andres
Published: November 2022

In the present study, the photocatalytic activity of carbon nanoparticles (CNPs) in the degradation of methylene blue (MB) using sunlight was analyzed. The CNPs were synthesized by solvent-assisted hydrothermal carbonization (HTC) and were characterized by various spectroscopic techniques: TEM and SEM microscopy, UV-Vis, FTIR, Fluorescence, and XPS. By changing the conditions of the HTC process, the surface chemistry of CNPs was functionalized, thus a great quantity of oxygenated functional groups was generated, which eventually influenced the photocatalytic process. Next, tests were carried out with different types of nanoparticles, varying the concentration of the dye and the type of light used in the irradiation. As a result of this, more than 93% of MB degradation was achieved in 20 min of irradiation using sunlight. This result is promising since it has not been achieved by other nanomaterial. This research can be a potential starting point for the development of new solar photocatalysts.
β-sitosterol inhibits trimethylamine production by regulating the gut microbiota and attenuates atherosclerosis in ApoE–/– mice
Authors: Wu Weiping , Liu Wugao , Wang Huafu , Wang Wei , Chu Weihua , Jin Jing
Published: November 2022

The intestinal microbial metabolite trimethylamine (TMA), which is activated by flavin monooxygenase (FMO) to produce trimethylamine-N-oxide (TMAO), has been implicated in the pathogenesis of atherosclerosis (AS), leading to the development of therapeutic strategies for AS. This study aimed to investigate whether β-sitosterol can inhibit TMA production in ApoE–/– mice by reshaping the gut microbial structure. 16S rRNA sequencing of the gut microbiota showed that β-sitosterol has beneficial effects on intestinal flora function, especially the inhibition of bacteria genera that contain the gene cholintrimethylamine lyase, which is responsible for the major pathway for TMA production. In parallel, β-sitosterol effectively reduced the TMA, FMO3, and TMAO levels while ameliorating the atherosclerotic plaques of AS mice. Moreover, β-sitosterol could alleviate cholesterol metabolism and the inflammatory response, and improve the antioxidant defense capacity. These studies offer new insights into the mechanisms responsible for the antiatherosclerotic effects of β-sitosterol, which targets the microbiota-metabolism-immunity axis as a possible therapy for AS.
A comparative study for landslide susceptibility assessment using machine learning algorithms based on grid unit and slope unit
Authors: Deng Niandong , Li Yuxin , Ma Jianquan , Shahabi Himan , Hashim Mazlan , de Oliveira Gabriel , Chaeikar Saman Shojae
Published: November 2022

Landslide susceptibility assessment is an important support for disaster identification and risk management. This study aims to analyze the application ability of machine learning hybrid models in different evaluation units. Three typical machine learning models, including random forest forest by penalizing attributes (FPA) and rotation forest were merged by random subspace algorithm. Twelve evaluation factors, including elevation, slope angle, slope aspect, roughness, rainfall, lithology, distance to rivers, distance to roads, normalized difference vegetation index, topographic wetness index, plan curvature, and profile curvature, were extracted from 155 landslides in Yaozhou District, Tongchuan City, China. Six landslide susceptibility maps were generated based on the slope units divided by curvature and 30 m resolution grid units. Multiple performance metrics showed that the RS-RF model based on slope units has excellent spatial prediction ability. At the same time, the method of slope unit division based on curvature is proved to be more suitable for the typical Loess tableland regions, which provides basis for the selection of evaluation units in landslide susceptibility assessment.
Teleworking in Romania during Covid-19 crisis: From conjunctional adaptation to change of economic paradigm
Authors: Gavril (Moldovan) Ioana Andrada , Frățilă (Adam) Alexandra , Iacob Silvia Elena , Lădaru Georgiana-Raluca
Published: November 2022

The COVID-19 crisis has led to a raise in the number of people working remotely. This paper aims at identifying the extent to which the pandemic will determine a paradigm change regarding teleworking in Romania Our research is based on two surveys designed to assess the impact of teleworking both on individuals and on efficiency at the organizational level. The results show that, generally, teleworking has significant advantages, both for employees and employers. As we become aware of these advantages, it is quite likely that Romania will experience a paradigm shift in terms of teleworking, as both managers and employees consider that teleworking becomes a very good option. However, the changes will be gradual and with different intensities at the sectoral level, as teleworking must be adapted to the specificities of each sector or activity. While some sectors tend to make teleworking the new organizational culture, others will capitalize on the benefits of teleworking progressively, in relation to technological endowments and structural changes that will continue to occur. On the other hand, teleworking has the advantage of promoting the improvement of digital skills for employees, which is a great step forward for a higher degree of digitisation.
Can FinTech improve corporate environmental, social, and governance performance?—A study based on the dual path of internal financing constraints and external fiscal incentives
Authors: Du Pengcheng , Huang Shijun , Hong Yu , Wu Woran
Published: November 2022

The fulfillment of ESG responsibility by enterprises is crucial to achieving China’s “double carbon goal” and the sustainable development of the whole society. However, ESG development is facing financing constraints and information asymmetry, while the rapid development of fintech supports ESG development to improve quality and efficiency. Therefore, it is crucial to study the impact of fintech on corporate ESG development. Can financial technology (FinTech) “empower” traditional financial institutions with technology to improve corporate ESG performance? Based on this, this paper examines the relationship between regional FinTech development and corporate ESG performance and its underlying mechanisms from internal and external perspectives, using data from Chinese A-share listed companies from 2011 to 2020. The following were found: 1) The level of regional FinTech development significantly contributes to firms’ ESG performance, and the results remain robust after mitigating endogeneity using Bartik instrumental variables and difference-in-differences model estimation. 2) Mechanistic analysis finds that FinTech not only alleviates the internal financing constraints of firms, but also enhances the external government subsidies and tax rebates of firms. These significantly contribute to the improvement of firms’ ESG performance. 3) Heterogeneity analysis shows that the contribution of FinTech to improving corporate ESG performance is more pronounced in the eastern region, mature firms and firms with CEOs with unbanked financial backgrounds. Therefore, in the context of sustainable development, we should continue to promote the development of FinTech, use modern technology to “empower” finance, and help enterprises balance economic and social benefits to build a sustainable country.
Rounding up the annual ryegrass genome: High-quality reference genome of Lolium rigidum
Authors: Paril Jefferson , Pandey Gunjan , Barnett Emma M. , Rane Rahul V. , Court Leon , Walsh Thomas , Fournier-Level Alexandre
Published: November 2022

The genome of the major agricultural weed species, annual ryegrass (Lolium rigidum) was assembled, annotated and analysed. Annual ryegrass is a major weed in grain cropping, and has the remarkable capacity to evolve resistance to herbicides with various modes of action. The chromosome-level assembly was achieved using short- and long-read sequencing in combination with Hi-C mapping. The assembly size is 2.44 Gb with N50 = 361.79 Mb across 1,764 scaffolds where the seven longest sequences correspond to the seven chromosomes. Genome completeness assessed through BUSCO returned a 99.8% score for complete (unique and duplicated) and fragmented genes using the Viridiplantae set. We found evidence for the expansion of herbicide resistance-related gene families including detoxification genes. The reference genome of L. rigidum is a critical asset for leveraging genetic information for the management of this highly problematic weed species.
Novel peripheral blood diagnostic biomarkers screened by machine learning algorithms in ankylosing spondylitis
Authors: Wen Jian , Wan Lijia , Dong Xieping
Published: November 2022

Background:Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown etiology that is hard to diagnose early. Therefore, it is imperative to explore novel biomarkers that may contribute to the easy and early diagnosis of AS.

Methods:Common differentially expressed genes between normal people and AS patients in GSE73754 and GSE25101 were screened by machine learning algorithms. A diagnostic model was established by the hub genes that were screened. Then, the model was validated in several data sets.

Results:IL2RBandZDHHC18were screened using machine learning algorithms and established as a diagnostic model. Nomograms suggested that the higher the expression ofZDHHC18, the higher was the risk of AS, while the reverse was true forIL2RB in vivo. C-indexes of the model were no less than 0.84 in the validation sets. Calibration analyses suggested high prediction accuracy of the model in training and validation cohorts. The area under the curve (AUC) values of the model in GSE73754, GSE25101, GSE18781, and GSE11886 were 0.86, 0.84, 0.85, and 0.89, respectively. The decision curve analyses suggested a high net benefit offered by the model. Functional analyses of the differentially expressed genes indicated that they were mainly clustered in immune response–related processes. Immune microenvironment analyses revealed that the neutrophils were expanded and activated in AS while some T cells were decreased.

Conclusion:IL2RBandZDHHC18are potential blood biomarkers of AS, which might be used for the early diagnosis of AS and serve as a supplement to the existing diagnostic methods. Our study deepens the insight into the pathogenesis of AS.
Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia
Authors: Kubicka Ewa , Lum Lawrence G. , Huang Manley , Thakur Archana
Published: November 2022

The management of relapsed or refractory acute myeloid leukemia (AML) continues to be therapeutically challenging. Non-toxic immunotherapy approaches are needed to provide long-term anti-leukemic effects. The goal of this study was to determine whether activated T cells (ATCs) armed with bispecific antibodies (BiAbs) could target and lyse leukemic and leukemic stem cells (LSCs). Anti-CD3 × anti-CD123 BiAb (CD123Bi) and anti-CD3 × anti-CD33GO (gemtuzumab ozogamicin [GO]) BiAb (CD33GOBi) were used to arm ATCs to produce bispecific antibody armed activated T cells (designated CD123 BATs or CD33GO BATs) to target AML cell lines, peripheral blood mononuclear cells from AML patients, and in vivo treatment of AML in xenogeneic NSG mice engrafted with leukemic cells. BATs exhibited high levels of specific cytotoxicity directed at AML cell lines at low 1:1 or 1:2 effector-to-target (E:T) ratios and secrete Th1 cytokines upon target engagement. In vivo study in AML-engrafted NSG mice showed significantly prolonged survival in mice treated with CD33GO BATs (p < 0.0001) or CD123 BATs (p < 0.0089) compared to ATC-treated control mice. Patient samples containing leukemic blasts and LSCs when treated with CD33GO BATs or CD123 BATs for 18 h showed a significant reduction (50%–100%; p < 0.005) in blasts and 75%–100% reduction in LSCs (p < 0.005) in most cases compared to unarmed ATCs. This approach may provide a potent and non-toxic strategy to target AML blasts and LSCs and enhance chemo-responsiveness in older patients who are likely to develop recurrent diseases.
Immune infiltration in aggressive papillary craniopharyngioma: High infiltration but low action
Authors: Jia Yanfei , Ma Lin , Cai Kefan , Zhang Bochao , Wu Wentao , Xiao Youchao , Qiao Ning , Ru Siming , Cao Lei , Gao Hua , Gui Songbai
Published: November 2022

Papillary craniopharyngiomas (PCPs) are biologically benign but clinically aggressive lesions hence affect the quality of life. The expression of inflammatory mediators and regulation of the immune microenvironment in PCPs have not been investigated much. In this study, for the first time, we assessed the immune cell infiltration and immune cell signatures in PCPs by analyzing the bulk-RNA sequencing data and immunohistochemical staining. Additionally, we performed qRT-PCR analysis to detect inflammatory mediators interleukin-1α (IL1A) and interleukin-6 (IL6) in different aggressive groups and then developed the IL1A and IL6 prediction models for defining the degree of hypothalamic invasion. Lastly, we defined differentially expressed genes related to invasiveness and implemented enrichment analysis to them. Our results indicated that PCPs are in a state of high immune infiltration but low action with abundant inflammatory cells. High infiltration of neutrophils may lead a low active immune microenvironment. Furthermore, the high expression level of IL1A and IL6 was positively correlated with the invasion of PCP tumors in the hypothalamus. These findings provide new pathological insights into the underlying mechanism of the immune microenvironment in PCP tumors. Moreover, IL1A and IL6 might serve as potential therapeutic targets for PCP tumors, especially to prevent their invasion into the hypothalamus.
Long-term human expansion and the environmental impacts on the coastal zone of China
Authors: Wang Yafei , Liao Jinfeng , Ye Yuxuan , Fan Jie
Published: November 2022

Monitoring the long-term human expansions in coastal zones and evaluating their associated environmental impacts are critical to promoting a sustainable transformation of a society. This paper evaluated the long-term human expansion of reclamation, aquaculture ponds (saltern) and artificial surface in the Circum-Bohai Coastal Zone (CBCZ) of China based on the Google Earth Engine (GEE) platform and time-series land use (LU) function classification, and analyzed the impact of human expansion on the sustainability of coastal environment. Results show: (i) human activities in this coastal zone have expanded dramatically during the past 30 years, including an increase of 1555.50 km2 (+76.9%) for the reclamation area, 2065.53 km2 (+51.33%) for the aquaculture pond area, and 14329.99 km2 (+308%) for the artificial surface area; (ii) there are substantial spatial and temporal variations in human expansion in this coastal zone, mainly for Bohai Bay, Laizhou Bay, and Liaoning Bay, with the most intense expansion in the period 2003-2013, (iii) the spatial and temporal evolution of human activity expansion is strongly related to changes of water environmental quality and wetland loss, with the coupling degree of 70.73% and 79.41%, respectively. The expansion of human activity has led to a considerable loss of wetland number (from 2666.54 km2 to 1698.27 km2), indirectly affecting changes in offshore water quality. We found that human expansion is mostly driven by economic interests such as port construction, industrial parks, resource development, and tourism development, as well as a direct response to coastal zone development and protection policies.
Biogeography of algae and invertebrates from wave-exposed rocky intertidal habitats along the Atlantic coast of Nova Scotia (Canada): Latitudinal and interannual patterns and possible underlying drivers
Authors: Scrosati Ricardo A. , Freeman Matthew J. , Ellrich Julius A. , Petzold Willy
Published: November 2022

Biogeographic studies aim to understand species distributions and are becoming increasingly relevant to establish baselines to monitor ecological change. The NW Atlantic coast hosts a cold-temperate biota, although knowledge about its biogeography is patchy. This study documents for the first time biogeographic variation at mid-to-high intertidal elevations in wave-exposed rocky intertidal habitats along the open Atlantic coast of Nova Scotia (Canada), a hydrographically distinct subregion of this cold-temperate region. For this goal, we measured the summer abundance of algae and invertebrates at the same nine locations over four consecutive years (2014 to 2017) spanning 415 km of coastline, which allowed us to examine latitudinal and interannual patterns. In addition, we looked for mensurative evidence on possible drivers underlying these patterns, focusing on sea surface temperature, daily maximum and minimum temperature (which often happen at low tides at thus differ from sea surface temperature), pelagic food supply for intertidal filter-feeders (phytoplankton abundance and particulate organic carbon), drift sea ice during the cold season (which can cause intertidal disturbance), and species associations. Our field surveys revealed that northern locations can be severely disturbed by ice scour when drift ice is abundant and, while biological recolonization occurs over the years, it differs in pace among locations. Southern locations, instead, did not experience ice scour during our study and, thus, generally exhibited a higher species richness and abundance than northern locations. Multivariate analyses indicated that the aforementioned expressions of temperature and pelagic food supply explained together 32–55% of the variation in alongshore biogeographic pattern, depending on the year. Species association analyses suggest that algal foundation species (generally more abundant at southern locations) contribute to increase location-wise species richness. Mensurative evidence for bottom-up forcing in seaweed–herbivore and filter-feeder–predator systems differed greatly among years. Overall, in addition to its inherent value to advance NW Atlantic intertidal biogeography, our species distribution database should be valuable to assess ecological change decades into the future as climate change and other anthropogenic influences unfold.
A review on flexion angle in high-flexion total knee arthroplasty for indonesian’s need
Authors: Darmanto D. , Novriansyah R. , Anggoro P. W. , Ismail R. , Jamari J. , Bayuseno A. P.
Published: November 2022

Total Knee Arthroplasty (TKA) proposed as an alternative treatment for damaged knee joints of humans is reviewed. The commercial application of TKA can help patients to improve their daily normal activities. Here the high-flex type total knee arthroplasty (High-Flex TKA) is typically designed for the patient’s convenience on which the greater range of motion can be adjusted for extreme activities such as Seiza and Muslim praying. However, the present High-Flex TKAs have not fulfilled the needs of Indonesians for religious activities with a flexion angle of 150°–165°. Therefore, this review aims to examine the flexion range of High-Flex TKAs proposed for the needs of Indonesians. This study is a narrative review, all studies published and reviewed are related to the range of flexion angles on the use of products from many manufacturers and various types that have been used by patients, as well as the development of a CAD-based TKA design. It was proposed in the present study that the flexion angle on High-Flex TKAs may be optimized by thickening the posterior femoral condyle, creating a medial pivot system, and applying a single radius system on the femoral component. Whereas, the tibial insert component could be designed by setting up the posterior tibial slope, and creating a post-cam stabilizer mechanism. Many knowledge gaps related to the population of research objects, lack of research on extreme angles, development of TKA components, are discussed. Further needs of extensive research on TKA in Mongoloid races are anticipated to be introduced for extreme angles and most comprehensive product development for optimization of the flexion angle.
The role of the mTOR pathway in diabetic retinopathy
Authors: Casciano Fabio , Zauli Enrico , Rimondi Erika , Mura Marco , Previati Maurizio , Busin Massimo , Zauli Giorgio
Published: November 2022

The retina, the part of the eye, translates the light signal into an electric current that can be sent to the brain as visual information. To achieve this, the retina requires fine-tuned vascularization for its energy supply. Diabetic retinopathy (DR) causes alterations in the eye vascularization that reduce the oxygen supply with consequent retinal neurodegeneration. During DR, the mammalian target of rapamycin (mTOR) pathway seems to coordinate retinal neurodegeneration with multiple anabolic and catabolic processes, such as autophagy, oxidative stress, cell death, and the release of pro-inflammatory cytokines, which are closely related to chronic hyperglycemia. This review outlines the normal anatomy of the retina and how hyperglycemia can be involved in the neurodegeneration underlying this disease through over activation or inhibition of the mTOR pathway.
The Food and Drug Administration-approved antipsychotic drug trifluoperazine, a calmodulin antagonist, inhibits viral replication through PERK-eIF2α axis
Authors: Mao Yizhi , Wang Ziyang , Yao Chen , Zeng Qi , Cheng Wei , Zhang Shimeng , Chen Shuai , Sheng Chunjie
Published: November 2022

Virus-related diseases are seriously threatening human health, but there are currently only 10 viruses with clinically approved antiviral drugs available. As non-cellular organisms, viruses parasitize in living cells and rely on the protein synthesis mechanism of the host cells. In this study, we found that the antipsychotic drug trifluoperazine (TFP), a dual dopamine receptor D2 (DRD2)/calmodulin (CALM) antagonist, increases the phosphorylation of eukaryotic initiation factor 2α (eIF2α), a key factor in the regulation of protein synthesis and significantly inhibits vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) replication. CALM but not DRD2 is involved in the antiviral activity of TFP. By knockdown of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) we found that the antiviral function of TFP is dependent on PERK, a stress response kinase that mediates eIF2α phosphorylation. Furthermore, the results of animal experiments showed that TFP protects mice from lethal VSV attacks, improving the survival rate and reducing lung injury. Taken together, these data suggests that TFP inhibits virus replication through PERK-eIF2α axis, and this broad-spectrum of mechanisms are worth further evaluation in clinical trials in the future.
Quantitative characterisation of ipRGCs in retinal degeneration using a computation platform for extracting and reconstructing single neurons in 3D from a multi-colour labeled population
Authors: Procyk Christopher A. , Rodgers Jessica , Zindy Egor , Lucas Robert J. , Milosavljevic Nina
Published: November 2022

Light has a profound impact on mammalian physiology and behavior. Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin, rendering them sensitive to light, and are involved in both image-forming vision and non-image forming responses to light such as circadian photo-entrainment and the pupillary light reflex. Following outer photoreceptor degeneration, the death of rod and cone photoreceptors results in global re-modeling of the remnant neural retina. Although ipRGCs can continue signaling light information to the brain even in advanced stages of degeneration, it is unknown if all six morphologically distinct subtypes survive, or how their dendritic architecture may be affected. To answer these questions, we generated a computational platform−BRIAN (Brainbow Analysis of individual Neurons) to analyze Brainbow labeled tissues by allowing objective identification of voxels clusters in Principal Component Space, and their subsequent extraction to produce 3D images of single neurons suitable for analysis with existing tracing technology. We show that BRIAN can efficiently recreate single neurons or individual axonal projections from densely labeled tissue with sufficient anatomical resolution for subtype quantitative classification. We apply this tool to generate quantitative morphological information about ipRGCs in the degenerate retina including soma size, dendritic field size, dendritic complexity, and stratification. Using this information, we were able to identify cells whose characteristics match those reported for all six defined subtypes of ipRGC in the wildtype mouse retina (M1−M6), including the rare and complex M3 and M6 subtypes. This indicates that ipRGCs survive outer retinal degeneration with broadly normal morphology. We additionally describe one cell in the degenerate retina which matches the description of the Gigantic M1 cell in Humans which has not been previously identified in rodent.
Multi-threshold image segmentation for melanoma based on Kapur’s entropy using enhanced ant colony optimization
Authors: Yang Xiao , Ye Xiaojia , Zhao Dong , Heidari Ali Asghar , Xu Zhangze , Chen Huiling , Li Yangyang
Published: November 2022

Melanoma is a malignant tumor formed by the cancerous transformation of melanocytes, and its medical images contain much information. However, the percentage of the critical information in the image is small, and the noise is non-uniformly distributed. We propose a new multi-threshold image segmentation model based on the two-dimensional histogram approach to the above problem. We present an enhanced ant colony optimization for continuous domains (EACOR) in the proposed model based on the soft besiege and chase strategies. Further, EACOR is combined with two-dimensional Kapur’s entropy to search for the optimal thresholds. An experiment on the IEEE CEC2014 benchmark function was conducted to measure the reliable global search capability of the EACOR algorithm in the proposed model. Moreover, we have also conducted several sets of experiments to test the validity of the image segmentation model proposed in this paper. The experimental results show that the segmented images from the proposed model outperform the comparison method in several evaluation metrics. Ultimately, the model proposed in this paper can provide high-quality samples for subsequent analysis of melanoma pathology images.
Genetic estimation of correlations and causalities between multifaceted modifiable factors and gastro-oesophageal reflux disease
Authors: Sun Yuanlin , Cao Xueyuan , Cao Donghui , Cui Yingnan , Su Kaisheng , Jia Zhifang , Wu Yanhua , Jiang Jing
Published: November 2022

Background

Gastro-oesophageal reflux disease (GORD) is a common gastrointestinal dysfunction that significantly affects the quality of daily life, and health interventions are challenging to prevent the risk of GORD. In this study, we used Mendelian randomization framework to genetically determine the causal associations between multifaceted modifiable factors and the risk of GORD.

Materials and methods

Sixty-six exposures with available instrumental variables (IVs) across 6 modifiable pathways were included in the univariable MR analysis (UVMR). Summary-level genome-wide association studies (GWAS) datasets for GORD were retrieved from the Neale Lab (GORDNeale, Ncases = 29975, Ncontrols = 390556) and FinnGen (GORDFinn, Ncases = 13141, Ncontrols = 89695). Using the METAL software, meta-analysis for single nucleotide polymorphisms (SNPs) from GORDNeale and GORDFinn was conducted with an inverse variance weighted (IVW) fixed-effect model. Moreover, we leveraged partition around medoids (PAM) clustering algorithm to cluster genetic correlation subtypes, whose hub exposures were conditioned for multivariable MR (MVMR) analyses. P-values were adjusted with Bonferroni multiple comparisons.

Results

Significant causal associations were identified between 26 exposures (15 risk exposures and 11 protective exposures) and the risk of GORD. Among them, 13 risk exposures [lifetime smoking, cigarette consumption, insomnia, short sleep, leisure sedentary behavior (TV watching), body mass index (BMI), body fat percentage, whole body fat mass, visceral adipose tissue, waist circumference, hip circumference, major depressive disorder, and anxious feeling], and 10 protective exposures (leisure sedentary behavior (computer use), sitting height, hand grip strength (left and right), birth weight, life satisfaction, positive affect, income, educational attainment, and intelligence) showed novel significant causal associations with the risk of GORD. Moreover, 13 exposures still demonstrated independent associations with the risk of GORD following MVMR analyses conditioned for hub exposures (educational attainment, smoking initiation and BMI). In addition, 12 exposures showed suggestive causal associations with the risk of GORD.

Conclusion

This study systematically elucidated the modifiable factors causally associated with the risk of GORD from multifaceted perspectives, which provided implications for prevention and treatment of GORD.
An olive-derived elenolic acid stimulates hormone release from L-cells and exerts potent beneficial metabolic effects in obese diabetic mice
Authors: Wang Yao , Wu Yajun , Wang Aiping , Wang Aihua , Alkhalidy Hana , Helm Richard , Zhang Shijun , Ma Hongguang , Zhang Yan , Gilbert Elizabeth , Xu Bin , Liu Dongmin
Published: November 2022

Insulin resistance and progressive decline in functional β-cell mass are two key factors for developing type 2 diabetes (T2D), which is largely driven by overweight and obesity, a significant obstacle for effective metabolic control in many patients with T2D. Thus, agents that simultaneously ameliorate obesity and act on multiple pathophysiological components could be more effective for treating T2D. Here, we report that elenolic acid (EA), a phytochemical, is such a dual-action agent. we show that EA dose-dependently stimulates GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts. In addition, EA induces L-cells to secrete peptide YY (PYY). EA induces a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling. Consistently, inhibition of (PLC) or Gαq ablates EA-stimulated increase of [Ca2+]i and GLP-1 secretion. In vivo, a single dose of EA acutely stimulates GLP-1 and PYY secretion in mice, accompanied with an improved glucose tolerance and insulin levels. Oral administration of EA at a dose of 50 mg/kg/day for 2 weeks normalized the fasting blood glucose and restored glucose tolerance in high-fat diet-induced obese (DIO) mice to levels that were comparable to chow-fed mice. In addition, EA suppresses appetite, reduces food intake, promotes weight loss, and reverses perturbated metabolic variables in obese mice. These results suggest that EA could be a dual-action agent as an alternative or adjuvant treatment for both T2D and obesity.
Bacillus amyloliquefaciens SC06 in the diet improves egg quality of hens by altering intestinal microbiota and the effect is diminished by antimicrobial peptide
Authors: Xu Shujie , Wang Fei , Zou Peng , Li Xiang , Jin Qian , Wang Qi , Wang Baikui , Zhou Yuanhao , Tang Li , Yu Dongyou , Li Weifen
Published: November 2022

This experiment investigated the effects of Bacillus amyloliquefaciens SC06 (BaSC06) and its combination with antimicrobial peptide (AMP) on the laying performance, egg quality, intestinal physical barrier, antioxidative status and immunity of commercial Jingbai strain laying hens. The results showed that BaSC06 significantly improved laying performance and egg quality of laying hens. However, there was a tendency to increase laying performance and decrease egg quality for the addition of AMP compared to the BaSC06 group. Also, both BaSC06 and its combination with AMP treatment increased length of microvilli and the content of tight junction protein in jejunum, and BaSC06 combination with AMP treatment is better than BaSC06 treatment alone. Compared to control, most of the serum antioxidant enzyme activities were significantly increased in the BaSC06+AMP group, the BaSC06 group only increased the activity of GSH-Px. Short-chain fatty acid analysis showed that BSC06 significantly increased the content of butyric, isobutyric and isovaleric acid in the cecum. However, the content of most of the short-chain fatty acids was even lower than that of the control group after the addition of AMP. Microbiota analysis showed that BaSC06 increased the absolute abundance of the butyrate-producing gut bacteria Ruminococaaoeae UCG-005, while the addition of AMP reduced the number of microorganisms detected and weakened the effect of BaSC06. BaSC06 acts as an anti-inflammatory agent by regulating the gut microbiota, and AMP further attenuates the immune response by reducing the number of gut microbes based on improved intestinal microbiota composition.
A prognostic signature model for unveiling tumor progression in lung adenocarcinoma
Authors: Li Zijian , Zeng Tao , Zhou Chong , Chen Yan , Yin Wu
Published: November 2022

A more accurate prognosis is important for clinical treatment of lung adenocarcinoma. However, due to the limitation of sample and technical bias, most prognostic signatures lacked reproducibility, and few were applied to clinical practice. In addition, understanding the molecular driving mechanism is indispensable for developing more promising therapies for lung adenocarcinoma. Here, we built an unbiased prognostic significance model to perform an integrative analysis, including differentially expressed genes and clinical data with lung adenocarcinoma patients from TCGA. Multivariable Cox proportional hazards model with the Lasso penalty and 10-fold cross-validate were used to identify the best gene signature. We generated a 17-gene signature for prognostic risk prediction based on the overall survival time of lung adenocarcinoma patients. To further test the model’s predictive ability, we have applied an independent GEO database to verify the predictive ability of prognostic signature. The model can more objectively describe several biological processes related to tumors and reveal important molecular mechanisms in tumor development by GO and KEGG analysis. Furthermore, differential expression analysis by GSEA revealed that tumor microenvironments such as ER stress, exosome, and immune microenvironment were enriched. Using single-cell RNA sequence technology, we found that risk score was positively correlated with lung adenocarcinoma marker genes and copy number variation but negatively correlated with lung epithelial marker genes. High-risk cell populations with the model had stronger cancer stemness and tumor-related pathway activation. As we expected, the risk score was in accordance with the malignancy of each cluster from tumor progression. In conclusion, the risking model established in this study is more reliable than others in evaluating the prognosis of LUAD patients.
Tissue specific considerations in implementing high intensity focussed ultrasound under magnetic resonance imaging guidance
Authors: deSouza Nandita M. , Gedroyc Wladyslaw , Rivens Ian , ter Haar Gail
Published: November 2022

High-intensity focused ultrasound can ablate a target permanently, leaving tissues through which it passes thermally unaffected. When delivered under magnetic resonance (MR) imaging guidance, the change in tissue relaxivity on heating is used to monitor the temperatures achieved. Different tissue types in the pre-focal beam path result in energy loss defined by their individual attenuation coefficients. Furthermore, at interfaces with different acoustic impedances the beam will be both reflected and refracted, changing the position of the focus. For complex interfaces this effect is exacerbated. Moreover, blood vessels proximal to the focal region can dissipate heat, altering the expected region of damage. In the target volume, the temperature distribution depends on the thermal conductivity (or diffusivity) of the tissue and its heat capacity. These are different for vascular tissues, water and fat containing tissues and bone. Therefore, documenting the characteristics of the pre-focal and target tissues is critical for effective delivery of HIFU. MR imaging provides excellent anatomic detail and characterization of soft tissue components. It is an ideal modality for real-time planning and monitoring of HIFU ablation, and provides non-invasive temperature maps. Clinical applications involve soft-tissue (abdomino-pelvic applications) or bone (brain applications) pre-focally and at the target (soft-tissue tumors and bone metastases respectively). This article addresses the technical difficulties of delivering HIFU effectively when vascular tissues, densely cellular tissues, fat or bone are traversed pre-focally, and the clinical applications that target these tissues. The strengths and limitations of MR techniques used for monitoring ablation in these tissues are also discussed.
Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li–Fraumeni-like family
Authors: Li Yuping , Xie Yupeng , Wang Di , Xu Hanyan , Ye Junru , Yin Jiani C. , Chen Junjie , Yan Junrong , Ye Bin , Chen Chengshui
Published: November 2022

Background

Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored.

Methods

We performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants.

Results

No germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation.

Conclusions

Leveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.