bluuebunny/crossref_metadata_2025 huggingface dataset:
ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition
Authors: Tang Jian , Ma Shinan , Gao Yujiu , Zeng Fan , Feng Ying , Guo Chong , Hu Lin , Yang Lingling , Chen Yanghui , Zhang Qiufang , Yuan Yahong , Guo Xingrong
Published: August 2022

Background

Ectopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.

Methods

We used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.

Results

ANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.

Conclusions

ANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.
In vitro assessment of pancreatic hormone secretion from isolated porcine islets
Authors: Mourad Nizar I. , Xhema Daela , Gianello Pierre
Published: August 2022

The potential use of porcine islets for transplantation in humans has triggered interest in understanding porcine islet physiology. However, the number of studies dedicated to this topic has remained limited, as most islet physiologists prefer to use the less time-consuming rodent model or the more clinically relevant human islet. An often-overlooked aspect of pig islet physiology is its alpha cell activity and regulation of its glucagon secretion. In vitro islet perifusion is a reliable method to study the dynamics of hormone secretion in response to different stimuli. We thus used this method to quantify and study glucagon secretion from pig islets. Pancreatic islets were isolated from 20 neonatal (14 to 21-day old) and 5 adult (>2 years) pigs and cultured in appropriate media. Islet perifusion experiments were performed 8 to 10 days post-isolation for neonatal islets and 1 to 2 days post-isolation for adult islets. Insulin and glucagon were quantified in perifusion effluent fractions as well as in islet extracts by RIA. Increasing glucose concentration from 1 mM to 15 mM markedly inhibited glucagon secretion independently of animal age. Interestingly, the effect of high glucose was more drastic on glucagon secretion compared to its effect on insulin secretion. In vivo, glucose injection during IVGTT initiated a quick (2-10 minutes) 3-fold decrease of plasmatic glucagon whereas the increase of plasmatic insulin took 20 minutes to become significant. These results suggest that regulation of glucagon secretion significantly contributes to glucose homeostasis in pigs and might compensate for the mild changes in insulin secretion in response to changes in glucose concentration.
Targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization for non-islet cell tumor hypoglycemia secondary to a liver metastatic solitary fibrous tumor: A case report and literature review
Authors: Jin Kai , Zhong Shan , Lin Liya , Wu Jianjun , Wang Yuqi , Cui Weijuan , Gu Wei , Chao Ming , Song Xiaoxiao
Published: August 2022

Doege–Potter syndrome is a rare paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. Doege–Potter syndrome always presents with recurrent fasting hypoglycemia, which can occasionally be life-threatening. The best choice of treatment for Doege–Potter syndrome and solitary fibrous tumor is complete resection. However, when it is unfeasible, local-regional treatment can be used as a palliative therapy. Herein, we report a case of a 46-year-old man with Doege–Potter syndrome that occurred secondary to the liver and pancreatic metastatic solitary fibrous tumors. After he received six rounds of targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization (TILA-TACE) treatment in our hospital, his hypoglycemia was clinically cured, and the liver metastatic tumor was well controlled. We suggest that TILA-TACE can be considered when curative resection is unfeasible for metastatic liver solitary fibrous tumors to help a patient obtain further surgery opportunities.
Association of long-term visit-to-visit variability of HbA1c and fasting glycemia with hypoglycemia in type 2 diabetes mellitus
Authors: Long Chen , Tang Yaling , Huang Jiangsheng , Liu Suo , Xing Zhenhua
Published: August 2022

Background

Self-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM.

Methods

In this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell’s C method.

Results

After adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03–1.16; P < 0.01) and HMA events (HR: 1.11; 95% CI: 1.03–1.20; P < 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31–1.49; P < 0.01) and HMA events (HR: 1.46; 95% CI: 1.35–1.57; P < 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P < 0.01).

Conclusions

Increased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability.

Trial registration

http://www.clinicaltrials.gov. Unique identifier: NCT00000620.
Research progress on the pharmacological effects of berberine targeting mitochondria
Authors: Fang Xinyi , Wu Haoran , Wei Jiahua , Miao Runyu , Zhang Yanjiao , Tian Jiaxing
Published: August 2022

Berberine is a natural active ingredient extracted from the rhizome of Rhizoma Coptidis, which interacts with multiple intracellular targets and exhibits a wide range of pharmacological activities. Previous studies have preliminarily confirmed that the regulation of mitochondrial activity is related to various pharmacological actions of berberine, such as regulating blood sugar and lipid and inhibiting tumor progression. However, the mechanism of berberine’s regulation of mitochondrial activity remains to be further studied. This paper summarizes the molecular mechanism of the mitochondrial quality control system and briefly reviews the targets of berberine in regulating mitochondrial activity. It is proposed that berberine mainly regulates glycolipid metabolism by regulating mitochondrial respiratory chain function, promotes tumor cell apoptosis by regulating mitochondrial apoptosis pathway, and protects cardiac function by promoting mitophagy to alleviate mitochondrial dysfunction. It reveals the mechanism of berberine’s pharmacological effects from the perspective of mitochondria and provides a scientific basis for the application of berberine in the clinical treatment of diseases.
Assessing Multidimensional Energy Poverty and Its Economic Impact on N11 Countries: Mediating Role of Energy Efficiency
Authors: Hong Manh Pham , Wang Kuan-Ting , Khudoykulov Khurshid , Trung Lam Minh , Ngo Thanh Quang , Nguyen Tran Thai Ha
Published: August 2022

This study seeks to estimate energy poverty using a multidimensional and wide-ranging category of indicators via the GRA-SRA approach. The study entails a case study analysis of the N-11 nations utilizing data from 2000 to 2017. Thus, a formulation of multidimensional energy poverty indexes of multidimensional indicators crosswise three dimensions is carried out. Energy availability, energy affordability, and energy cleanability, with regard to the N11 nations, are taken into account. The findings reveal that total energy poverty has progressed. We discover that Bangladesh (0.65) and Pakistan (0.47) are at risk concerning energy poverty, whereas the Philippines (0.36), Indonesia (0.33), and Vietnam (0.28) are less exposed to energy poverty. The relative changes in energy poverty are discovered among the N11 nations, where South Korea witnessed a consistent advancement in energy poverty, whereas Iran displayed a reduced trajectory and a vacillating trend. The findings indicate that the energy sources utilized for warming homes are essential within the scenario of energy poverty and inequality. Contrary to traditional steps, we assess the multidimensional energy poverty at the national level instead of the depths of gravity of energy poverty specifically for the energy-poor as against the whole population.
A Mine Ventilation System Energy Saving Technique Based on an Improved Equilibrium Optimizer
Authors: Yu Bao-cai , Shao Liang-shan
Published: August 2022

Over the years, the ventilation systems used in coal mines have become more and more complex. Due to a lack of scientific and effective management, the energy consumed by ventilation systems has rapidly increased, resulting in considerable wasted energy. To solve this problem, the authors established a nonlinear optimization model aimed at minimizing the total energy consumption of a mine ventilation network. Furthermore, the authors propose an improved equilibrium optimizer algorithm to solve the model. First, the population is initialized by a chaotic map. Second, the adjustment strategy of a trigonometric function is introduced to improve the index F, which improves the global development ability of the algorithm, avoids falling into local optimum, and can improve the local search ability in the later stages. Then, Gaussian disturbance is introduced to enhance the diversity of particles and avoid falling into the local optimum. Finally, a learning factor was introduced to improve the generation rate G and improve the algorithm’s integrity; it was then compared with other algorithms. The simulation results show that the performance of the improved algorithm is significantly better than other algorithms. It was tested with the ventilation system of Wangjialing mine of Zhongmei Huajin Energy Co., Ltd. The results showed that the energy consumption of the ventilation system was reduced by 17.83%. This method can save the mine about 2 million yuan RMB every year. The economic effect is remarkable, we achieved the purpose of energy conservation and emission reduction, and the effectiveness of the proposed method was verified.
A multi-stakeholder potential game model in active distribution network considering the bounded rationality of small users
Authors: Wang Hongli , Ligao Junjie , Wu Fuzhang , Yang Jun , Zhu Xu , Wan Li , Zhang Kanjun , Yang Shaobo , Kamel Salah
Published: August 2022

The increase in the penetration rate of distributed renewable energy sources has brought unprecedented challenges to the economic and stable operation of the active distribution network (ADN). To improve the operating efficiency and total benefits of the ADN, it is necessary to establish an optimization model considering the stakeholders’ market behavior and the game relationship among them under the market environment. In this paper, a multi-stakeholder potential game model in the ADN considering the bounded rationality of small users is proposed. The game relationships among five stakeholders, including the distributed photovoltaic generation aggregators, the distributed wind power aggregators, the energy storage operators, the large users and the load aggregators, are modeled on an hourly time scale. Existing research has proved that the game equilibrium of the potential game model must exist. Based on the information transfer and the strategy update mode on the social network, a demand response evolutionary game model for small users is established. Moreover, a distributed algorithm is designed to obtain the pure strategy equilibrium. Finally, a case with five stakeholders and 160 small users is used to verify the rationality and feasibility of the proposed model.
Dynamic assessment of China’s re-electrification level considering carbon peaking and carbon neutrality goals: A study based on functional data analysis
Authors: Guo Xiaoxuan , Sun Leping , Han Shuai , Lu Jianbin
Published: August 2022

Electrification is currently the most mature technological path to carbon neutrality. However, the traditional measurement methods of the electrification levels cannot meet the development requirements of China’s electrification under the dual-carbon strategy. Thus, this study incorporated carbon constraints into the re-electrification-level evaluation system and evaluated the re-electrification level of 30 provinces in China from 2007 to 2019 using the entropy weight method. Then, the functional data analysis method was employed to further explore the dynamic variation rule of the regional re-electrification level. The evaluation results show that the top three provinces in the mean value of the re-electrification index are Guangdong (0.628), Jiangsu (0.617), and Zhejiang (0.573). The clustering results show that there are great spatial differences in the development of electrification in China. According to the fitted function curve, China’s electrification development can be roughly divided into the following four stages: uptrend, brief decline, sharp uptrend, and slight and steady decline. At present, China’s electrification is entering a new stage. To implement re-electrification further, the government and the power grid enterprises need to find the priority and breakthroughs under carbon emissions and environmental constraints. Our research results provide reference for the improvement of regional re-electrification levels in China.
Supply chain risks of critical metals: Sources, propagation, and responses
Authors: Sun Xiaoqi
Published: August 2022

In the era of globalization, industries of critical metals are organized through the global supply chain. However, the global supply chains have been disrupted since 2020 by the outbreak of COVID-19 and a series of geopolitical crises. To better address the supply chain challenges of critical metals, a review is needed about the sources, propagation, and responses of the supply chain risks. Firstly, this review provides an overview about the research progress in identifying the risk sources and assessing the risks and then proposes a new supply chain framework, categorizing relevant risk factors into upstream risks, middle-stream risks, downstream risks, and general risks, for risk analysis of critical metals. Secondly, this review offers a comprehensive understanding about how the risks propagate horizontally and vertically. Finally, responses such as supply diversification, stockpiling, material substitution, recycling and circular economy strategy, price volatility hedging, and supply chain traceability are reviewed. This survey features the supply chain perspective, overviews on network-based studies, and affirms the urgency and need for further studies on supply chain risks and resilience, which may contribute to a smooth clean energy transition.
Emerging Themes and Future Directions of Multi-Sector Nexus Research and Implementation
Authors: Khan Zarrar , Abraham Edo , Aggarwal Srijan , Ahmad Khan Manal , Arguello Ricardo , Babbar-Sebens Meghna , Bereslawski Julia Lacal , Bielicki Jeffrey M. , Campana Pietro Elia , Silva Carrazzone Maria Eugenia , Castanier Homero , Chang Fi-John , Collins Pamela , Conchado Adela , Dagani Koteswara Rao , Daher Bassel , Dekker Stefan C. , Delgado Ricardo , Diuana Fabio A. , Doelman Jonathan , Elshorbagy Amin A. , Fan Chihhao , Gaudioso Rossana , Gebrechorkos Solomon H. , Geli Hatim M. E. , Grubert Emily , Huang Daisy , Huang Tailin , Ilyas Ansir , Ivakhnenko Aleksandr , Jewitt Graham P. W. , Ferreira dos Santos Maria João , Jones J. Leah , Kellner Elke , Krueger Elisabeth H. , Kumar Ipsita , Lamontagne Jonathan , Lansu Angelique , Lee Sanghyun , Li Ruopu , Linares Pedro , Marazza Diego , Mascari María Pía , McManamay Ryan A. , Meng Measrainsey , Mereu Simone , Miralles-Wilhelm Fernando , Mohtar Rabi , Muhammad Abubakr , Opejin Adenike Kafayat , Pande Saket , Parkinson Simon , Payet-Burin Raphaël , Ramdas Meenu , Ramos Eunice Pereira , Ray Sudatta , Roberts Paula , Sampedro Jon , Sanders Kelly T. , Saray Marzieh Hassanzadeh , Schmidt Jennifer , Shanafield Margaret , Siddiqui Sauleh , Suriano Micaela , Taniguchi Makoto , Trabucco Antonio , Tuninetti Marta , Vinca Adriano , Weeser Björn , White Dave D. , Wild Thomas B. , Yadav Kamini , Yogeswaran Nithiyanandam , Yokohata Tokuta , Yue Qin
Published: August 2022

Water, energy, and food are all essential components of human societies. Collectively, their respective resource systems are interconnected in what is called the “nexus”. There is growing consensus that a holistic understanding of the interdependencies and trade-offs between these sectors and other related systems is critical to solving many of the global challenges they present. While nexus research has grown exponentially since 2011, there is no unified, overarching approach, and the implementation of concepts remains hampered by the lack of clear case studies. Here, we present the results of a collaborative thought exercise involving 75 scientists and summarize them into 10 key recommendations covering: the most critical nexus issues of today, emerging themes, and where future efforts should be directed. We conclude that a nexus community of practice to promote open communication among researchers, to maintain and share standardized datasets, and to develop applied case studies will facilitate transparent comparisons of models and encourage the adoption of nexus approaches in practice.
Forecasting the volatility of European Union allowance futures with time-varying higher moments and time-varying risk aversion
Authors: Wu Xinyu , Mei Xueting , Ding Zhongming
Published: August 2022

There is increasing evidence that European Union allowance (EUA) futures return distributions exhibit features of time-varying higher moments (skewness and kurtosis), which plays an important role in modeling and forecasting EUA futures volatility. Moreover, a number of studies have shown that time-varying risk aversion (RA) contains useful information for forecasting EUA futures volatility. In light of this, this paper proposes the GARCH-MIDAS with skewness and kurtosis (hereafter GARCH-MIDAS-SK) to empirically investigate the impact and predictive role of RA on EUA futures volatility. Our empirical results show that RA has a significantly negative impact on the long-term volatility of EUA futures. The EUA futures return distributions exhibit obvious features of time-varying higher moments. Incorporating RA and time-varying higher moments improves the in-sample fitting of the model. Furthermore, out-of-sample results suggest that incorporating RA and time-varying higher moments leads to significantly more accurate volatility forecasts. This finding is robust to alternative out-of-sample forecasting windows.
Signifying the relationship between education input, social security expenditure, and urban-rural income gap in the circular economy
Authors: Wang Yuan , Huang Yingjun , Sarfraz Muddassar
Published: August 2022

This paper takes the inter-provincial panel data of China from 1999 to 2015 as the research sample and uses the GMM estimation method to empirically test the relationship among education input, social security expenditure, and urban-rural income gap. The results show that education input and social security expenditure have a significant impact on the urban-rural income gap, and there are regional differences. Specifically, the augments of education input and social security expenditure widens the urban-rural income gap in the western region, and narrows the urban-rural income gap of the eastern and central regions but has less impact on the eastern region. The paper provides a new perspective for understanding the urban-rural income gap in China, and has a significance meaning for further increasing the educational investment in the western rural areas, and improving the redistribution efficiency of social security expenditure.
The chemical code for attracting Culex mosquitoes
Authors: Spanoudis Christos G. , Wondwosen Betelehem , Isberg Elin , Andreadis Stefanos S. , Kline Daniel L. , Birgersson Göran , Ignell Rickard
Published: August 2022

Mosquitoes use chemical codes to locate and discriminate among vertebrate hosts to obtain a blood meal. Recent advances have allowed for the identification of the chemical codes used by mosquitoes to locate and discriminate humans from other vertebrate hosts. Humans are incidental “dead-end” hosts for the West Nile virus, which is maintained in an enzootic cycle, primarily through its transmission between infected birds by Culex mosquitoes. Host-seeking Culex mosquitoes are attracted to the odor of chicken, which are used in sentinel traps to monitor West Nile virus transmission. Using combined gas chromatography and electroantennography and mass spectrometry we identify a blend of volatile organic compounds present in chicken emanates, including mostly salient bioactive compounds previously identified in human emanates. When released at their identified ratios, this blend elicits behavioral responses of Culex pipiens molestus and Culex quinquefasciatus similar to that to the natural chicken odor. Tested under field conditions, this blend attract Culex spp. and other species of mosquitoes using birds among their hosts. This study provides evidence for conserved chemical codes for resource location by mosquitoes, and highlights the intricate role of CO2 for host-seeking mosquitoes. The identification of conserved chemical codes, which drive innate preference behaviors that are fundamental for survival and reproduction, provides important substrates for future control interventions targeting disease vector mosquitoes.
In Silico Characterization of Uncharacterized Proteins From Multiple Strains of Clostridium Difficile
Authors: Abbasi Bilal Ahmed , Dharan Aishwarya , Mishra Astha , Saraf Devansh , Ahamad Irsad , Suravajhala Prashanth , Valadi Jayaraman
Published: August 2022

Clostridium difficile (C. difficile) is a multi-strain, spore-forming, Gram-positive, opportunistic enteropathogen bacteria, majorly associated with nosocomial infections, resulting in severe diarrhoea and colon inflammation. Several antibiotics including penicillin, tetracycline, and clindamycin have been employed to control C. difficile infection, but studies have suggested that injudicious use of antibiotics has led to the development of resistance in C. difficile strains. However, many proteins from its genome are still considered uncharacterized proteins that might serve crucial functions and assist in the biological understanding of the organism. In this study, we aimed to annotate and characterise the 6 C. difficile strains using in silico approaches. We first analysed the complete genome of 6 C. difficile strains using standardised approaches and analysed hypothetical proteins (HPs) employing various bioinformatics approaches coalescing, including identifying contigs, coding sequences, phage sequences, CRISPR-Cas9 systems, antimicrobial resistance determination, membrane helices, instability index, secretory nature, conserved domain, and vaccine target properties like comparative homology analysis, allergenicity, antigenicity determination along with structure prediction and binding-site analysis. This study provides crucial supporting information about the functional characterization of the HPs involved in the pathophysiology of the disease. Moreover, this information also aims to assist in mechanisms associated with bacterial pathogenesis and further design candidate inhibitors and bona fide pharmaceutical targets.
Environmental scan of family chart linking for genetic cascade screening in a U.S. integrated health system
Authors: Haas Cameron B. , Ralston James , Fullerton Stephanie M. , Scrol Aaron , Henrikson Nora B.
Published: August 2022

Background: An alternative to population-based genetic testing, automated cascade genetic testing facilitated by sharing of family health history, has been conceptualized as a more efficient and cost-effective approach to identify hereditary genetic conditions. However, existing software and applications programming interfaces (API) for the practical implementation of this approach in health care settings have not been described.

Methods: We reviewed API available for facilitating cascade genetic testing in electronic health records (EHRs). We emphasize any information regarding informed consent as provided for each tool. Using semi-structured key informant interviews, we investigated uptake of and barriers to integrating automated family cascade genetic testing into the EHR.

Results: We summarized the functionalities of six tools related to utilizing family health history to facilitate cascade genetic testing. No tools were explicitly capable of facilitating family cascade genetic testing, but few enterprise EHRs supported family health history linkage. We conducted five key informant interviews with four main considerations that emerged including: 1) incentives for interoperability, 2) HIPAA and regulations, 3) mobile-app and alternatives to EHR deployment, 4) fundamental changes to conceptualizing EHRs.

Discussion: Despite the capabilities of existing technology, limited bioinformatic support has been developed to automate processes needed for family cascade genetic testing and the main barriers for implementation are nontechnical, including an understanding of regulations, consent, and workflow. As the trade-off between cost and efficiency for population-based and family cascade genetic testing shifts, the additional tools necessary for their implementation should be considered.
Cell-based analysis of CLIC5A and SLC12A2 variants associated with hearing impairment in two African families
Authors: Adadey Samuel Mawuli , Wonkam-Tingang Edmond , Alves de Souza Rios Leonardo , Aboagye Elvis Twumasi , Esoh Kevin , Manyisa Noluthando , De Kock Carmen , Awandare Gordon A. , Mowla Shaheen , Wonkam Ambroise
Published: August 2022

We have previously reported CLIC5A and SLC12A2 variants in two families from Cameroon and Ghana, segregating non-syndromic hearing impairment (NSHI). In this study, biological assays were performed to further functionally investigate the pathogenicity of CLIC5 [c.224T>C; p.(L75P)] and SCL12A2 [c.2935G>A: p.(E979K)] variants. Ectopic expression of the proteins in a cell model shows that compared to wild-type, both the CLIC5A and SLC12A2 variants were overexpressed. The mutant CLIC5A protein appears as aggregated perinuclear bodies while the wild-type protein was evenly distributed in the cytoplasm. Furthermore, cells transfected with the wild-type CLIC5A formed thin membrane filopodia-like protrusions which were absent in the CLIC5A mutant expressing and control cells. On the other hand, the wild-type SLC12A2 expressing cells had an axon-like morphology which was not observed in the mutant expressing and control cells. A network analysis revealed that CLIC5A can interact with at least eight proteins at the base of the stereocilia. This study has generated novel biological data associated with the pathogenicity of targeted variants in CLIC5A and SLC12A2, found in two African families, and therefore expands our understanding of their pathobiology in hearing impairment.
Elevated exposures to persistent endocrine disrupting compounds impact the sperm methylome in regions associated with autism spectrum disorder
Authors: Maggio Angela G. , Shu Henry T. , Laufer Benjamin I. , Bi Chongfeng , Lai Yinglei , LaSalle Janine M. , Hu Valerie W.
Published: August 2022

Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of men from the Faroe Islands (Denmark) who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders.
Marker-assisted transfer of leaf and stripe rust resistance from Triticum turgidum var. durum cv. Trinakria to wheat variety HD2932
Authors: Mallick Niharika , Jha Shailendra K. , Agarwal Priyanka , Kumar Sachin , Mall Anchal , M Niranjana , Choudhary Manish K. , Chandra Ajay Kumar , Bansal Shreshtha , Saharan M. S. , Sharma J. B. , Vinod
Published: August 2022

A marker-assisted backcrossing program initiated to transfer leaf rust resistance gene LrTrk from Triticum turgidum cv. Trinakria to hexaploid wheat variety HD2932 cotransferred a stripe rust resistance gene, YrTrk, along with LrTrk. The cross of hexaploid recurrent parent HD2932 with tetraploid donor parent Trinakria produced pentaploid F1 plants. F1s were backcrossed with recurrent parent HD2932 to produce BC1F1 generation. Foreground and background selection was conducted in each backcross generation to identify plants for backcrossing or selfing. While foreground selection for LrTrk was carried out with linked and validated molecular marker Xgwm234, for background selection, 86 polymorphic SSR markers from the A and B genomes were used. Single selected plants from BC1F1 and BC2F1 generations backcrossed and selfed to produce BC2F1and BC2F2 generations, respectively. Background selection resulted in 83.72%, 91.86%, and 98.25% of RPG recovery in BC1F1, BC2F1, and BC2F2 generations, respectively. A total of 27 plants with LrTrk in homozygous state were identified in BC2F2 generation and selfed to produce 27 BC2F3 NILs. All the NILs were tested for leaf and stripe rust resistance at the seedling stage using seven Puccinia triticina and one Puccinia striiformis f.sp. tritici rust pathotypes. All the 27 NILs were found to be resistant to both leaf and stripe rust pathotypes. So, these NILs are designated to carry leaf and stripe rust resistance genes LrTrk/YrTrk.
Identification of m6A- and ferroptosis-related lncRNA signature for predicting immune efficacy in hepatocellular carcinoma
Authors: Xie Hongjun , Shi Muqi , Liu Yifei , Cheng Changhong , Song Lining , Ding Zihan , Jin Huanzhi , Cui Xiaohong , Wang Yan , Yao Dengfu , Wang Peng , Yao Min , Zhang Haijian
Published: August 2022

Background

N6-methyladenosine (m6A) methylation and ferroptosis assist long noncoding RNAs (lncRNAs) in promoting immune escape in hepatocellular carcinoma (HCC). However, the predictive value of m6A- and ferroptosis-related lncRNAs (mfrlncRNAs) in terms of immune efficacy remains unknown.

Method

A total of 365 HCC patients with complete data from The Cancer Genome Atlas (TCGA) database were used as the training cohort, and half of them were randomly selected as the validation cohort. A total of 161 HCC patients from the International Cancer Genome Consortium (ICGC) database were used as external validation (ICGC cohort).

Results

We first identified a group of specific lncRNAs associated with both m6A regulators and ferroptosis-related genes and then constructed prognosis-related mfrlncRNA pairs. Based on this, the mfrlncRNA signature was constructed using the least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Notably, the risk score of patients was proven to be an independent prognostic factor and was better than the TNM stage and tumor grade. Moreover, patients with high-risk scores had lower survival rates, higher infiltration of immunosuppressive cells (macrophages and Tregs), lower infiltration of cytotoxic immune cells (natural killer cells), poorer immune efficacy (both immunophenoscore and score of tumor immune dysfunction and exclusion), higher IC50, and enrichment of the induced Treg pathway, which confirmed that the mfrlncRNA signature contributed to survival prediction and risk stratification of patients with HCC.

Conclusions

The mfrlncRNA signature, which has great prognostic value, provides new clues for identifying “cold” and “hot” tumors and might have crucial implications for individualized therapy to improve the survival rate of patients with HCC.
Crosstalk of three novel types of programmed cell death defines distinct microenvironment characterization and pharmacogenomic landscape in breast cancer
Authors: Xu Lijun
Published: August 2022

Background

Prior studies have highlighted that novel programmed cell death (PCD) modalities, including ferroptosis, pyroptosis, and necroptosis, are correlated with tumor progression and antitumor immunity. Nonetheless, comprehensive analysis of tumor microenvironment (TME) profiles mediated by the crosstalk of distinct PCD forms has not been conducted in breast cancer (BC).

Methods

Here, we curated 34 identified PCD-associated genes (PCDAGs) and applied the consensus clustering algorithm to establish PCD-mediated tumor patterns in BC. Subsequently, based on prognostic differentially expressed genes extracted from distinct PCD-mediated patterns, we applied the LASSO algorithm to construct CD_Score. Furthermore, the correlation analysis between CD_Score and TME features, molecular subtypes, clinicopathological characteristics, drug response, and immunotherapeutic efficacy was performed.

Results

Three distinct PCD-clusters were determined among 2,038 BC samples, which did not only display different clinical outcomes but highly correlated to the established immunological tumor phenotypes: “desert,” “excluded,” and “inflamed” immune profiles. Based on the CD_Score derived from the PCD-related gene signature, BC patients could be stratified into CD_Score-low and -high group, of which the former displayed satisfactory survival outcome and enhanced immune infiltration. Further exploration identified that the CD_Score-high group significantly correlated with elevated neoantigen load and higher mutation frequency in SMGs (e.g., TP53 and MAP3K1) and reduced expression of immune checkpoint proteins.

Conclusions

This research is the first to emphasize the close relationship between distinct cell death modalities and the diversity and complexity of immune infiltration in TME. We established the CD_Score, which could help enhance our cognition of TME features and facilitate the clinical application of immunotherapy.
Contribution of pathogenic T helper 1 and 17 cells to bursitis and tenosynovitis in polymyalgia rheumatica
Authors: Reitsema Rosanne D. , Jiemy William F. , Wekema Lieske , Boots Annemieke M. H. , Heeringa Peter , Huitema Minke G. , Abdulahad Wayel H. , van Sleen Yannick , Sandovici Maria , Roozendaal Caroline , Diepstra Arjan , Kwee Thomas , Dasgupta Bhaskar , Brouwer Elisabeth , van der Geest Kornelis S. M.
Published: August 2022

Background

Although polymyalgia rheumatica (PMR) is a very common rheumatic inflammatory disease, current insight into the pathobiology of PMR is limited and largely based on studies in blood. We investigated T helper 1 (TH1) and T helper 17 (TH17) cell responses in blood, synovial fluid and bursa tissue of patients with PMR.

Materials and methods

Blood samples were collected from 18 patients with new-onset PMR and 32 healthy controls. Synovial fluid was aspirated from the inflamed shoulder bursae or biceps tendon sheath of 13 patients. Ultrasound-guided biopsies of the subacromial-subdeltoid (SASD) bursa were obtained from 11 patients. T cells were examined by flow cytometry, immunohistochemistry and immunofluorescence staining.

Results

Besides an increase of TH17 (CD4+IL-17+IFN-γ-) cells and T cytotoxic 17 (TC17; CD8+IL-17+IFN-γ-) cells, no other major changes were noted in the circulating T cell compartment of patients with PMR. Absolute numbers of CD4+ and CD8+ T cells were similar in blood and synovial fluid of patients with PMR. Synovial fluid T cells showed an effector-memory (CD45RO+CCR7-) phenotype. Percentages of TH1 (CD4+IFN-γ+IL-17-) cells and TH1/TH17 (CD4+IFN-γ+IL-17+) cells, but not TH17 or TC17 cells, were increased in the synovial fluid. Bursa tissue biopsies contained a small number of T cells, which were mostly CD8 negative. The majority of bursa tissue T cells produced IFN-γ but not IL-17. For comparison, B cells were scarcely detected in the bursa tissue.

Conclusion

Although the circulating TH17 cell pool is expanded in patients with PMR, our findings indicate that TH1 cells are involved in the inflammation of bursae and tendon sheaths in this condition. Our study points towards the TH1 cell pathway as a potential target for therapy in PMR.
Circulating microRNA signatures associated with disease severity and outcome in COVID-19 patients
Authors: Giannella Alessandra , Riccetti Silvia , Sinigaglia Alessandro , Piubelli Chiara , Razzaboni Elisa , Di Battista Piero , Agostini Matteo , Dal Molin Emanuela , Manganelli Riccardo , Gobbi Federico , Ceolotto Giulio , Barzon Luisa
Published: August 2022

Background

SARS-CoV-2 induces a spectrum of clinical conditions ranging from asymptomatic infection to life threatening severe disease. Host microRNAs have been involved in the cytokine storm driven by SARS-CoV-2 infection and proposed as candidate biomarkers for COVID-19.

Methods

To discover signatures of circulating miRNAs associated with COVID-19, disease severity and mortality, small RNA-sequencing was performed on serum samples collected from 89 COVID-19 patients (34 severe, 29 moderate, 26 mild) at hospital admission and from 45 healthy controls (HC). To search for possible sources of miRNAs, investigation of differentially expressed (DE) miRNAs in relevant human cell types in vitro.

Results

COVID-19 patients showed upregulation of miRNAs associated with lung disease, vascular damage and inflammation and downregulation of miRNAs that inhibit pro-inflammatory cytokines and chemokines, angiogenesis, and stress response. Compared with mild/moderate disease, patients with severe COVID-19 had a miRNA signature indicating a profound impairment of innate and adaptive immune responses, inflammation, lung fibrosis and heart failure. A subset of the DE miRNAs predicted mortality. In particular, a combination of high serum miR-22-3p and miR-21-5p, which target antiviral response genes, and low miR-224-5p and miR-155-5p, targeting pro-inflammatory factors, discriminated severe from mild/moderate COVID-19 (AUROC 0.88, 95% CI 0.80-0.95, p<0.0001), while high leukocyte count and low levels of miR-1-3p, miR-23b-3p, miR-141-3p, miR-155-5p and miR-4433b-5p predicted mortality with high sensitivity and specificity (AUROC 0.95, 95% CI 0.89-1.00, p<0.0001). In vitro experiments showed that some of the DE miRNAs were modulated directly by SARS-CoV-2 infection in permissive lung epithelial cells.

Conclusions

We discovered circulating miRNAs associated with COVID-19 severity and mortality. The identified DE miRNAs provided clues on COVID-19 pathogenesis, highlighting signatures of impaired interferon and antiviral responses, inflammation, organ damage and cardiovascular failure as associated with severe disease and death.
Finding and eliminating the reservoirs: Engage and treat, and test and treat strategies for lymphatic filariasis programs to overcome endgame challenges
Authors: de Souza Dziedzom K. , Otchere Joseph , Sumboh Jeffrey G. , Asiedu Odame , Opare Joseph , Asemanyi-Mensah Kofi , Boakye Daniel A. , Gass Katherine M. , Long Elizabeth F. , Ahorlu Collins S.
Published: August 2022

Many lymphatic filariasis (LF) endemic countries, including Ghana, have successfully implemented mass drug administration (MDA) and made significant progress towards the elimination of the disease as a public health problem. Unfortunately, the existence of individuals who seldom or never take part in MDA pose a threat to this success, as they may serve as reservoirs of infection, re-infecting their communities. In this study we implemented strategies to identify and treat these individuals, while also assessing their level of infection, to inform programme actions. The study was undertaken in the Ahanta West hotspot district in Ghana, which has received more than 17 rounds of MDA. Through the community registers used in recording participation in MDAs, we identified and offered treatment to individuals who were ineligible or inadvertently missed the last MDA in April 2021 (Engage and Treat – E&T), or testing using the filariasis test strip followed by treatment to community members who for various reasons chose not to participate in the last MDA (Test and Treat – T&T). During the study, 23,879 individuals ranging from 5 to 98 years were reached, of whom 78% were not captured in the MDA register. Among the E&T group, 75.06% willingly received and swallowed the treatment drugs. The remaining 24.94% were offered testing followed by a re-engagement to receive the drug in the T&T group. Overall, 22,830 (95.61%) of participants were treated by either strategy. Of the participants in the T&T group, 516 (8.66%; 95% CI= 7.96 – 9.41) were positive by the FTS. The highest antigen prevalence was detected among children 5 to 10 years, with 16.59% (95% CI= 12.02 – 22.06) and 22.54% (95% CI= 17.11 – 28.74) among females and males, respectively. Mapping of the data revealed that most infections are in a few select communities. Of the 516 FTS positives, 27.33% reportedly missed MDA once, 18.41% missed MDA twice and 54.26% missed all of the last three MDAs. The main reasons for missing MDA included absence (25.49%), travel (21.24%), being unaware of MDA (20.27%), refusals to take the drug (10.65%), illnesses (7.07%) and fear of adverse events (6.13%). This study demonstrates that greater sensitization and engagement strategies, with a test and treat strategy reserved for the most hesitant individuals, could significantly increase the number of individuals who receive treatment and therefore help districts reach their elimination targets by reducing the remaining reservoir or infection. NTD programmes require new tools to help them identify, engage and treat these individuals, as part of their overall monitoring and evaluation strategy.
Low-Cost, Deep-Sea Imaging and Analysis Tools for Deep-Sea Exploration: A Collaborative Design Study
Authors: Bell Katherine L. C. , Chow Jennifer Szlosek , Hope Alexis , Quinzin Maud C. , Cantner Kat A. , Amon Diva J. , Cramp Jessica E. , Rotjan Randi D. , Kamalu Lehua , de Vos Asha , Talma Sheena , Buglass Salome , Wade Veta , Filander Zoleka , Noyes Kaitlin , Lynch Miriam , Knight Ashley , Lourenço Nuno , Girguis Peter R. , de Sousa João Borges , Blake Chris , Kennedy Brian R. C. , Noyes Timothy J. , McClain Craig R.
Published: August 2022

A minuscule fraction of the deep sea has been scientifically explored and characterized due to several constraints, including expense, inefficiency, exclusion, and the resulting inequitable access to tools and resources around the world. To meet the demand for understanding the largest biosphere on our planet, we must accelerate the pace and broaden the scope of exploration by adding low-cost, scalable tools to the traditional suite of research assets. Exploration strategies should increasingly employ collaborative, inclusive, and innovative research methods to promote inclusion, accessibility, and equity to ocean discovery globally. Here, we present an important step toward this new paradigm: a collaborative design study on technical capacity needs for equitable deep-sea exploration. The study focuses on opportunities and challenges related to low-cost, scalable tools for deep-sea data collection and artificial intelligence-driven data analysis. It was conducted in partnership with twenty marine professionals worldwide, covering a broad representation of geography, demographics, and domain knowledge within the ocean space. The results of the study include a set of technical requirements for low-cost deep-sea imaging and sensing systems and automated image and data analysis systems. As a result of the study, a camera system called Maka Niu was prototyped and is being field-tested by thirteen interviewees and an online AI-driven video analysis platform is in development. We also identified six categories of open design and implementation questions highlighting participant concerns and potential trade-offs that have not yet been addressed within the scope of the current projects but are identified as important considerations for future work. Finally, we offer recommendations for collaborative design projects related to the deep sea and outline our future work in this space.